International Journal of

Molecular Sciences

Review
Neuroprotective Effects of Coffee Bioactive Compounds:
A Review
Katarzyna Socała 1, * , Aleksandra Szopa 2 , Anna Serefko 2 , Ewa Poleszak 2 and Piotr Wlaź 1

1 Department of Animal Physiology and Pharmacology, Institute of Biological Sciences,

Maria Curie-Skłodowska University, Akademicka 19, 20-033 Lublin, Poland;
[email protected]
2 Laboratory of Preclinical Testing, Chair and Department of Applied and Social Pharmacy,
Medical University of Lublin, Chodźki 1, 20-093 Lublin, Poland; [email protected] (A.S.);
[email protected] (A.S.); [email protected] (E.P.)
* Correspondence: [email protected]

Abstract: Coffee is one of the most widely consumed beverages worldwide. It is usually identified as
a stimulant because of a high content of caffeine. However, caffeine is not the only coffee bioactive
component. The coffee beverage is in fact a mixture of a number of bioactive compounds such as
polyphenols, especially chlorogenic acids (in green beans) and caffeic acid (in roasted coffee beans),
alkaloids (caffeine and trigonelline), and the diterpenes (cafestol and kahweol). Extensive research
shows that coffee consumption appears to have beneficial effects on human health. Regular coffee
intake may protect from many chronic disorders, including cardiovascular disease, type 2 diabetes,
obesity, and some types of cancer. Importantly, coffee consumption seems to be also correlated with
a decreased risk of developing some neurodegenerative conditions such as Alzheimer’s disease,
Parkinson’s disease, and dementia. Regular coffee intake may also reduce the risk of stroke. The
mechanism underlying these effects is, however, still poorly understood. This review summarizes
the current knowledge on the neuroprotective potential of the main bioactive coffee components,
i.e., caffeine, chlorogenic acid, caffeic acid, trigonelline, kahweol, and cafestol. Data from both
in vitro and in vivo preclinical experiments, including their potential therapeutic applications, are



reviewed and discussed. Epidemiological studies and clinical reports on this matter are also described.


Moreover, potential molecular mechanism(s) by which coffee bioactive components may provide
Citation: Socała, K.; Szopa, A.;
neuroprotection are reviewed.
Serefko, A.; Poleszak, E.; Wlaź, P.
Neuroprotective Effects of Coffee
Keywords: coffee consumption; caffeine; chlorogenic acid; caffeic acid; trigonelline; neuroprotection;
Bioactive Compounds: A Review. Int.
Alzheimer’s disease; Parkinson’s disease; stroke
J. Mol. Sci. 2021, 22, 107. https://dx.doi.
org/10.3390/ijms22010107

Received: 10 November 2020

Accepted: 22 December 2020 1. Introduction
Published: 24 December 2020 The genus Coffea L. (family: Rubiaceae, subfamily: Ixoroideae, tribe: Coffeeae) includes
at least 125 species which naturally occur in Tropical and East Africa, Tropical Asia, and
Publisher’s Note: MDPI stays neu- Australia and also in the Comoros, Madagascar, and the Mascarenes [1]. Only three of
tral with regard to jurisdictional claims these species are used in the commercial coffee production, i.e., Coffea arabica L. (Arabica
in published maps and institutional coffee), Coffea canephora Pierre ex A. Froehner (Robusta coffee), and Coffea liberica Hiern
affiliations. (Excelsa coffee) [2–6].
Coffee beans are obtained from the tart red fruit of the evergreen coffee tree. They
are used primarily in the food industry but also in cosmetology and medicine. Nowadays,
Copyright: © 2020 by the authors. Li-
coffee is considered to be one of the most highly popular and widely consumed pharma-
censee MDPI, Basel, Switzerland. This cologically active universal beverages [7,8], and its drinking has become a regular part
article is an open access article distributed of daily life [9]. It is estimated that in 2019/2020 world coffee consumption amounted to
under the terms and conditions of the about 10.1 million kg [10]. Most of all coffee is used due to its psychostimulating effect,
Creative Commons Attribution (CC BY) taste and aroma as well as health-promoting properties [11].
license (https://creativecommons.org/ The health effects of coffee consumption have been investigated in numerous re-
licenses/by/4.0/). search [12–19]. The outcomes from many of these studies showed the positive impact of

Int. J. Mol. Sci. 2021, 22, 107. https://dx.doi.org/10.3390/ijms22010107 https://www.mdpi.com/journal/ijms

 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 63
Int. J. Mol. Sci. 2021, 22, 107 2 of 64

The health effects of coffee consumption have been investigated in numerous re-
search [12–19]. The outcomes from many of these studies showed the positive impact of
coffee intake
coffee intakeon onvarious
variousaspects
aspectsofof health,
health, e.g.,
e.g., coffee
coffee possesses
possesses anti-oxidant
anti-oxidant (especially
(especially the
the medium-roasted
medium-roasted coffee)
coffee) [20] and[20]anti-inflammatory
and anti-inflammatory properties
properties [15] and [15] andthe
limits limits the
overall
risk of stroke
overall risk ofand coronary
stroke heart disease
and coronary [21–23],
heart disease cancercancer
[21–23], [22,24,25], mortality
[22,24,25], associated
mortality asso-
with
ciatedcardiovascular
with cardiovasculardiseasedisease
[22,26],[22,26],
Parkinson’s [22,27,28]
Parkinson’s and Alzheimer’s
[22,27,28] and Alzheimer’s disease and
disease
other neurodegenerative
and other neurodegenerative disorders
disorders[29,30], depression
[29,30], depression andandsuicide [31,32],
suicide liver
[31,32], damage
liver dam-
particularly
age particularlyin patients at high
in patients risk for
at high riskliver disease,
for liver such as
disease, suchcirrhosis, hepatocellular
as cirrhosis, hepatocellularcarci-
noma and hepatic injury [22,23,33], and developing type 2 diabetes
carcinoma and hepatic injury [22,23,33], and developing type 2 diabetes [7,19,22,23]. How- [7,19,22,23]. However,
excessive coffeecoffee
ever, excessive drinkers also experience
drinkers negative
also experience effectseffects
negative of its use,
of itse.g.,
use,caffeine raises
e.g., caffeine
concentration
raises concentrationof totalofcholesterol and lowers
total cholesterol high density
and lowers lipoprotein
high density in serum
lipoprotein in serum[34] and
[34]
causes
and causescardiovascular
cardiovascularproblems, including
problems, increased
including bloodblood
increased pressure, tachycardia,
pressure, and
tachycardia,
arrhythmia
and arrhythmia [21,23,24].
[21,23,24].
Such
Such multidirectionaleffects
multidirectional effectsofofcoffee
coffeeonon thethe
human
human health andand
health bodybodyare due to the
are due tofact
the
that it is a complex mixture of bioactive ingredients and both nutrients
fact that it is a complex mixture of bioactive ingredients and both nutrients and non-nu- and non-nutrients
which
trients act together
which [35]. The
act together [35].composition
The composition of these elements
of these in coffee
elements beansbeans
in coffee differs and
differs
depends on (1) species of coffee; (2) conditions of roasting of the coffee
and depends on (1) species of coffee; (2) conditions of roasting of the coffee beans, includ- beans, including
temperature,
ing temperature, time,time,
and speed of thisof
and speed process; (3) coffee
this process; (3)brewing conditions,
coffee brewing i.e., the brewing
conditions, i.e., the
method,
brewing method, coffee/water ratio, temperature of water, size of coffee grind, andofdura-
coffee/water ratio, temperature of water, size of coffee grind, and duration this
process [35–37]. The most important bioactive compounds in coffee
tion of this process [35–37]. The most important bioactive compounds in coffee that might that might serve as
physiologically effective agents include caffeine, chlorogenic acids,
serve as physiologically effective agents include caffeine, chlorogenic acids, cafestol and cafestol and kahweol,
trigonelline (Figure 1),(Figure
kahweol, trigonelline and melanoidins (Figure 2)(Figure
1), and melanoidins [17,38,39]. The detailed
2) [17,38,39]. chemicalchem-
The detailed com-
position and content of active, nutritional, and mineral substances in green and roasted
ical composition and content of active, nutritional, and mineral substances in green and
coffee beans and coffee beverage or brew are given in Tables 1 and 2, respectively.
roasted coffee beans and coffee beverage or brew are given in Tables 1 and 2, respectively.

Figure 1.
Figure 1. Structures
Structures of
of the
the most
most important
important bioactive
bioactive compounds
compounds in in coffee.
coffee. (A)
(A) structures
structures of
of key
key compounds
compounds not
not belonging
belonging
to chlorogenic acids, (B) general structure of chlorogenic acids and the most important groups found in chlorogenic
to chlorogenic acids, (B) general structure of chlorogenic acids and the most important groups found in chlorogenic acids acids
from coffee beans, (C) structures of caffeoylquinic acids found in coffee beans.
from coffee beans, (C) structures of caffeoylquinic acids found in coffee beans.
 Int. J. Mol. Sci. 2021, 22, 107 3 of 64

Mol. Sci. 2020, 21, x FOR PEER REVIEW 3 of 63

Figure 2. Examples of 2.
Figure theExamples
structureof
ofthe
coffee melanoidins
structure [38,39].
of coffee melanoidins [38,39].

2. Bioavailability and Pharmacokinetics of Coffee Bioactive Compounds

2. Bioavailability and Pharmacokinetics of Coffee Bioactive Compounds
2.1. Caffeine
2.1. Caffeine
Caffeine is rapidly absorbed–primarily from the small intestine, but also partially
Caffeine is rapidly absorbed–primarily from the small intestine, but also partially
from the stomach. According to Arnoud [40], the peak plasma concentration of caffeine
from the stomach. According to Arnoud [40], the peak plasma concentration of caffeine
(4–5 mg/kg) is(4–5 mg/kg)within
observed 30–120within
is observed min after administration
30–120 with half-lives
min after administration usually
with half-lives usually
ranged between 2.5 and 5 h. It seems that caffeine absorption is not influenced by age,
gender, genetics, undergoing disease, concomitant drugs, or stimulants such as alcohol
Int. J. Mol. Sci. 2021, 22, 107 4 of 64

ranged between 2.5 and 5 h. It seems that caffeine absorption is not influenced by age,
gender, genetics, undergoing disease, concomitant drugs, or stimulants such as alcohol
and nicotine. Caffeine is distributed to all body fluids (including plasma, saliva, bile,
cerebrospinal fluid, breast milk, semen, and umbilical cord blood) and to all tissue organs.
Due to its lipophilic properties, it crosses cellular membranes easily, including the placental
barrier and the blood–brain barrier. Caffeine’s plasma protein binding is limited since its
blood/plasma ratio is almost equal to 1. Physiologically no long-term accumulation of this
compound or its metabolites is observed [41–44].

Table 1. The chemical composition of green and roasted coffee beans [17,35,36].

% Content in Dry Weight of Coffee Beans

Compounds
Green Coffee Roasted Coffee
Carbohydrates
– polysaccharides—cellulose, arabinogalactan, galactomannan
– oligosaccharides—stachyose, raffinose 60 43
– disaccharides—sucrose
– monosaccharides—glucose, galactose, arabinose, fructose, mannose,
mannitol, xylose, ribose
Lipids
– triglyceride
– sterols—stigmasterol, sitosterol
– fatty acids—linoleic, linolenic, oleic, palmitic, stearic, arachidic,
lignoceric, behenic acid
8–18 10–15
– fatty acids with pentacyclic
– diterpenes—cafestol, kahweol
– waxes
– tocopherols
– phosphatides
Proteins
9–16 7.5–10
– amino acids—asparagines, glutamic acid, alanine, aspartic acid, lysine
Other nitrogenous compounds 1–6 1–2
– caffeine 0.9–3.33 1
– trigonelline 0.88–3.42 0.7–1
– nicotinic acid 2 × 10−6 –3 × 10−6 0.01–0.04
Melanoidins – 25
Minerals 4 3.7–5
Organic and inorganic acids and esters 6–15 6
– chlorogenic acids 4–14.4 1–4
– aliphatic acids and quinic acid 0.7–2.5 1.4–2.5
– other organic and inorganic acids 2 <0.3

In humans, pharmacokinetics of caffeine also is not affected by the hepatic first-pass ef-
fect, and its elimination is regarded as a first-order process described by a one-compartment
open model system within the intake range of 2–10 mg/kg [45–47]. Caffeine pharmacoki-
netics may be affected by food and gastric emptying [48], fluid intake [49], and genetic
and environmental factors [50], but not by chronovariation [51] or gender [52]. The major
caffeine metabolites are paraxanthine, theobromine, and theophylline. All of them are
biologically active. Several cytochrome P450 (CYP) isoforms are implicated in caffeine
demethylation and C8 hydroxylation (i.e., CYP1A2, CYP1A1, CYP2E1, CYP2D6-Met, and
CYP3A), but liver CYP1A2 is mainly responsible for caffeine clearance. Therefore, distur-
bances of CYP1A2 functioning due to for example genetic polymorphisms or exposure to its
inducers significantly influence caffeine metabolism [53,54]. CYP1A2-related modifications
Int. J. Mol. Sci. 2021, 22, 107 5 of 64

in caffeine metabolism were observed during pregnancy or in smoking women taking

oral contraceptives [55]. Pharmacokinetics of this methylxanthine may also be affected by
genetic determinants [56], specific diet (grapefruit juice, quercetin, brassica vegetables, api-
aceous vegetables, large quantities of vitamin C, curcumin, turmeric) [57–61] and lifestyle
(i.e., smoking) [62], environmental factors, diseases (particularly liver conditions) [63,64]
or concurrent drugs (i.e., clozapine, rofecoxib, quinolones, calcium antagonists, and an-
tiarrhythmics) [65–68]. However, at least in humans, aging does not impact caffeine
metabolism [69,70]. Renal excretion of caffeine dominates in both animals and humans,
and ca. 70% of the received caffeine dose is recovered in urine. Approximately 0.5–2% of
caffeine is excreted in an unchanged form [71].

2.2. Chlorogenic Acids

Chlorogenic acids are a family of esters formed between trans-cinnamic acids and
quinic acid. They can be divided into three main groups: caffeoylquinic acids, dicaf-
feoylquinic acids, and feruloylquinic acids. The most abundant chlorogenic acid in coffee
beans and other plant sources is 5-O-caffeoylquinic acid, also called chlorogenic acid or
wrongly 3-O-caffeoylquinic acid. This is due to the fact that the term “chlorogenic acid”
originally referred to 3-O-caffeoylquinic acid. In 1976, the International Union of Pure and
Applied Chemistry reversed the order of numbering of atoms on the quinic acid ring and
the name for 3-O-caffeoylquinic acid is really 5-O-caffeoylquinic acid [72,73].
In humans, chlorogenic acids are either absorbed untransformed in the stomach
and/or duodenum, or absorbed in the stomach and/or small intestine and further metabo-
lized, or subjected to metabolism mediated by gut microbiota with subsequent absorption
of catabolites that are not further metabolized or subjected to metabolism mediated by gut
microbiota with subsequent absorption of catabolites that are further metabolized (i.e., by
reduction, demethylation, dehydroxylation, isomerization, and others) [74]. About 1/3
of consumed chlorogenic acids are absorbed in the small intestine [75,76] and about 2/3
of consumed chlorogenic acids is absorbed in the large intestine. According to the litera-
ture data [77–79], absorption of the chlorogenic acids in the stomach and in the intestine
occurs mainly by passive diffusion with contribution of the active/facilitated transport for
several compounds. Though individual differences are noted [75,80], Cmax of chlorogenic
acids that are metabolized in the stomach and/or small intestine is detected relatively
quickly, i.e., within 1–2 h. Fatty or sweet food as well as pectins due to diminished rate of
gastric emptying can delay detection of their tmax values which may result in prolonged
plasma clearance. Cmax of chlorogenic acids that require gut microbiota-related metabolism
occurs much later, i.e., within ≥5 h. Absorption of the chlorogenic acids metabolized
by gut microbiota is only observed in patients with intact colon. Metabolites obtained
after absorption in the stomach and/or small intestine are cleared from plasma within
5–6 h, but colon-associated metabolites may be detectable in plasma after 24 h. Some
metabolites are biphasic and show both an early and a late tmax values. They also can be
still present in plasma after 24 h [81]. Apart from the primary metabolites, chlorogenic
acids are also detected in plasma in conjugated forms. Usually chlorogenic acids from
green and roasted coffee are absorbed in ca. 33% [82–84], but in ileostomized patients the
absorption range is between 8% and 34% [80,84]. Chlorogenic acids mainly undergo phase
II metabolism (in the intestine, liver and/or kidney), being sulphated by sulfotransferases
(i.e., SULT1A1 and SULT1A3 isoforms) and glucuronidated by uridine 50 -diphosphate
(UDP)-glucuronyltransferases (i.e., UGT1A1 and UGT1A9 isoforms) [79,85]. Furthermore,
both primary and secondary metabolites can be conjugated with glycine [76,80]. Several
authors found that chlorogenic acids can be excreted by digestive fluids and that they
can be recycling by enterohepatic recirculation. Urinary excretion of chlorogenic acids
occurs primarily in sulphated, glucuronidated and glycine conjugated form. Apart from
that, about 40 other compounds identified as the primary or secondary metabolites of
chlorogenic acids are found in urine [76,80,86].
Int. J. Mol. Sci. 2021, 22, 107 6 of 64

Table 2. The chemical composition of coffee beverages or drew [35].

Content in Coffee Beverages or Brew

Compound Obtained from Blends of Arabica and
Robusta Coffee [mg per 100 mL]
Water 94,000–98,500
Aliphatic acids and quinic acid 692–2140
Polysaccharides
200–700
(galactomannans and type II arabinogalactans)
Lipids 180–400
Proteins 120–400
Simple saccharides
0–200
(arabinose, mannose, galactose, sucrose)
Bioactive ingredients:
Melanoidins 500–1500
Chlorogenic acids 32–500
Caffeine 50–380
Trigonelline 12–50
Diterpenes (cafestol and kahweol) 0.2–10
N-methylpyridinium 2.9–8.7
Serotonin 0–1.4
Polyamines (spermine and spermidine) 0.4
Phenolic substances 0.1–0.2
β-carbolins (norharman and harman) 0.004–0.08
Melatonin 0.006–0.008
Minerals:
Total ashes 150–500
Potassium (K) 115–320
Sodium (Na) 1–14
Phosphorous (P) 3–7
Calcium (Ca) 2–4
Iron (Fe) 0.02–0.13
Manganese (Mn) 0.02–0.05
Zinc (Zn) 0.01–0.05
Vitamins:
B3 0.8–10
B9 1
C 0.2
B2 0.177
K 0.1
E 0.01
B6 0.002
B1 0.001
Undesirable substances:
Acrylamide 3.9–840
Furan 3.8–262
N-alkanoyl-5-hydroxytryptamides 1.2–34.3

2.3. Caffeic Acid

According to Olholf et al. [86] about 95% of caffeic acid is absorbed in the first parts
of the alimentary system in humans, i.e., in the stomach and/or small intestine. Most
probably, in the stomach caffeic acid is absorbed by passive non-ionic mechanism, whereas
in the small intestine, this compound can be absorbed via active transport. Its maxi-
mum plasma concentration occurs within 1 h after consumption and decreases quite
rapidly [87,88]. After absorption, caffeic acid undergoes enzymatic conjugation, i.e., methy-
lation, sulphation, and glucuronidation by sulfotransferases, UDP-glucotransferases, and
Int. J. Mol. Sci. 2021, 22, 107 7 of 64

catechol-O-methyltransferases, respectively [89]. Manach and colleagues [87] found out

that caffeic acid is primarily excreted in urine (up to 27%). Free caffeic acid that has not
been absorbed in the small intestine can be reduced (by gut microbiota) into dihydro-
caffeic acid (3-(3,4-dihydroxyphenyl)-propionic acid) which in turn is transformed into
3-(3-hydroxyphenyl)-propionic acid and 3-phenylpropionic acid. After that, the latter
compounds are absorbed in the colon. In the liver, they undergo beta-oxidation, and
in consequence, benzoic acid and hydroxybenzoic acid are produced. Benzoic acid and
hydroxybenzoic acid conjugated with glycine and the obtained metabolites (i.e., hippuric
acid and 3-hydroxyhippuric acid) are excreted with urine [90].

2.4. Trigonelline
In humans, plasma levels of trigonelline vary depending on the coffee type, and the
amount of consumed coffee is a reliable predictor of plasma trigonelline values [91,92].
Considerably higher Cmax , Cmin , Cavg , AUC0-24 values as well as the 24-h total excretion
concentrations for trigonelline were detected in subjects that drank three cups of espresso
coffee per day when compared to volunteers drinking only one cup of espresso coffee with
or without two cocoa-based products containing coffee [91]. Most probably, absorption of
trigonelline took place primarily in the small intestine, and the circulating levels of this
compound are significantly elevated within the first hours after coffee consumption [91,93].
Trigonelline levels seem to drop to the basal values after 24 h post-coffee exposure, though
Bresciani et al. [91] suggested a sort of plasma accumulation after its repeated administra-
tion. This feature can be related to the long elimination half-life (ca. 5 h) [94]. It seems
that trigonelline plasma levels were influenced by food and age since nonfasting subjects
presented its higher values (by 20%) as compared to the fasting ones. Trigonelline plasma
concentrations augmented with age (i.e., by 9%/10 years) [92]. Furthermore, sex-dependent
differences in trigonelline pharmacokinetics were observed, with higher Cmax or Cavg val-
ues in women [91,93]. In experiments by Yuyama and colleagues [95,96], about 10% of the
oral dose of trigonelline was excreted in urine as N 0 -methyl-2-pyridone-5-carboxylic (an
oxidation product), and ca. 20% was recovered unchanged. Sex-dependent differences in
relation to trigonelline renal excretion have been detected [93].

2.5. Kahweol and Cafestol

There is scarce availability of data on pharmacokinetics of cafestol and kahweol in
humans. Most of them are from studies by de Roos et al. [97] carried out on healthy
ileostomy volunteers. The authors found that ca. 30% of consumed cafestol is broken down
by gastric juices, whereas about 64–70% of ingested cafestol is absorbed, with duodenal
absorption ranging between 84 and 93%. Furthermore, it was observed that only 1.2% of
ingested cafestol is excreted in a form of glucuronidated or sulphated conjugates in urine.
As for kahweol, when consumed, ca. 70–73% of this compound is absorbed by healthy
ileostomists, with the small intestine absorption within the range of 91–95%. The rest of
it is degraded by gastric enzymes. Only insignificant amount of consumed kahweol (i.e.,
0.4%) is excreted in a glucuronidated or sulphated form in urine.

3. Neurodegenerative Diseases
Neurodegenerative disorders encompass a heterogeneous group of diseases that
are related to progressive deterioration of the structure and functioning of the central or
peripheral nervous system. Neurons, synapses, glial cells, and their networks are affected.
Usually, accumulation of pathological proteins in both neurons and glial cells of the human
brain and the spinal cord or their extracellular depositions (plaques) are responsible for
the nervous system damage. Classification of the neurodegenerative disorders depends
on clinical symptoms, impaired brain areas, affected cell types, altered proteins, and
etiology. Patients suffering from these diseases present movement disorders (such as hyper-
or hypokinesia, cerebellar dysfunctions, and problems with the upper and lower motor
Int. J. Mol. Sci. 2021, 22, 107 8 of 64

neurons), cognitive decline, dementia, and disturbances in many high-order brain functions.
Affected brain areas have signs of atrophy and/or defective metabolic activity [98].

3.1. Dementias, Including Alzheimer’s Disease

According to the literature data [99], about 50 million people worldwide currently
suffer from dementia. This number is increasing all the time due to population growth
and aging, and most probably by 2050, it will be doubled [100]. Dementia, defined as an
acquired chronic or progressive cognitive impairment is one of the major causes of depen-
dence, disability and even mortality in elderly people. In this syndrome, deterioration
of cognitive functions is far beyond the aging-related physiological decline, and it affects
profoundly the quality of patient’s life. Though the consciousness of people with dementia
is not usually disturbed, they present deteriorated learning capacity, reduced visuospa-
tial, language, calculation, and judgment skills as well as worsened memory, thinking,
and orientation. Furthermore, their emotional control, social behavior, and motivation
are also negatively changed. There are several different forms of dementia, including
Alzheimer’s disease (about 60–70% of all cases), vascular dementia, dementia with Lewy
bodies, frontotemporal dementia, mixed dementia, and others [101].
Typical, sporadic Alzheimer’s disease with a late onset is usually associated with an
interplay between environmental factors and genetics. Apart from that, a familial form of
Alzheimer’s disease is also known, which is related to mutations in amyloid precursor pro-
tein (APP), PS1 presenilin 1 (PS1), and presenilin 2 (PS2) genes [102]. It has been suggested
that cognitive impairment in patients with Alzheimer’s disease is induced by the progres-
sive degeneration of the neocortex [103], basal forebrain [104], and the limbic system [105],
with an initial damage of synapses, followed by deterioration of axons, and atrophy of
dendrites and somas [106–109]. Both “positive” and “negative” lesions, with their charac-
teristic distribution, are implicated in the pathogenesis of Alzheimer’s disease. Amongst
the positive ones, amyloid plaques and neurofibrillary tangles seem to be most important,
but neuropil threads and dystrophic neurites with hyperphosphorylated protein tau are
also mentioned. They may co-exist with formation of Hirano bodies, congophilic amyloid
angiopathy, astrogliosis, microglial cell activation, and granulovacuolar degeneration. As
for the negative lesions, neuronal, synapse, and neuropil loss are observed.
Amyloid plaques are accumulated outside neurons, mainly in the isocortex. However,
in advanced cases, they can also be found in the subcortical structure. Amyloid plaques
mostly consist of the abnormally folded amyloid beta (Aβ) peptide with 40 or 42 amino
acids. They are produced during metabolism of the amyloid precursor protein. Since
Aβ peptide with 42 amino acids is less soluble and presents higher rate of fibrillization,
it is more abundant within the plaques [110]. Unfortunately, Aβ pathology is not a reli-
able indicator of the disease progression, since it relatively quickly reaches the plateau
level [111]. Neurofibrillary degeneration seems to be a better marker. A number of studies
have revealed that the density and distribution of the neurofibrillary tangles correspond to
the severity of the disease. The intracellular neurofibrillary tangles consist of paired helical
filaments that are built of the aberrantly misfolded and hyperphosphorylated microtubule-
associated protein tau. Neurofibrillary pathology begins in the allocortex of the medial
temporal lobe, and then, it spreads to the associative isocortex. The primary sensory, motor,
and visual areas are involved only at the latest stage of the disease [110]. It has been
suggested that Aβ plaques perturb communication between neurons in synapses, and
consequently, they contribute to cell death and brain atrophy. Tau tangles most probably in-
hibit transportation of nutrients and other vital compounds inside neurons. Furthermore, it
is believed that both amyloid plaques and neurofibrillary tangles stimulate immune cells in
microglia, which results in chronic inflammation. Thus, it is certain that both amyloid and
tau pathologies are crucial for the development of Alzheimer’s disease. However, scientists
are not unanimous in relation to which of them is the primary process. The tau hypothesis
of Alzheimer’s disease assumes that the hyperphosphorylation of tau is the predominant
mechanism [112], whereas according to the amyloid hypothesis of Alzheimer’s disease,
Int. J. Mol. Sci. 2021, 22, 107 9 of 64

accumulation of the amyloid plaque as a result of imbalance between production and clear-
ance of Aβ peptide is the primary cause of the disease with development of neurofibrillary
tangles, neuronal dysfunction, and degeneration as the secondary processes [113]. In fact,
mutations in Aβ genes can be causative factors of Alzheimer’s disease [114], while tau
mutations by themselves do not induce this disease [115]. Available literature provides
also other explanations for Alzheimer’s disease development, suggesting that progres-
sive loss of cholinergic neurons with subsequent reduction in acetylcholine levels in the
cerebral cortex [116,117], dysfunction of the brain mitochondria [118], reduced cerebral
blood flow [119], or imbalance in metabolic processes (i.e., diabetes, obesity, hypercholes-
terolemia) [120,121] contributes at least partially to Alzheimer’s disease onset. Furthermore,
patients with Alzheimer’s disease present signs of neuroinflammation [122] and oxidative
stress [123].
For the time being, there is no effective prophylactic or causative therapy for Alzheimer’s
disease. Symptomatic drugs are used, including cholinesterase inhibitors (i.e., donepezil,
rivastigmine, and galantamine) and memantine (i.e., an antagonist of the N-methyl-D-
aspartate (NMDA) receptor). Additionally, antipsychotics and antidepressants for the
treatment of behavioral symptoms are prescribed [124].

3.2. Parkinson’s Disease

Parkinson’s disease is another progressive and degenerative disorder that globally
affects more than 6 million people [125]. It is manifested by both motor and nonmotor
symptoms. The motor symptoms include resting tremor (usually unilateral in extremity,
though the head, jaw, and tongue can also be involved), bradykinesia, postural instability,
and rigidity. Spontaneous movement are significantly decreased, with the loss of facial
expression, reduced blink rate, and impaired spontaneous swallowing that results in sialor-
rhea. Furthermore, hand movements are limited and periods of “freezing” and gait changes
are noted. Patients with Parkinson’s disease may experience propulsion or retropulsion,
and festination [126,127]. Amongst the nonmotor symptoms cognitive decline, anosmia,
depression, anxiety, dysautonomia, gastrointestinal and urinary complaints, sleep distur-
bances, and orthostatic hypotension are listed [128–132]. On the cellular level, substantia
nigra and locus coeruleus depigmentation as well as neuronal deficits in the pars compacta
of the substantia nigra are observed. These pathologies seem to be related to apoptosis and
autophagy [133]. Furthermore, Lewy bodies or Lewy neuritis, i.e., cytoplasmic abnormal
aggregations of misfolded α-synuclein, are detected in certain regions of the central and
peripheral nervous system [134], including basal and celiac ganglia, locus coeruleus, dorsal
motor nucleus of the vagus, olfactory bulb, or the intermediolateral nucleus in the spinal
cord [135,136]. It was demonstrated that phosphorylation and fibrillization of α-synuclein
induce neuronal death [137]. There is a general notion that the neurodegeneration in
Parkinson’s disease concerns mainly dopaminergic neurons and thus, it has a noxious
impact on dopamine levels and dopamine-related neurotransmission [138,139]. However,
neuronal deficits and Lewy formations have been found in the noradrenergic, serotonergic,
and cholinergic systems, as well [140]. Therefore, the abovementioned pathways can also
be affected. Though in some patients Parkinson’s disease has a genetic origin, the primary
cause of the most Parkinson’s disease cases has not been discovered yet. Inflammation, ox-
idative stress, mitochondrial dysfunction along with disturbances in protein handling and
in activity of calcium channels are mentioned as the contributing factors to the observed
neuronal loss [134].
Currently, there is no effective cure for Parkinson’s disease. Prescribed medications
help to alleviate symptoms and improve the quality of patient’s life. Most of them stim-
ulate dopaminergic neurotransmission. Levodopa, i.e., a precursor of dopamine, is still
considered as the most potent active substance that controls Parkinson’s disease manifes-
tations. Usually, it is given with carbidopa that increases its bioavailability and inhibits
its peripheral metabolism. Dopaminergic agonists (pramipexole, ropinirole, rotigotine, or
apomorphine) activating dopaminergic receptors as well as inhibitors of catechol-O-methyl
Int. J. Mol. Sci. 2021, 22, 107 10 of 64

transferase (entacapone, opicapone) and monoamine oxidase aldehyde dehydrogenase B

(rasagiline, selegiline, safinamide) that slow down enzymatic degradation of levodopa and
dopamine are also used. Rigidity, dystonia, and tremor are usually treated with anticholin-
ergic drugs (trihexyphenidyl and benztropine), whereas hallucinations and delusions are
controlled with antipsychotics, such as quetiapine, clozapine, or pimavanserin [141,142].

3.3. Ischemic Stroke

It has been estimated that globally about 13–15 million people undergo stroke each
year, which results in more than 5 million deaths [143]. About 85% of strokes are ischemic
ones. Ischemic stroke occurs when the blood flow to the brain is decreased. It may be
caused by a thrombotic event or an embolic event. In the thrombotic event, the blood flow
is obstructed due to vessel problems (i.e., as a consequence of arterial dissection, atheroscle-
rotic disease, fibromuscular dysplasia), whereas in the embolic event, the blood flow is
obstructed due to a clot that originated in another location within the body (frequently in
the heart) and was dislodged to the brain vasculature. Depending on the affected artery,
several ischemic stroke syndromes are diagnosed, including middle cerebral artery infarc-
tion, anterior cerebral artery infarction, vertebrobasilar infarction, cerebellar infarction, and
lacunar infarction. Thus, the clinical presentation of a given ischemic stroke is different
depending on the brain regions that are supplied by the involved vessel. The observed
deficits in motor functions and cognition are caused by the loss (necrosis) of brain tissue
in the influenced areas. Most frequently, weakness of the face, tongue, and/or laryngeal
muscles, speech disorders, contralateral hemiparesis, visual disturbances, impaired coordi-
nation and balance, severe headaches, or impaired consciousness are reported [144–148].
The main treatment goal in an acute ischemic stroke is to avoid necrosis of the tissue in
the affected region. Therefore, when possible, a thrombolytic compound (i.e., tissue plas-
minogen activator) is administered. Apart from that, mechanical thrombectomy, aspirin or
heparin, and antihypertensive drugs (i.e., labetalol, nicardipine, clevidipine, hydralazine,
enalaprilat) are used. In order to obtain neuroprotective effect, drugs should be given as
soon as possible after the stroke onset [149–151].
There are several mechanisms responsible for the brain sensitivity to ischemia. One
of them is the excitatory activity of glutamate. It has been found that ischemia causes a
significant decrease in adenosine-50 -triphosphate (ATP), which in consequence disturbs
activity of glutamate transporters responsible for removal of glutamate from the synaptic
cleft. Elevated level of glutamate leads to overstimulation of glutamate receptors and
excessive increase of calcium levels. These processes generate excitotoxicity, neurons
damage and their death [152]. Furthermore, acidification of brain tissue observed after
stroke worsens the brain injury [153,154]. Most probably, acidosis-mediated stimulation
of the so-called acid-sensing ion channels and the subsequent influx of calcium ions are
implicated in this pathological mechanism [155]. After ischemic stroke, neuroinflammation,
oxidative stress, and disruption of the blood–brain barrier are also detected. Microglia and
astrocytes are activated which intensifies production of chemokines and cytokines along
with infiltration of leukocytes [156]. Eventually, epigenetic remodeling including DNA
methylation and histone modifications may be responsible for memory deficits diagnosed
in patients that underwent ischemic stroke [157]. Unfortunately, necrosis of tissues at
the site of infarction may instigate further damage of the brain, spreading to the regions
anatomically related to that site. This process is called the secondary neurodegenera-
tion [158]. Surprisingly, areas affected by the secondary neurodegeneration share common
features with typical neurodegenerative disorders, such as neuroinflammation, progressive
neuronal loss, or accumulation of Aβ which is specific to Alzheimer’s disease [159]. It
seems that the thalamus is particularly vulnerable to the secondary degeneration after
stroke. Its disturbances are detected within few weeks after infarction and can persist for
several years. Stroke-induced degenerations in thalamus include neuronal loss, severe glial
dysfunction [160–162], and Aβ accumulation [163]. Preclinical studies by Ong et al. [164]
confirmed that stroke-induced accumulation of Aβ in the thalamus may be connected not
Int. J. Mol. Sci. 2021, 22, 107 11 of 64

only with an increase of the high molecular weight soluble amyloids but also with Aβ
oligomers and that this form of Aβ may also be implicated in neuronal loss after stroke.
Interestingly, chronic stress [164] or administration of the human bone marrow-derived
mesenchymal stem cells [165] in a rodent stroke model aggravate accumulation of Aβ
in the thalamus, whereas administration of a γ-secretase inhibitor [166], calcium channel
blocker [167], or autophagy inhibitor [168] reduces amounts of Aβ in the thalamus as well
as improves functioning of neurons after stroke.

3.4. Epilepsy
One of the most common neurological diseases is epilepsy, which affects about 50 mil-
lion people worldwide. It has been estimated that ca. 5 million people are diagnosed with
epilepsy per year [169]. The disease is characterized by recurrent seizures that can be gener-
alized (tonic-clonic, involving both hemispheres and multiple structures) or focal (limited
to one hemisphere). Though up to 70% of epileptic patients can be seizure-free taking
antiepileptic drugs, there is still a great number of people that do not respond to the avail-
able treatment. Drugs are selected individually (usually starting with monotherapy) with
several different factors taken into consideration, including seizure type, comorbidities,
concomitant drugs, patient’s lifestyle, and their preferences [170].
Hippocampal sclerosis, i.e., pyramidal cell loss in Ammon’s horn, gliosis, granule
cell dispersion, and axonal fiber sprouting, has been found in epileptic patients [171–173].
Briellmann et al. [174] and Jackson et al. [175] reported a significant reduction in hippocam-
pal volume and altered hippocampal architecture associated with seizure episodes. Most
probably, the seizure-induced neuronal death is caused by upregulated glutamatergic
neurotransmission (excitotoxicity) which results in extensive influx of calcium ions into
cells, osmolytic stress, and stimulation of cell death pathways [176]. Proliferation and hy-
pertrophy of microglia, astrocytes, and oligodendrocytes detected in patients with epilepsy
is associated with elevated levels of proinflammatory cytokines in the brain [177,178].
Impairments in the blood–brain barrier as well as changes in the brain vascular system
are also observed in epilepsy. However, it has not been determined whether microvessel
proliferation and disruption in the blood–brain barrier are the causative factors of seizures
or they occur as a consequence of seizures [179,180].

4. Neuroprotective Effects of Coffee Bioactive Compounds

Epidemiological studies suggest that regular coffee consumption may be associated
with a reduced risk of numerous neurodegenerative disorders (including Parkinson’s dis-
ease, Alzheimer’s disease, and neurocognitive decline), though conflicting results have also
been reported [181–183]. When consumed in moderate amount, coffee may reduce demen-
tia and improve cognitive performance [183,184]. Moreover, habitual coffee consumption
can potentially decrease the risk of stroke incidence and stroke mortality [182,183,185]
and has positive impact on the course of autoimmune diseases such as multiple sclero-
sis [183,184]. Caffeine is the most widely investigated coffee component, and benefits
from regular coffee intake are typically attributed to caffeine. However, coffee is a mixture
of many bioactive compounds and some of them have the potential to produce neuro-
protective effects as well. Here, we provide a comprehensive overview of the data from
in vitro and in vivo studies on the neuroprotective potential of the main bioactive coffee
components. Studies in humans, although limited, are also discussed.

4.1. Neuroprotective Effects of Caffeine

Caffeine (1,3,7-trimethylxanthine), because of its chemical structure, is classified as a
purine alkaloid and is the dominant physiologically active compound in coffee beans and
soft beverages. This methylxanthine belongs to the most favorable used psychostimulant
worldwide [7,12,186]. By consuming a cup of brewed coffee (about 430–440 mL), an average
of 188 mg caffeine is delivered to the body (range 147–259 mg depending on the genus of
coffee beans) [187]. Moderate caffeine intake (3–5 cups/24 h) is associated with reducing
Int. J. Mol. Sci. 2021, 22, 107 12 of 64

fatigue, revised cognitive, and improved alertness, leading to better yield in psychomotor
tasks needing quick response [188,189]. Furthermore, studies have shown that caffeine
has antioxidant [20,190,191], anti-inflammatory [15,191], anti-cancer [22,24,25], as well as
neuroprotective properties. The mechanisms underlying these caffeine activities have been
thoroughly investigated over the last decade. In this paragraph, an overview of the most
important preclinical and clinical studies that investigated the neuroprotective effects of
caffeine has been presented.
Preclinical studies. Both neuroprotective effects of caffeine and the mechanism of this
action have been examined in different experimental models of central nervous system
(CNS) diseases. Preliminary studies on a long-term caffeine administration on behavior of
naïve rodents revealed no effect on spatial learning and memory responses [192]. However,
later, the protective impact of the chronic caffeine administration on the onset of cognitive
impairment in Alzheimer’s mice has been revealed in several works. Costa et al. [193]
demonstrated that a 12-month treatment with caffeine averts memory impairment in ag-
ing rodents. The caffeine-treated aging mice presented a similar recognition memory as
adult mice and an improved recognition memory when compared to their age-matched
control animals. Furthermore, it was noted that caffeine prevents the age-depending en-
hancement in the hippocampal immunocontent of the brain-derived neurotrophic factor
(BDNF) and tirosine kinase receptor (TrkB), which might be a mechanism for caffeine’s
neuroprotective action [193]. Citied outcomes are corroborated with results of preclinical
studies conducted by Arendash et al. [194,195]. This research team demonstrated that
giving caffeine in the daily diet to Swedish mutation transgenic mice (animals carrying the
mutant APPK670N,M671L gene, APPsw), starting in young adulthood, results in cognitive
protection in various tests across a multiple of cognitive domains, such as spatial learning,
memory, identification, strategy switching, and working memory. Moreover, these compre-
hensive cognitive profits did not contribute to the occurrence of undesirable effects, such
as disturbances in sensorimotor functions or an increase in the level of anxiety, which may
be caused by a single caffeine administration [194,195]. More recent research by Arendesh
and co-workers [195] indicated that a long-term moderate caffeine consumption has also a
desirable effect on already existing Alzheimer’s disease symptoms in older (18–19 month
old) APPsw mice [195]. They observed that aged APPsw rodents after 4–5 weeks caffeine
administration in drinking water characterized significantly better working memory in
comparison to the control APPsw animal group [195]. In both studies, they indicated,
that prolonged caffeine intake decreases hippocampal Aβ levels, which are most likely
associated with reduced expression of both PS1 and β-secretase-1, and hence diminished
production of Aβ in caffeine-treated APPsw mice [194,195]. Besides, an evidence that
observed β-secretase-1 suppression after caffeine treatment involves the cRaf-1/NFκB
(nuclear factor κ-light-chain-enhancer of activated B cells) inflammatory pathway was pre-
sented [195]. Additionally, the ability of caffeine to impair Aβ synthesis (in a concentration-
dependent manner) [194] and to decrease total glycogen synthase kinase 3 (GSK-3) levels
(in a concentration- and time-dependent manner) [195] were revealed in the nerve cell
cultures SweAPP N2a. As emphasized by the authors, it is also probable that the mecha-
nism of caffeine’s protective effect on cognition may be due to the restoration of adenosine
levels to normal in transgenic mice, despite the lack of effect on the density of A1 and A2A
adenosine receptors [194]. Moreover, they showed that chronic caffeine consumption from
adulthood to old age does not provide cognitive benefits in normal mice [195]. These find-
ings are in agreement with the outcomes of Dall’Igna et al. [196,197] showing that chronic
as well as sub-chronic caffeine administration resulted in a robust protection against Aβ
peptide toxicity in cerebellar neuron cultures [196] and prevented the Aβ-induced cognitive
impairment [197]. Recent in vitro analyses conducted by Giunta et al. [198] also showed
that caffeine prevents neuroblastoma cell death induced by co-exposure to Aβ and alu-
minum chloride (AlCl3 ). Additionally, they demonstrated, that caffeine treatment, through
a non-selective blockade of A1 and A2A adenosine receptors, inhibits the co-neurotoxicity
of Aβ and AlCl3 [198].
Int. J. Mol. Sci. 2021, 22, 107 13 of 64

The impact of prolonged caffeine administration on memory impairment and oxida-

tive stress generated by aging in rats was investigated by Leite et al. [199]. The obtained
outcomes indicated that the memory deficits appearing with age are reversed by oral
administration of caffeine. In addition, biochemical studies demonstrated that the ap-
plied treatment contributes to the normalization of the enhanced levels of oxygen and
nitrogen reactive species (ROS and RNS, respectively) and the inhibited Na+ /K+ -ATPase
activity noted in the brain of elderly rats [199]. Antioxidant-like properties of chronic
caffeine administration as a mechanism of its protective effect on memory deficits, neu-
roinflammation and neurodegeneration induced by D-galactose treatment were indicated
by Ullah et al. [191]. Results of these studies demonstrated that prolonged caffeine ad-
ministration in the D-galactose-treated rats: (1) reverses oxidative stress via decrease of
8-oxoguanine; (2) attenuates phoshorylation of key stress-responsive kinases level, i.e.,
C-Jun N-terminal kinases (p-JNK); (3) normalizes the level of inflammatory mediators,
such as cyclooxygenase-2 (COX-2), nitric oxide synthase-2 (NOS-2), tumor necrosis factor
α (TNF-α), and interleukin-1β (IL-1β); (4) prevents apoptosis and neurodegeneration
(decreased level of cytochrome C, Bax/Bcl2 ratio, caspase-9, caspase-3, and PARP-1); (5) im-
proves the pre-synaptic proteins synaptophysin and post-synaptic density proteins (PSD95)
level, and (6) improves spontaneous alternation behavior [191]. Beneficial caffeine effects
on the parameters of oxidative stress have also been demonstrated in in vitro examina-
tions using human neuroblastoma cells exposed to the toxic effect of Aβ and AlCl3 . In
addition, Giunta et al. [198] presented caffeine ability to prevent the activation of the
NF-κB pathway, elevation of both β-secretase-1 and APP levels, and ability to inhibit ROS
production. Caffeine effects in the cell toxicity model were similar to these noted for an
antioxidant–N-acetylcysteine and a metal chelator–desferrioxamine [198].
In 2014, Laurent et al. [200] provided the evidence that chronic caffeine intake in
drinking water is sufficient to prevent the development of spatial memory deficits in a
mice model of progressive Alzheimer’s disease-like tau pathology. Further, the improve-
ment of memory was connected with decreased phosphorylation of hippocampal tau
and proteolytic fragments. In addition, in the hippocampus of THY-Tau22 mice, caffeine
reduced levels of several pro-inflammatory and oxidative stress markers (i.e., CD45, TLR2,
CCl4, and TNF-α) which were upregulated in animals with Alzheimer’s disease [200]. The
evidence for the protective activity of caffeine against oxidative stress and Alzheimer’s
disease-like pathology has also been presented by Prasanthi et al. [201]. They demon-
strated that caffeine treatment reversed changes induced by cholesterol-enriched diet, i.e.,
it decreased ROS generation, glutathione depletion, as well as Aβ synthesis, whereas it
increased adenosine A1 receptors concentration in the rabbit hippocampus [201]. Another
hypothesis assumes that increased cerebrospinal fluid (CSF) production is a possible mech-
anism underlying caffeine’s protective effect against Alzheimer’s disease. Han et al. [202]
showed that the long-term caffeine consumption might induce ventriculomegaly and in-
tensify production of CSF as a result of the enhancement of expression of Na+ /K+ -ATPase
and cerebral blood flow (CBF). In contrast, acute caffeine administration has an opposite
effect on the production of CSF [202] (for review see [203]).
Numerous studies have attempted to determine the effects of caffeine consumption on
the development and course of Parkinson’s disease in various animal models. It has been
demonstrated that caffeine attenuated dopaminergic lesions caused by 1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine (MPTP) [204–209], 6-hydroxydopamine (6-OHDA) [210,211],
and pesticides (paraquat/maneb) [212]. What is more, caffeine pre-treatment decreased
neuronal damage and improved motor activity [204] and attenuated dopamine loss [208]
and microglia activation in the substantia nigra [213]. Additionally, Sonsalla et al. [213]
recorded that both caffeine administration for 1 week and 3 weeks after initiating MPTP
infusion (the early stage of loss of nigrostriatal dopamine and the late stage of loss of
nigrostriatal dopamine, respectively) decreased the decline of nigral cells in rats by 94%
and 69%, respectively. Reduction in the loss of nigrostriatal dopamine neurons in rats
was also observed when caffeine was taken orally after MPTP administration [213]. In
Int. J. Mol. Sci. 2021, 22, 107 14 of 64

turn, an acute caffeine pretreatment was demonstrated to be only partially beneficial

against neurotoxic changes obtained in the MPTP [209] and 6-OHDA [214] of Parkinson’s
disease rodent models. Some of these studies have shown that the observed protective
activity on dopaminergic neurons/dopamine levels is dose-dependent, and that the max-
imum neuroprotective effect is achieved after caffeine administration at a daily dose of
10 mg/kg. Moreover, this effect was grater in young (10 weeks) mice in comparison to the
old (6–9 months) ones [208]. Moreover, Xu et al. [209] indicated that caffeine metabolites
(both theophylline and paraxanthine) also significantly attenuated the MPTP-induced
dopamine depletion in mice, thus also providing neuroprotective effects in this model of
Parkinson’s disease.
The exact mechanism by which caffeine provides neuroprotection against toxins is still
unclear. The most prominent theory about antiparkinsonian potential of caffeine is that this
methylxanthine acts as an antagonist of adenosine A2A receptors. In the substantia nigra,
caffeine via competitive inhibition of these receptors might prevent the adenosine-mediated
neuroinflammatory actions [213]. Laboratory data showed that various A2A antagonists
(both non-selective and selective) protect against acute toxin exposure in Parkinson’s dis-
ease models [208,212,215–219]. Through blockade of adenosine A2A receptors, caffeine
inhibits activation of adenylyl cyclase and consequently protein kinase A. Therefore, it
restrains the extracellular calcium influx into a cell and reduces the excitotoxic glutamate
release in the CNS [204,218,220,221]. Moreover, Morelli et al. [222] indicated that caffeine
by blocking A2A receptors and reducing glutamate release contributes to attenuation of
microglia activation and production of both cytokines and free radicals, hence precluding
further damage of striatal and nigral neurons [222]. Caffeine is also capable to bind to
adenosine A2A receptors situated on astroglial cells, thereby inhibiting their activity and
regulating the neuroinflammation generated by astroglia in the vicinity of dopaminergic
neurons [214,217]. The essential role of neuronal adenosine A2A receptors in chronic neu-
rodegeneration was confirmed in mice with the A2A receptors knockout. Such animals
showed resistance to dopaminergic neuron damage caused by a chronic [223], although
not an acute [219] exposure to MPTP. However, adenosine A1 receptors antagonism did
not produce the neuroprotective effect observed after caffeine treatment [215]. Likewise,
neurochemical and immunohistochemical studies conducted in recent years indicated that
long-term caffeine intake in various animal models of Parkinson’s disease: (1) increased
dopamine levels, (2) reversed the enhanced dopamine and noradrenalin levels in striatum,
(3) improved the hippocampal neuronal viability, (4) increased tyrosine hydroxylase im-
munoreactivity in the striatum, (5) reduced the number of immunopositive cells for histone
deacetylase, (6) decreased the level of pro-inflammatory cytokines, such as TNF-α and
IL-1β [204,210,212–215].
The anti-ischemic effect of caffeine has been examined using animal models of ischemic
brain injury. Rudolphi et al. [224] observed that chronic oral pretreatment with caffeine
greatly reduces the degree of ischemic necrosis of pyramidal cells of the CA1 hippocampal
area in Mongolian gerbils subjected the bilateral carotid occlusion. Moreover, this study
outcome provided the evidence that a caffeine-induced upregulation of A1 adenosine
receptors in the CNS impairs the level of experimentally induced ischemic brain injury [224].
Similar outcomes following chronic treatment of mice with very low doses of caffeine were
reported by Georgiev et al. [225]. In the study by Evans et al. [226], caffeine administered
to the cortex 60 min prior to the development of ischemia decreased the ischemia-induced
attenuation of the amplitude of recorded somatosensory evoked potentials and accelerated
recovery to control levels [226].
The effect of caffeine on ischemic neuronal injury in rats using magnetic resonance
imaging (MRI) and histopathological examination was investigated by Sutherland et al. [227].
Acute caffeine-treated animals exhibited accelerated changes in the MRI scans, while quan-
tification of the histopathological evidence revealed no meaningful distinction in neuronal
injury in any brain region in comparison with control-ischemic rats. Moreover, chronic
caffeine-treated rodents had significantly minor neuronal damage in all sensitive brain
Int. J. Mol. Sci. 2021, 22, 107 15 of 64

areas (including cerebral cortex, striatum, and hippocampus) than either of the other is-
chemic rats’ groups. Additionally, on the basis of the obtained results, they indicated
that protection against ischemic injury after chronic administration of caffeine might be
effectuated via an enhancement in the concentration of adenosine receptors [227] in the
CNS, which is consistent with the caffeine neuroprotection mechanism in ischemic brain
injury proposed by Rudolphi et al. [224].
Therapeutic activity of caffeine treatment in neonatal hypoxic-ischemic (HI) injury
model was studied by Alexander et al. [228]. Results of this research showed that caffeine-
untreated HI animals had significant deficits in the Morris water maze test, which have been
attenuated by caffeine administration immediately after the induction of HI. Furthermore,
they also found a decrease in cortical volume in the HI saline-treated animals, while
cortical volume in the HI caffeine-treated animals was intermediate. Similarly, Kilicdag
and co-workers [229] observed the reduced neuronal apoptosis in the developing brain
in caffeine-treated rats in a HI neonatal model. Moreover, later findings presented by
Potter et al. [230] supported the continued investigation of caffeine as a neuroprotectant
in a preterm model of HI. All of these research teams concluded that caffeine might be
efficacious in extenuating ischemic brain injury [228–230].
Summary of in vivo studies on the neuroprotective effects of caffeine is presented in
Table 3. Clinical studies. A case-control study carried out by Maia and de Mendonça [231]
with 74 patients with Alzheimer’s disease and 72 healthy subjects aimed to answer the
question whether caffeine intake protects from Alzheimer’s disease [231]. Consequently,
the authors calculated the average daily caffeine intake (mg/day) by estimated caffeine
content in various food products, which are widely recognized as the primary sources of
this methylxanthine (e.g., instantaneous coffee–60 mg, decaffeinated coffee–3 mg, espresso
coffee–100 mg, instantaneous tea–20 mg, leaf tea–30 mg, and cola-drinks–18 mg) and
counted how many dosages each patient consumed for the period of 20 years before
diagnosis of Alzheimer’s disease and the period from early adulthood to 20 years be-
fore diagnosis of Alzheimer’s disease, as well as for the period after the diagnosis of
Alzheimer’s disease until the time the questionnaire. This study showed that caffeine
intake was inversely correlated with the hazard ratio of developing Alzheimer’s disease–
an increased caffeine consumption was associated with a 60% reduction in the risk of
Alzheimer’s disease (average consumption was 199 ± 136 mg/day in healthy subjects
compared to 74 ± 98 mg/kg in patients with Alzheimer’s disease) [231]. Caffeine’s ben-
eficial effects in Alzheimer’s disease patients were also observed in the Canadian Study
of Health and Aging. A prospective analysis of risk factors for Alzheimer’s disease was
conducted on a group of 1023 individuals aged 65 years or older in 1991–1992, and its out-
comes showed that coffee consumption was associated with a reduced risk of Alzheimer’s
disease and amounted to 31% [232]. Interesting results were also obtained by Eskeli-
nen and co-workers [233,234] in studies assessing the association between the long-term
coffee consumption at midlife and Alzheimer’s disease/dementia risk in late-life. Af-
ter an average follow-up of 21 years, in the group of 1409 individuals (534 men and
875 women) aged 50 years in 1972–1977, moderate coffee drinkers (3–5 cups/24 h) had
lower risk of Alzheimer’s disease and dementia (by 62–64% and 65–70%, respectively)
in comparison with low coffee consumers (0–2 cups/24 h). Results from this clinical
study indicate that regular consumption of coffee/caffeine seems to be protective for
Alzheimer’s disease and dementia [233,234]. Likewise, several meta-analyses [235,236] and
some systematic reviews [237–239] demonstrated an inverse association between cognitive
impairment/decline and the risk of Alzheimer’s disease. Furthermore, there are several
trials in which caffeine seemed to have no beneficial properties in patients with Alzheimer’s
disease/dementia. In a large prospective population study (4197 women and 2820 men
aged 65 years and over) by Ritchie et al. [240] no impact on dementia incidence in women
and men and no association between caffeine intake and cognitive decline in men were
found. In turn, in women with a high level of caffeine intake (>3 cups/day) a lesser decline
in the visuospatial memory over 4 years than in women consuming ≤1 cup/day was noted.
Int. J. Mol. Sci. 2021, 22, 107 16 of 64

Moreover, it was noticed that the protective activity of caffeine increased with age [240].
The meta-analysis of the observational epidemiological research by Kim et al. [241] also
showed no significant relationship between caffeine intake from coffee and the hazard ratio
of cognitive disorders, including Alzheimer’s disease and dementia, as well as cognitive
decline, in spite of the 18% tendency to reduce the risk of developing these disorders.
Numerous clinical studies and meta-analysis/systematic reviews have also linked
caffeine use with a lower risk of Parkinson’s disease. The possible association between
Parkinson’s disease risk and caffeinated beverages has been examined since the early
1970s. A significant negative relationship was found for caffeine consumption and hazard
ratio of Parkinson’s disease in one of the recent systematic review and meta-analysis–in
caffeine drinkers the relative risk of Parkinson’s disease was reduced by approximately
30–38% [242–245]. Moreover, in 2014 Qi and Li [245] presented the dose-response meta-
analysis which suggested a linear association between the decreased risk of Parkinson’s
disease and caffeine use, and a non-linear relationship between the decreased risk of Parkin-
son’s disease and coffee consumption. A five-time lower risk of developing Parkinson’s
disease in 45–68 year old people drinking coffee in the amount of ≥794 g/day (which cor-
responds to 421 mg of caffeine per day) and a lower risk of Parkinson’s disease depending
on the amount of consumed caffeine, was reported by Ross et al. [246] based on 27 years
of follow-up American Japanese. Convergent results were obtained by Hu et al. [247]
in a nearly 13-year control study involving about 14,500 people (approximately 62 years
old). The Parkinson’s disease hazard ratio was estimated at 1.00, 0.55, and 0.41 for subjects
drinking 0, 1–4 and ≥5 cups of coffee per day, respectively [247]. Liu et al. [248] noted that
the level of Parkinson’s disease risk reduction is similar in 61 year old women and men
consuming ≥5 cups of coffee a day for 10 years. Similarly, Hu et al. [247] reported that
the inverse relationship between coffee consumption and the Parkinson’s disease hazard
ratio did not differ significantly between men and women in Finland. Palacios et al. [249]
indicated that men who consumed ≥2 cups of coffee/day (i.e., 274 mg/day of caffeine)
had a lower risk of Parkinson’s disease than women who consumed 3.2 cups of coffee/day
(i.e., 435 mg/day of caffeine) (50% and 40% lower risk of Parkinson’s disease, respectively).
In 2011, Altman et al. [250] demonstrated that caffeine may have positive effects on
some motor as well as nonmotor aspects in patients suffering from Parkinson’s disease.
Moreover, the maximum tolerated dose of caffeine in Parkinson’s disease subjects was
200–400 mg/day [250]. A year later, Postuma et al. [251] in a randomized, controlled trial
showed that administration of caffeine at a dose of 200 mg/day for 3 weeks followed
by a further 3 weeks at a dose of 400 mg/day significantly improved the overall unified
Parkinson’s disease rating scale and motor manifestation (by 4.7 and 3.2 points, respec-
tively). However, results of these studies are in contrast to the recent randomized trial
that indicated that caffeine did not produce sustained motor improvement in Parkinson’s
disease [252].
Based on the cited clinical studies, meta-analyses and systematic reviews, it is not
possible to establish the biological mechanism(s) behind the correlation between cof-
fee/caffeine intake and the risk of Alzheimer’s disease/dementia and/or Parkinson’s
disease. Tan et al. [253] analyzing the association between caffeine consumption and
hazard ratio of Parkinson’s disease in both fast and slow caffeine metabolizers suggested
that both caffeine and its major metabolite, paraxanthine, have neuroprotective proper-
ties. These observations supported experimental evidence obtained in animal models (see
preclinical studies). Furthermore, several studies showed that decaffeinated coffee con-
sumption was not associated with neurodegenerative disorders risk, including Alzheimer’s
disease and Parkinson’s disease [29,249,254]. Therefore, it can be assumed that caffeine is
responsible for the observed inverse correlation between coffee intake and the hazard ratio
of Alzheimer’s disease and Parkinson’s disease incidents.
Until recently, coffee was classified as one of the cardiovascular risk factors [255–259].
While, caffeine is known to increase peripheral vascular resistance, but also to reduce
blood flow in the brain through its vasoconstrictive effects and consequently poses a
Int. J. Mol. Sci. 2021, 22, 107 17 of 64

risk of hypertension (one of the risk factors of stroke) [260], some epidemiological and
cohort studies, as well as meta-analysis found there was no significant association between
coffee consumption and stroke risk [261–266], and several showed a prophylactic effect of
coffee consumption on stroke incidence [18,185,267–269]. In turn, a study conducted by
Mostofsky et al. [270] found an increase in the hazard ratio of an ischemic stroke within
60 min after drinking coffee. Likewise, an acute increase in the risk of ischemic stroke was
observed immediately after drinking coffee by Washio et al. [271], but as these authors
emphasized, the reason of observed coffee impact may be caused by other factors rather
than an elevation in pressure in the cerebral circulation [271].
In 2011, Larsson and Orsini [272] published results of meta-analysis involving 11
prospective studies (a total of 479,689 individuals and 10,003 stroke incidents) which
showed a non-linear connection between coffee consumption and the hazard ratio of stroke.
In comparison to the absolute risk of total stroke, the relative risk of total stroke amounted to
0.87, 0.84, 0.88, and 0.94 for 2, 3–4, 6, and 8 cups of coffee per day, respectively. Additionally,
estimated hazard ratios were suchlike for hemorrhagic and ischemic stroke [272]. A non-
linear relationship between coffee consumption and a lower risk of stroke (relative risk 0.80,
95% confidence interval 0.75 to 0.86) was also presented by Poole et al. [18] in umbrella
review of meta-analyses (including 201 meta-analyses of observational studies, 67 unique
health outcomes, and 17 meta-analyses of interventional studies). A 5% and 15% reduction
in a relative hazard ratio of stroke with an average consumption of 5 and 3.5 cups per day
versus non-drinkers, respectively, were noted by Ding et al. [267] in a large meta-analysis of
36 cohort studies (36,352 patients with cardiovascular diseases including stroke). Likewise,
a prospective study by Larsson [255] confirmed an inverse relationship, but not very
marked, between moderate coffee drinking and the risk of stroke.
Otherwise, in some large cohort studies/meta-analyses the association between cof-
fee consumption and the risk of stroke in women and in men was assessed. Larsson
and Orsini [272] found that hazard ratios were similar for women and men at lower
coffee intake (≤2 cups per day). These results are consistent with those obtained by
Lopez-Garcia et al. [261] in the cohort study of women, in which they indicated that long-
term coffee drinking was not associated with an increased risk of stroke in women. Fur-
thermore, coffee intake may modestly decrease hazard ratio of stroke in that sex. In this
research, women who drank moderate to high amounts of coffee had a lower risk of stroke
than women who consumed <1 cup/month coffee (relative risks of stroke: 0.98, 0.88, 0.81,
and 0.80 for women drinking 1–16 cup/month, 20–28 cups/month, 60–90 cups/month and
≥120 cups/month, respectively) [261]. As for men, when coffee drinkers were compared
to non-coffee drinkers, the stroke risk ratio for those drinking 1–6 cups per week, 1–2 cups
per day, and ≥3 cups per day were estimated at 0.78, 0.67, and 0.45, respectively [264]. To
explain the likely causal association and elucidate the mechanisms underlying caffeine’s
protective effects on stroke, further studies are required.
Both clinical and preclinical studies have shown a beneficial effect of the combination
of caffeine and alcohol (caffeinol) in acute ischemic stroke. Strong et al. [273] indicated that
co-administration of a low dose of ethanol and caffeine protects the CNS from damage
produced by focal ischemia in rats. Moreover, caffeine at a dose of 6 mg/kg with ethanol at
a dose of 0.2 g/kg in the caffeinol were effective in decreasing volume of cortical infarct and
behavioral dysfunction after reversible common carotid/middle cerebral artery occlusion
in rat [274]. Beneficial therapeutic effects as well as safety and tolerability of caffeinol
observed in animal studies were later examined and confirmed in clinical research [275,276].
Zhao et al. [277] based on in vivo studies results suggested that observed anti-excitotoxic
activity may be the possible anti-ischemic effect of caffeinol, and caffeine can augment
anti-ischemic properties of the NMDA receptors antagonists [277].
Int. J. Mol. Sci. 2021, 22, 107 18 of 64

Table 3. Summary of in vivo studies on the neuroprotective effects of caffeine.

Animals Treatment Model Behavioral Tests Main Outcomes Ref.

Open-field test, balance beam (1) Improvement of cognitive task of spatial
test, string-suspension, learning/reference memory, working
0.3 mg/mL caffeinated water
APPsw transgenic mice Y-maze test, elevated memory, and recognition/identification, (2)
beginning at 4 months of age for Genetic model of
(background C57, B6, SJL plus-maze test, Morris water decrease in Aβ production due to reduced [194]
4 months (daily dose of 1.5 mg Alzheimer’s disease
and Swiss-Webster mice) maze test, circular platform expression of presenilin 1 and β-secretase,
caffeine to each mouse)
test, platform recognition test, (3) restored adenosine levels in the brain to
radial arm water maze test normal
(1) Improvement of superior working
Open-field test, balance beam
memory, (2) reduced Aβ deposition in the
test, string-suspension,
0.3 mg/mL caffeinated water hippocampus and entorhinal cortex, (3)
APPsw transgenic mice Y-maze test, elevated
beginning at 18–19 months of age Genetic model of decrease in brain soluble Aβ levels, (4) aged
(background C57, B6, SJL plus-maze test, Morris water [195]
for 4–5 weeks (daily dose of 1.5 mg Alzheimer’s disease APPsw mice exhibited memory restoration
and Swiss-Webster mice) maze test, circular platform
caffeine to each mouse) and reversal of AD pathology, (5) caffeine
test, platform recognition test,
suppression of β-secretase involves the
radial arm water maze test
cRaf-1/NFκB pathway
Albino rats (Morini, Wistar 15, 45, and 80 mg/kg/day (s.c.) for
– Staircase test No effect on memory retention [192]
derived strain) 15 days
(1) Aged mice exhibited lower performance
in the recognition memory compared with
adults, (2) caffeine-treated mice showed
similar performance to adult mice in the
CF1 mice 1 mg/mL for 12 months – Object recognition test object recognition test and an improvement [193]
compared with their age-matched control
mice, (3) caffeine counteracted the
age-related increase in BDNF and TrkB
immunocontent
chronic (12 days) treatment with
caffeine (1 mg/mL, p.o.); (1) Chronic and subchronic treatment with
subchronic (4 days) treatment with caffeine prevent Aβ-induced cognitive
Aβ25–35 -induced Inhibitory avoidance test,
CF1 mice caffeine (30 mg/kg, i.p.); acute impairment, (2) A2A receptors are engaged [197]
neurotoxicity Y-maze test
caffeine treatment (30 or 80 mg/kg, in the control of Aβ-induced cognitive
i.p.) 30 min treatment before Aβ dysfunction
administration
Int. J. Mol. Sci. 2021, 22, 107 19 of 64

Table 3. Cont.

Animals Treatment Model Behavioral Tests Main Outcomes Ref.

(1) Reversed age-related memory deficit, (2)
normalized oxygen and NRS levels
increased in brains of aged rats, (3)
Novel object recognition
Wistar rats 30 mg/kg (p.o.) daily per 10 days Aging normalized Na+ /K+ -ATPase activity [199]
memory test, open field test
inhibited in brains of aged rats, (4) A2A
receptors affect the impact and formation of
free radicals in neuronal preparations
(1) Attenuated memory impairment; (2)
reduced oxidative stress via the reduction of
8-oxoguanine; (3) suppressed stress kinases
p-JNK; (4) reduced D-galactose-induced
D -Galactose induced
Sprague-Dawley rats 3 mg/kg/day (i.p.) for 60 days Y-maze test neuroinflammation through alleviation of [191]
neurodegeneration
COX-2, NOS-2, TNFα, and IL-1β; (5)
reduced cytochrome C, Bax/Bcl2 ratio,
caspase-9, caspase-3, and PARP-1 levels; (6)
prevented neurodegeneration
(1) Prevented development of spatial
0.3 mg/mL caffeinated water memory impairments, (2) reduced tau
THY-Tau22 male mice beginning at 2 months until Genetic model of phosphorylation and proteolytic fragments,
Morris water maze test [200]
(C57Bl6/J background) 12 months of age (daily dose of Alzheimer’s disease (3) modulated hippocampal
1.5 mg caffeine to each mouse) neuroinflammatory and oxidative stress
markers
Chronic caffeine treatment (1) induced
ventriculomegaly, (2) increased production
0.3 or 0.6 mg/mL caffeinated water
Sprague-Dawley rats – – of CSF, which were associated with the [202]
for 3 weeks or just once
enhancement of the expression of
Na+ /K+ -ATPase and increased CBF
Int. J. Mol. Sci. 2021, 22, 107 20 of 64

Table 3. Cont.

Animals Treatment Model Behavioral Tests Main Outcomes Ref.

(1) Decreased cholesterol-enriched
diet-induced increase in Aβ production and
accumulation, (2) reduced
cholesterol-induced increase in tau
phosphorylation, (3) attenuated
0.5 mg/day or 30 mg/day in the 2% cholesterol-enriched
New Zealand white rabbits – cholesterol-induced increase in ROS and [201]
drinking water for 12 weeks diet
8-Iso-PGF2α levels, (4) reduced glutathione
depletion, (5) protection against
cholesterol-induced endoplasmic reticulum
stress, (6) reversed cholesterol-induced
decrease in A1 receptor levels
chronically (twice weekly for
8 weeks) caffeine 5 mg/kg or Chronic dual-pesticide
Horizontal locomotor activity Caffeine at 20 mg/kg reduced TH+ neuron
C57BL/6NCrl mice 20 mg/kg (i.p.), followed 10 min exposure model of [212]
test loss
later 10 mg/kg PQ first and Parkinson’s disease
30 mg/kg MB second
20 mg/kg (i.p.) 1 h before surgery
and twice a day (10 mg/kg, i.p.)
for 1 month; apomorphine Caffeine (1) reduced apomorphine-induced
hydrochloride (0.5 mg/kg, i.p.) 6-OHDA-induced Apomorphine-induced rotations in a 6-OHDA toxicity model, (2)
Wistar rats [211]
1 week before (baseline) and neurotoxicity rotation tests protected the neurons of substantia nigra
4 weeks after the surgery with pars compacta against 6-OHDA toxicity
1-day interval after the last caffeine
injection
Caffeine (1) reduced apomorphine-induced
rotations in a 6-OHDA toxicity model, (2)
10 and 20 mg/kg (i.p.) daily for 6-OHDA-induced Apomorphine-induced
Wistar rats reversed decreased noradrenaline and [210]
14 days neurotoxicity rotation tests
dopamine levels caused by 6-OHDA
unilateral intrastriatal injection
Int. J. Mol. Sci. 2021, 22, 107 21 of 64

Table 3. Cont.

Animals Treatment Model Behavioral Tests Main Outcomes Ref.

Caffeine (1) partially protected
MPTP-induced neurodegenerative changes,
MPTP-induced (2) modulated MPTP-mediated alterations in
Swiss Albino mice 20 mg/kg (i.p.) for 8 weeks – [207]
neurotoxicity the expression and catalytic activity of
CYP1A2, expression of adenosine A2A
receptor and DAT
Caffeine induced learning and memory
improvement, what was independent of the
0.1, 0.3, or 1.0 mg/kg (i.p.) 45 min MPTP-induced Two-way active avoidance
Wistar rats locomotor stimulant effect; observed effects [206]
before the training session neurotoxicity test
may be realized via
dopamine/adenosine-receptor interaction
Caffeine (1) protected against loss of
dopaminergic neuron in striatum, (2)
attenuated gliosis, (3) blocked leakage of the
MPTP-induced
FVB mice 10 mg/kg/day (i.p.) for 2 weeks – blood–brain barrier in striatum, (3) blocked [205]
neurotoxicity
decreases in levels of striatal tight junction
proteins, (4) blocked increases in MMP9
activity
Caffeine protected against (1) the reduction
MPTP-induced of paw grip strength, (2) perturbation in the
C57BL6 mice 30 mg/kg (i.p.) for 8 days Paw grip strength test [204]
neurotoxicity homeostasis of neurometabolites in the
striatum and olfactory bulb
Caffeine (1) produced a dose-dependent
attenuation of MPTP-induced striatal
dopamine loss in both young and retired
breeder male, but not female, mice; (2) was
less potent or altogether ineffective in female
MPTP-induced mice as a neuroprotectant after sham
C57BL6 mice 10, 20, 40 mg/kg (i.p.) – [208]
neurotoxicity surgery compared to ovariectomy or after
ovariectomy plus estrogen replacement
compared to ovariectomy plus placebo
treatment; (3) protection against dopamine
loss in young male mice was blocked by
estrogen administration
Int. J. Mol. Sci. 2021, 22, 107 22 of 64

Table 3. Cont.

Animals Treatment Model Behavioral Tests Main Outcomes Ref.

Caffeine (1) pre-treatment attenuated
MPTP-induced striatal dopamine depletion
when it was given 10 min, 30 min, 1 h, or 2 h
but not 6 h before MPTP treatment; (2)
MPTP-induced
C57BL6 mice 30 mg/kg (i.p.) – post-treatment attenuated striatal dopamine [209]
neurotoxicity
loss when it was given 10 min, 30 min, 1 h or
2 h but not 4 h, 8 h or 24 h after MPTP
injection; (3) metabolites also provide
neuroprotective effect
Caffeine treatment (1) initiated
simultaneously or during the course of
ongoing neurodegeneration reduces loss of
nigral dopaminergic neurons, (2) did not
MPTP-induced
Sprague–Dawley rats 1 g/l in drinking water – modify MPTP-induced decreases in striatal [213]
neurotoxicity
dopamine or tyrosine hydroxylase, (3)
attenuated microglia activation in the
substantia nigra but not in the striatum of
MPTP-treated rats
Caffeine treatment (1) blocked partially
decreased locomotor activity and a high
number of apomorphine-induced rotations,
(2) increased dopamine contents and
Open field test, reversed the decrease dopamine level in the
10 or 20 mg/kg/day in the 6-OHDA-induced
Wistar rats apomorphine-induced striatum, (3) improved the hippocampal [214]
drinking water neurotoxicity
rotation tests neuronal viability, (4) increased TH+ in the
striatum, (5) decreased the number of
immunopositive cells for histone deacetylase
and pro-inflammatory cytokines TNF-α and
IL-1β in the 6-OHDA-lesioned group
Int. J. Mol. Sci. 2021, 22, 107 23 of 64

Table 3. Cont.

Animals Treatment Model Behavioral Tests Main Outcomes Ref.

Caffeine treatment (1) reduced the degree of
ischemic necrosis of pyramidal cells of the
CA1 hippocampal area after 5 min of
0.1% caffeine drinking solution for bilateral carotid occlusion, (2) induced
Mongolian gerbils Ischemia model – [224]
4 weeks upregulation of A1 adenosine receptors in
the CNS, what probably impaired the level
of experimentally induced ischemic brain
injury
Caffeine treatment (1) attenuated deficits on
10 mg/kg (i.p.) immediately Water escape test, Morris the Morris water maze test observed in HI
Wistar rat pups HI neonatal model [228]
following HI induction water maze test animals, (2) might be a potential therapeutic
agent in reducing ischemic brain injury
10 mg/kg/day (i.p.) immediately Caffeine treatment (1) reduced neuronal
Wistar rat pups before HI and at 0, 24, 48 and 72 h HI neonatal model – apoptosis in the developing brain, (2) might [229]
post hypoxia be effective in reducing ischemic brain injury
Caffeine treatment (1) significantly
10 mg/kg (i.p.) immediately after Rota rod test, silent gap improved some behavioral outcomes in rat
Wistar rat pups the 120 min of HI and 24 h HI neonatal model detection, non-spatial water with a neonatal HI brain injury induced on [230]
following the initial injection maze test postnatal day 6 and (2) partially rescued
neuropathology
10 mg/kg (i.v.) 30 min prior to the Acute caffeine treatment (1) accelerated
induction of ischemia (acute changes in the magnetic resonance images
treatment) 20 mg/kg (p.o.) three with increased hippocampal intensity
times daily per dose for the appearing at 24 h post-ischemia, but (2)
Reversible forebrain
Sprague-Dawley rat first week and 30 mg/kg (p.o.) – caused no changes in the extent of neuronal [227]
ischemia model
three times daily for the second injury in any brain region compared to
and third weeks; caffeine was control-ischemic rats; (3) chronic caffeine
withdrawn 24 h prior to ischemia. treatment caused significantly less neuronal
(chronic treatment) injury
Int. J. Mol. Sci. 2021, 22, 107 24 of 64

Table 3. Cont.

Animals Treatment Model Behavioral Tests Main Outcomes Ref.

Caffeine plus ethanol treatment (1) almost
entirely eliminated the ischemic injury, (2)
10 mg/kg of caffeine and 5% or
Carotid/middle cerebral initiated at 30-, 60-, 90-, and 120-min
10% ethanol (0.325 or 0.65 g/kg,
Long-Evans rats artery occlusion model of – post-ischemia significantly reduced the [273]
respectively) acute or chronic
ischemia infarct volume; (3) for 3 weeks prior to
(3 weeks) (p.o.)
ischemia eliminates the neuroprotection
seen after acute treatment
Caffeinol (0.2 g/kg of ethanol and 6 mg/kg
Sensorimotor tests:
2.5 h infusion at doses ranging Carotid/middle cerebral of caffeine) treatment (1) reduced cortical
measurement of forelimb
Long-Evans rats from 2 to 10 mg/kg for caffeine and artery occlusion model of infarct volume and (2) decreased behavioral [274]
placing and foot-fault
from 0.2 to 0.65 g/kg for ethanol ischemia dysfunction after transient carotid/middle
asymmetry
cerebral artery occlusion
Sensorimotor tests: Caffeinol treatment reduced size of
10 mg/kg caffeine and/or ethanol Carotid/middle cerebral
measurement of forelimb excitotoxic lesion and caffeine may
Sprague–Dawley rats 0.32 g/kg infusion via the left artery occlusion model of [277]
placing and foot-fault augmented the anti-ischemic effect of
femoral vein ischemia
asymmetry, postural reflex NMDA receptor blockers
Int. J. Mol. Sci. 2021, 22, 107 25 of 64

Although caffeine is a widely used psychoactive substance around the world, its
potential therapeutic value has only recently been seriously explored in Alzheimer’s
disease, dementia, Parkinson’s disease as well as other cognitive impairments. Animal and
human studies showed significantly positive effects of caffeine intake with dose-dependent
improvement.

4.2. Neuroprotective Effects of Chlorogenic Acid

Chlorogenic acid is a polyphenol that can be found in fruit, vegetables, spices, olive
oil, wine, tea, and especially in coffee. Both caffeinated and decaffeinated coffee contains
a large amount of chlorogenic acid (70–350 mg per cup of coffee), which makes it one of
the most abundant polyphenols in a diet of coffee-consuming populations [278]. Due to a
wide distribution in the human diet, chlorogenic acid has gained much research attention.
Numerous studies have shown that it exerts multiple health-beneficial effects such as anti-
inflammatory, hepatoprotective, cardioprotective, chemopreventive, antidiabetic, and anti-
obesity activities. There is also mounting evidence that chlorogenic acid has neuroprotective
properties and it appears that its regular intake may reduce risk of neurodegenerative
diseases and improve cognition [73,278,279].
Preclinical studies. The neuroprotective effects of chlorogenic acid are linked mainly
with its ability to reduce oxidative stress. Like other polyphenols, it has free radical scaveng-
ing activity and metal-chelating properties [280], and there is considerable in vitro evidence
demonstrating protective effects of chlorogenic acid against neuronal damage caused by
oxidative stress. For instance, Cho et al. [281] showed that chlorogenic acid suppressed
the H2 O2 -induced PC12 cell death. The protective effect was related to the attenuation
of intracellular ROS accumulation and the inhibition of JNK and p38 MAPK activation.
In the study by Kim et al. [282], chlorogenic acid reduced apoptosis in primary cortical
neurons by inhibiting the H2 O2 -induced downregulation of anti-apoptotic proteins Bcl-2
and Bcl-XL as well as by blocking the H2 O2 -induced pro-apoptotic cleavage of caspase-3
and pro-poly(ADP-ribose) polymerase (pro-PARP). In addition, it increased the expression
of the antioxidant enzyme–NAD(P)H quinone oxidoreductase (NQO-1). In this study, it
was also demonstrated that the neuroprotective effects of caffeinated and decaffeinated
coffee were similar, which suggests that other compounds than caffeine (e.g., chlorogenic
acids) may be responsible for the neuroprotective properties of coffee [282]. Similar results
were obtained by Chu et al. [283] who reported that green and roasted coffees (regular
and decaffeinated) protected primary neuronal cells against the H2 O2 -induced oxida-
tive damage and improved their survival by inhibiting the extracellular signal-regulated
kinase-1 and -2 (ERK1/2) activation. Of note, there was a significant correlation between
chlorogenic acid content and the neuroprotective efficacy of the tested samples [283]. In
other studies, chlorogenic acid attenuated the H2 O2 -induced neurotoxicity, scavenged
hydroxyl radical, decreased ROS production in neuro-2A cells [284], and attenuated the
H2 O2 -induced increases in malondialdehyde (MDA) and ROS levels in rat brain slices [285].
A protective effect against the H2 O2 -mediated oxidative insult was also reported in rat
pheochromocytoma cells. In this study, chlorogenic acid provided neuroprotection via
directly neutralizing free radicals and indirectly inducing the endogenous antioxidant
enzymes by activation of nuclear factor erythroid 2–related factor 2 (Nrf2) [286]. Similarly,
chlorogenic acid protected against the aluminum-induced cytotoxicity in primary hip-
pocampal neuronal cells by decreasing ROS production and by increasing the expression
of Nrf2 and its target phase 2 enzymes [287].
The antioxidant properties of chlorogenic acid also contributed to its neuroprotective
effects against the L-buthionine-(S,R)-sulfoximine-induced damage in cultured retinal gan-
glion cells [288], methylmercury-induced apoptosis in PC12 cells [289], and FeSO4 -evoked
oxidative stress in rat whole brain homogenates [290]. Furthermore, chlorogenic acid
protected cultured cerebellar granule neurons from death induced by sodium nitroprusside
(SNP)—a NO donor [291] and reduced the SNP-induced increase in MDA content in rat
brain homogenates [290]. It also decreased NO level in cerebral neurons exposed to SNP,
Int. J. Mol. Sci. 2021, 22, 107 26 of 64

suggesting that its protective effects against the NO-induced neurotoxicity is likely due to
direct free radical scavenging activity [291].
It is widely known that chronic neuroinflammation is closely associated with the
pathogenesis of neurodegenerative diseases. Chlorogenic acid was found to reduce neu-
roinflammation and neurotoxicity in SH-SY5Y cells caused by toxic factors released from
activated microglia and astrocytes. Moreover, it decreased production of pro-inflammatory
cytokines (TNFα and IL-6) from lipopolysaccharide (LPS)/interferon-γ-stimulated mi-
croglia and THP-1 cells, as well as from interferon γ-stimulated astrocytes and U373
cells [292].
Chlorogenic acid was also reported to protect neurons from excitotoxic insults. These
are important observations as the glutamate-mediated neurotoxicity is considered to play
a crucial role in several neurodegenerative conditions, especially in Alzheimer’s disease,
Parkinson’s disease, ischemic stroke, and epilepsy [293]. Oboh et al. [290] showed that it
significantly reduced lipid peroxidation in quinolinic acid-treated rat brain homogenates.
Quinolinic acid acts through the NMDA subtype of glutamate receptors, and it evokes
glutamate-type excitotoxicity [294]. In further studies, chlorogenic acid protected pri-
mary cortical neurons from glutamate-induced injury. Importantly, glutamate-induced
excitotoxic insult causes an elevation in the concentration of cytosolic Ca2+ and chloro-
genic acid attenuated the increase in the intracellular Ca2+ level [295,296]. In the study
by Rebai et al. [296], the neuroprotective effect of chlorogenic acid was mediated by sup-
pressing the accumulation of ROS, restoring the mitochondrial membrane potential, and
increasing superoxide dismutase (SOD) activity. Chlorogenic acid also reduced apoptosis
by suppressing activation of pro-caspases (i.e., caspase 1, 8, and 9) and calpain. Moreover,
it has been proposed that the protein kinase C signaling pathways may be involved in
the protective effect of chlorogenic against glutamate-induced neurotoxicity [296]. In an-
other study, chlorogenic acid prevented the AMPA-mediated excitotoxicity in optic nerve
oligodendrocytes by inhibiting ROS formation and activation of the antioxidant enzymatic
system through the protein kinase C-dependent pathway as well as by the anti-apoptotic
caspase and calpain-dependent targets [297].
Several studies focused on the protective effects of chlorogenic acid against the neuro-
toxicity caused by exposure to Aβ peptide. For example, it displayed significant protective
effects towards Aβ25–35 -induced neuronal damage in PC12 cells as well as in neuroblastoma
SH-SY5Y cells [298,299]. In addition, chlorogenic acid suppressed the Aβ1–42 self-induced
aggregation in PC12 cells [300]. It was also a potent inhibitor of Aβ1–40 fibrillization in
the ThT assay but it did not inhibit the oligomerization of Aβ1–42 , which suggests that its
interaction with monomeric/oligomeric Aβ proteins differs from the interaction with larger
Aβ aggregates [301]. Importantly, chlorogenic acid significantly inhibited Aβ25–35 -induced
autophagy in SH-SY5Y cells by modulating lysosomal function. In the same study, it
elevated protein levels of p-mTOR, p-p70s6k and nuclear transcription factor EB (TFEB)
indicating that it may enhance the autophagic flux in Aβ25-35 -treated SH-SY5Y cells via the
regulation of the mTOR/TFEB signaling pathway [299].
The cholinergic deficit in Alzheimer’s disease is a well-known phenomenon, and
the restoration of cholinergic function by inhibiting the (acetylcholinesterase) AChE and
butyrylcholinesterase (BChE) activity is an effective treatment strategy for Alzheimer’s
disease. Given that chlorogenic acid has emerged as a promising neuroprotective agent,
its ability to inhibit AChE and BChE activity has also been evaluated. In in vitro stud-
ies, it significantly inhibited AChE activity in mouse brain homogenates [302] and in
primary hippocampal neuronal cells [287] as well as both AChE and BChE activities in
rat brain homogenates [290]. Its inhibitory activity towards AChE and BChE was also
demonstrated by using the spectrophotometric Ellman assay [303,304]. Importantly, the
anti-AChE [302,304] and anti-BChE [304] activity of chlorogenic was also confirmed in
in vivo models of scopolamine-induced amnesia in mice.
In in vitro model of Parkinson’s disease, the impaired viability and enhanced apop-
tosis of 6-OHDA-damaged SH-SY5Y cells were significantly attenuated by chlorogenic
Int. J. Mol. Sci. 2021, 22, 107 27 of 64

acid pretreatment [305,306]. Chlorogenic acid also suppressed the 6-OHDA-induced ROS
production and endoplasmic reticulum (ER) stress in SH-SY5Y cells [305]. Its protec-
tive effects against the 6-OHDA-induced toxicity were also reported in the mouse nerve
growth factor (mNGF)-differentiated PC12 cells. It prevented cell damage by reducing
the 6-OHDA-induced increase in intracellular Ca2+ level, suppressing ROS production
and inhibiting caspase 3 and 9 activities [307]. Additionally, chlorogenic acid produced
a cytoprotective effect against α-synuclein-induced toxicity in catecholaminergic PC12
cells [308] and inhibited α-synuclein fibril assembly [309].
In vivo preclinical studies also provide substantial evidence on the neuroprotective
effects of chlorogenic acid. For instance, Vardi et al. [310] demonstrated that chlorogenic
acid protected the rat brain cerebellum from oxidative damage induced by methotrexate—a
chemotherapeutic agent with severe neurotoxic effects. A 24-day treatment with chloro-
genic acid significantly reduced Purkinje cell injury, prevented the methotrexate-induced
increase in MDA level as well as decrease in SOD and catalase activity, and reduced glu-
tathione (GSH) content in the cerebellum. In rats with cadmium-induced oxidative brain
damage, chlorogenic acid inhibited lipid peroxidation, augmented the antioxidant defense
system, and prevented mitochondrial dysfunction and DNA fragmentation [311]. The
antioxidant activity of chlorogenic acid also contributed to its protective effect against
scopolamine-induced amnesia in mice [302,304]. Acute administration of chlorogenic
acid significantly attenuated learning and short-term and long-term memory impairments
caused by scopolamine injection in mice. The effect was accompanied by decreased MDA
level and increased AChE activity in the hippocampus and frontal cortex [302]. Likewise,
repeated administration of chlorogenic acid attenuated the scopolamine-induced learning
and memory decline. It also decreased AChE and BChE activities as well as free radical
production in the cortex and hippocampus of scopolamine-treated mice [304]. An inter-
esting observation was made by Guo and Li [312] who reported the protective effect of
chlorogenic acid against alcohol-induced brain damage in neonatal rats. Treatment with
chlorogenic acid attenuated the altered cognitive function in ethanol-exposed pups. In the
cerebral cortex and hippocampus, it decreased AChE and caspase-3 activity, reduced MDA
and nitrite levels, increased SOD and catalase activity, reduced TNF-α and IL-1β levels,
and decreased the level of transcription factor p65 of NF-kB. Thus, the chlorogenic acid
protected neonatal rats from ethanol-induced brain damage by decreasing oxidative stress,
inflammation, and apoptosis of neuronal cells. In the study by Alarcón-Herrera et al. [313],
chlorogenic acid ameliorated the 3-nitropropionic acid-induced toxicity and genotoxicity
in mice suggesting its potential protective effect in Huntington’s disease.
Chlorogenic acid was also reported to ameliorate brain ischemia-induced injury in
rodents. In models of cerebral ischemia/reperfusion injury, it significantly reduced mortal-
ity [314], improved neurological deficit scores [314,315], attenuated sensory-motor func-
tional deficits [316], reduced infarct volume [314–317], suppressed CA1 pyramidal cell
loss [318–320], decreased brain edema [315–317], and attenuated blood–brain barrier (BBB)
damage [316,317]. Importantly, it was demonstrated that chlorogenic acid has a neuro-
protective effect against ischemia-induced cognitive deficits. It attenuated learning and
memory impairments in ischemic rats [315,319] and in Mongolian gerbils [320]. The protec-
tive effect of chlorogenic acid against ischemia-induced brain injury appears to be related
with its ability to reduce oxidative stress, neuroinflammation, and cell apoptosis. In rats
with cerebral ischemia/reperfusion injury, chlorogenic acid dose-dependently increased
the activity of SOD and GSH and suppressed ROS production, lactate dehydrogenase
(LDH) release, and MDA accumulation as well as promoted the expression of Nrf2, NQO-1
and heme oxygenase 1 (HO-1) [315]. Likewise, it reduced ROS production and increased
SOD2 expression in the CA1 hippocampal region of gerbils with transient global cerebral
ischemia [320]. Overexpression of SOD2 (but not SOD1) was also observed in ischemic rats
treated with chlorogenic acid [319]. Furthermore, chlorogenic acid suppressed the ischemia-
induced increase in pro-inflammatory cytokines, i.e., TNF-α [317,320] and IL-2 [320], as
well as overexpression of anti-inflammatory cytokines IL-4 and IL-13 [320]. It also down-
Int. J. Mol. Sci. 2021, 22, 107 28 of 64

regulated the expression of an apoptotic marker–caspase-3 [315,317] and increased the

expression of an anti-apoptotic protein–Bcl2 in ischemic animals [319]. Moreover, it pro-
moted BDNF [315] and NGF [314,315] expression in the brain of rats subjected to cerebral
ischemia/reperfusion. Interestingly, chlorogenic acid was shown to downregulate matrix
metalloproteinases (i.e., MMP-2 and MMP-9) mRNA and protein expression in the brain
of ischemic rats and to inhibit MMP-2 and MMP-9 activity in in vitro zymography assays.
Since extracellular matrix is involved in maintaining the integrity of the BBB and MMP-2
and MMP-9 degrade the extracellular matrix, it seems that the protective effect of chloro-
genic acid on BBB damage may result from its ability to reduce expression and activity of
MMP-2 and MMP-9 [316]. Interestingly, chlorogenic acid also increased the expression of
CD31 (an endothelial marker) and decreased the expression of endothelin-1 in rats with
global ischemia, which suggests that it may improve the vascular response by repairing
the ischemia-induced endothelial cell damage [319].
Only few studies aimed to evaluate the potential beneficial effects of chlorogenic
acid in animal models of Parkinson’s disease. Shan et al. [305] showed that chlorogenic
acid attenuated the 6-OHDA-induced Parkinson’s-like behavioral impairments in rats
and suppressed the 6-OHDA-induced decrease in striatal dopamine concentration. It also
prevented α-synuclein accumulation, increased SOD and glutathione peroxidase (GSH-Px)
activities, and restored Bcl-2/Bax expression in the striatum [305]. In rotenone-injected
mice, chlorogenic acid ameliorated degeneration of dopaminergic neurons in the substantia
nigra and upregulated the antioxidative molecules–metallothionein-1 and 2, in striatal
astrocytes [321]. In the study by Singh et al. [322], chlorogenic acid improved motor coordi-
nation and neurobehavioral activity in the MPTP-induced model of Parkinson’s disease
in mice. Of note, the behavioral effects were accompanied by reduced degeneration of
dopaminergic neurons in the substantia nigra. Moreover, chlorogenic acid improved mito-
chondrial function, suppressed ROS generation, increased SOD and mitochondrial GSH
activity, inhibited activation of proapoptotic proteins (Bax and caspase-3), and elevated
expression of the anti-apoptotic protein (Bcl2). Since it improved the phosphorylation state
of Akt, ERK1/2, and GSK3β, it appears that the neuroprotective effects of chlorogenic
acid against MPTP-induced neurotoxicity are mediated, at least in part, by the GSK3β
phosphorylation-associated Akt/ERK pathway [322]. It is also worth noticing that chloro-
genic acid attenuated the extensive release of release of TNF-α and IL-1β in the substantia
nigra of the LPS-injected mice suggesting that this compound may suppress inflammatory
response or damage in neurodegenerative diseases including Parkinson’s disease [323].
Two in vivo studies focused on neuroprotective effects of chlorogenic acid against
excitotoxicity. In the kainic acid-induced neurotoxicity model in mice, repeated admin-
istration of chlorogenic alleviated learning and memory impairments and protected the
nNOS-positive neurons in the hippocampal CA1-4 regions from kainic acid-induced in-
jury [324]. Chlorogenic acid also attenuated neuronal loss in the hippocampal CA1 region
and produced an anticonvulsant-like effect in the pilocarpine-induced seizure model in
mice. In pilocarpine-injected mice, it restored glutamate and gamma-aminobutyric acid
(GABA) levels, and decreased NMDA, mGluR1, and mGluR5 receptors expression, which
could contribute to the anticonvulsant and neuroprotective effect. Chlorogenic acid also
protected from the pilocarpine-induced oxidative stress [325].
Recently, chlorogenic acid has been reported to produce beneficial effects in the
APP/PS2 transgenic mice [299]. These double transgenic mice overexpress mutant forms
of human APP and human PS2. The APP/PS2 mice display Alzheimer’s-like impairments,
e.g., cognitive dysfunction, amyloidosis, inflammation, and impaired synaptic plastic-
ity [326]. Prolonged (180 days) treatment with chlorogenic acid significantly improved
spatial memory, decreased neuronal damage in the hippocampus, and suppressed the
excessive autophagy in the APP/PS2 mice. It was suggested that neuroprotective effect
was likely related with modulation of the mTOR/TFEB signaling pathway [299]. It is
noteworthy that cognitive dysfunctions in APP/PS2 mice were also prevented by chronic
Int. J. Mol. Sci. 2021, 22, 107 29 of 64

treatment with coffee polyphenols (including chlorogenic acid). The polyphenols also
reduced Aβ plaque deposition in the hippocampus [326].
Summary of in vivo studies on the neuroprotective effects of chlorogenic acid is
introduced in Table 4.
Clinical studies. While numerous preclinical in vitro and in vivo experiments have
been designed to evaluate the neuroprotective effects of chlorogenic acid, only few studies
on this matter have been performed in human subjects. Cropley et al. [327] investigated
the acute effects of caffeinated coffee, decaffeinated coffee with regular chlorogenic acid
content (224 mg), and decaffeinated coffee with higher chlorogenic acid content (521 mg/kg)
on cognitive processes and mood in a randomized, double-blind, crossover study with
39 healthy older volunteers. Compared to regular decaffeinated coffee, the chlorogenic
acid-rich coffee produced positive effects on mood and mood-related processes. Specifically,
it increased alertness, decreased mental fatigue, and alleviated headaches. However, it did
not produce substantial pro-cognitive effects. In another randomized placebo-controlled
trial, 60 healthy older participants received 6 g of a decaffeinated green coffee blend or
540 mg pure chlorogenic acids or placebo. Cognitive measures were made at 40 and
120 min post-intake. Pure chlorogenic acid did not produce any significant improvement
in cognition function when compared to placebo. On the contrary, there was a trend
towards chlorogenic acid consumption being associated with slower reaction time and
slower information processing speed in comparison to placebo. Decaffeinated green
coffee blend improved sustained attention, decision time, and alertness. In addition, both
pure chlorogenic acid and the decaffeinated green coffee blend significantly improved
symptoms of headache [328]. Despite the lack of significant pro-cognitive effects after
single administration [327,328], chlorogenic acid was reported to increase cognitive function
following regular prolonged intake [329,330]. Saitou et al. [330] investigated the effects of a
16-week intake of chlorogenic acid-added beverage or placebo on cognitive functions in
38 healthy volunteers (aged 50–69 years) with subjective memory complaints. The obtained
results showed that chlorogenic acid improves some cognitive functions (i.e., motor speed,
executive function, psychomotor speed, and attention shifting) suggesting that its regular
intake may increase individuals’ ability to perform complex tasks by improving both
motor activity and cognitive functions. Importantly, blood analysis showed increased
levels of apolipoprotein A1 and transthyretin, which are considered biomarkers for the
early-stage cognitive decline [330]. Similar effects were observed in the pilot study by
Kato et al. [331], who reported that a 6-month intake of chlorogenic acid (330 mg) improved
composite and verbal memory, cognitive flexibility, complex attention, executive function,
and motor speed in 8 participants with complaints of subjective memory loss. Moreover,
biochemical studies revealed decreased plasma Aβ42 and Aβ42 /Aβ40 levels and elevated
dehydroepiandrosterone sulfate level [331]. In a recent randomized controlled crossover
trial, the effect of prolonged chlorogenic acids intake on cognitive function in mild cognitive
impairment was investigated [329]. The study was performed on 34 individuals and
comprised two 12-week chlorogenic acids intake periods (553.6 mg of chlorogenic acids or
placebo twice daily) with a 4-week washout period between them. The cognitive function
tests showed that the continuous intake of chlorogenic acids improved cognitive functions
in patients with mild cognitive impairment, especially attention and executive function.
Taken together, clinical data on the neuroprotective properties of chlorogenic acid are
limited. However, some initial evidence suggests that its regular intake may have beneficial
effects on cognition function.
Int. J. Mol. Sci. 2021, 22, 107 30 of 64

Table 4. Summary of in vivo studies on the neuroprotective effects of chlorogenic acid.

Animals Treatment Model Behavioral Tests Main Outcomes Ref.

(1) Reduced Purkinje cell damage and the
Methotrexate-induced expression of apoptotic cells, (2) decreased
Wistar rats 100 mg/kg (i.p.) for 24 days cerebellar Purkinje cell – production of MDA and increase in SOD and [310]
damage catalase activity and GSH content in the
cerebellum
(1) Restored AChE, SOD, catalase, GSH-Px, and
GST activity; (2) restored GSH, vitamins C and
Cadmium-induced brain E, and lipid peroxidation level; (3) increased
Wistar rats 60 mg/kg (p.o.) for 30 days – [311]
damage membrane-bound ATPase activity; (4)
attenuated mitochondrial dysfunction and DNA
fragmentation
(1) Attenuation of the scopolamine-induced
Y-maze test, passive
3–9 mg/kg (p.o.) 30 min Scopolamine-induced learning and memory impairment, (2) decreased
ICR mice avoidance test, Morris water [302]
before scopolamine injection amnesia AChE activity and MDA level in the
maze test
hippocampus and frontal cortex.
(1) Attenuation of the scopolamine-induced
learning and memory impairments, (2)
1–10 mg/kg (p.o.) for 8 days Scopolamine-induced Y-maze test, novel object
Swiss Albino mice decreased AChE and BChE activities in the [304]
before scopolamine injection amnesia recognition test
cortex and hippocampus, (3) increased free
radical scavenging activity
(1) Attenuation of the altered cognitive function
in ethanol-exposed pups, decreased AChE and
100 and 200 mg/kg (p.o.) caspase-3 activity, (2) reduced MDA and nitrite
Alcohol-induced brain
Wistar rats (5 days old pups) from PD 6 to 28 (with Morris water maze test levels, (3) increased SOD and catalase activity, [312]
damage
ethanol) (4) decreased TNF-α and IL-1β levels, as well as
decreased level of p65 of NF-κB in the cerebral
cortex and hippocampus
3-Nitropropionic acid Reduction of the 3-nitropropionic acid induced
C57BL/6 mice 100 mg/kg (i.p.) for 5 days – [313]
induced neurotoxicity toxicity and genotoxicity
Int. J. Mol. Sci. 2021, 22, 107 31 of 64

Table 4. Cont.

Animals Treatment Model Behavioral Tests Main Outcomes Ref.

(1) Reduced mortality and improved
neurological deficit scores, (2) decreased
15–60 mg/kg (p.o.) for 7 days Focal cerebral cerebral infarction area, (3) reduced ICAM-1 and
Wistar rats Neurological deficit scoring [314]
before ischemia induction ischemia/reperfusion injury VCAM-1 levels, (4) increased erythropoietin and
HIF-1α levels, and (5) increased expression of
NGF in the brain
(1) Attenuation of the learning and memory
impairments; (2) improved neurological deficit
scores; (3) decreased cerebral infarction volume,
cerebral water content and cerebral index; (4)
20–500 mg/kg (p.o) for
Cerebral Neurological deficit scoring, promoted BDNF and NGF expression; (5)
Sprague-Dawley rats 7 days before ischemia [315]
ischemia/reperfusion injury step-down test, Y maze test increased SOD activity and GSH levels; (6)
induction
decreased production of ROS, LDH, and MDA;
(7) inhibited expression of caspase 3 and 9; and
(8) promoted Nrf2, NQO-1, and HO-1
expression
(1) Reduced sensory-motor functional deficits,
3–30 mg/kg (i.p.) twice at 0 h
Focal cerebral infarct volume, BBB damage, and brain edema
Sprague-Dawley rats and 2 h after ischemia Balance-beam test [316]
ischemia/reperfusion injury and (2) decreased lipid peroxidation and the
induction
expressions of matrix metalloproteinases
(1) Reduced cerebral infarction volume and BBB
damage; (2) restored the brain water content; (3)
10 mg/kg (i.n.) after 2 h of Global cerebral reduced calcium, nitrate, and glutamate levels
Charles foster albino rats – [317]
occlusion ischemia/reperfusion injury in the cortex, hippocampus, cerebellum, and
cerebrospinal fluid, and (4) decreased
expression of TNF-α, iNOS, and caspase-3
Enhanced neuroprotective activity of
100 µg/kg (i.p.) 60 min Transient cerebral
Mongolian gerbils – PEP-1-rpS3 against the ischemia-induced [318]
before injection of PEP-1-rpS3 ischemia/reperfusion injury
hippocampal damage
(1) Attenuation of the spatial memory
impairment; (2) decreased CA1 pyramidal cell
15–60 mg/kg (i.p.) 30 min Transient global
Wistar rats Morris water maze test loss; (3) increased Bcl-2, SOD2, and CD31 [319]
after ischemia induction ischemia/reperfusion injury
expressions; and (4) decreased endothelin-1
expression
Int. J. Mol. Sci. 2021, 22, 107 32 of 64

Table 4. Cont.

Animals Treatment Model Behavioral Tests Main Outcomes Ref.

(1) Attenuation of cognitive impairment; (2)
decreased CA1 pyramidal cell loss; (3) increased
7.5–30 mg/kg (i.p.) for 5 days Transient global cerebral 8 Arm radial maze test,
Mongolian gerbils SOD2 expression; (4) reduced production of [320]
before ischemia induction ischemia injury passive avoidance task
ROS, TNF-α, and IL-2 and elevated expression
of IL-4 and IL-13
(1) Reversed motor deficits, (2) attenuated
20–60 mg/kg (i.p.) 60 min Rotarod test, decrease in striatal dopamine concentration, (3)
6-OHDA-induced
Sprague-Dawley rats before 6-OHDA injection, for apomorphine-induced reduced α-synuclein accumulation, (4) [305]
neurotoxicity
7 days rotational test increased SOD and GSH-Px activities, and (5)
restored Bcl-2/Bax expression in the striatum
50 mg/kg (p.o.) for 1 week
before rotenone exposure, (1) Prevented degeneration of dopaminergic
Rotenone-induced
C57BL/6J mice and then 5 days/week during – neurons in the substantia nigra, (2) upregulated [321]
neurotoxicity
the 4 weeks of rotenone metallothionein-1 and 2 in striatal astrocytes
treatment
(1) Improved motor coordination and
neurobehavioral activity; (2) improved
mitochondria function; (3) reduced ROS
Rotarod test, generation; (4) increased SOD and
Swiss Albino mice 50 mg/kg (p.o.) for 24 days MPTP-induced neurotoxicity pole test, mitochondrial GSH activity; (5) inhibited [322]
traction test, catalepsy test activation of proapoptotic proteins (Bax and
caspase-3); (6) elevated expression of Bcl-2; (7)
improved phosphorylation state of Akt,
ERK1/2, and GSK3β
100 mg/kg (i.p.) for 7 days Attenuation of the LPS-induced IL-1β and
C57BL/6J mice LPS-induced neurotoxicity – [323]
before LPS injection TNF-α release in the substantia nigra
(1) Attenuation of learning and memory
1 ml (p.o.) twice daily for Kainic acid-induced impairment, (2) increased number of
Kunming mice Y maze test [324]
35 days neurotoxicity nNOS-positive neurons in the hippocampal
CA1–4 regions
Int. J. Mol. Sci. 2021, 22, 107 33 of 64

Table 4. Cont.

Animals Treatment Model Behavioral Tests Main Outcomes Ref.

(1) Anticonvulsant-like effect; (2) attenuated
neuronal loss in the hippocampal CA1 region;
(3) restored glutamate and GABA levels; (4)
5 mg/kg (p.o.) for 15 days,
Seizure assessment (duration decreased NMDA, mGluR1, and mGluR5
Swiss Albino mice last injection 30 min before Pilocarpine-induced seizures [325]
of clonic and tonic seizure) receptor expression; (5) decreased lipid
pilocarpine
peroxidation and nitrite content; (6) increased
SOD, catalase, and GSH activity; (7) restored
AChE and monoamine oxidase activity
(1) Improved spatial memory, (2) decreased
Genetic model of Alzheimer’s neuronal damage in the hippocampus, (3)
APP/PS2 transgenic mice 40 mg/kg (p.o.) for 180 days Morris water maze test [299]
disease inhibited autophagy, and (4) activation of the
mTOR/TFEB signaling pathway
Int. J. Mol. Sci. 2021, 22, 107 34 of 64

Taken together, emerging evidence, from both in vitro and in vivo studies, demon-
strates neuroprotective effects of chlorogenic acid. It protects neurons from a wide range
of stressors and cell death-inducing agents by ameliorating oxidative stress and neuroin-
flammation as well as by inhibiting apoptosis and autophagy. In addition, it possesses
anti-amyloidogenic effects and inhibits AChE activity. Several signaling pathways, many
of which are interdependent, have been proposed to be involved in the neuroprotective
effects of chlorogenic acid. No differences between neuroprotective effects of caffeinated
and decaffeinated coffee suggest that chlorogenic acid, the most abundant active coffee
compound, may significantly contribute to the beneficial effects of coffee on some neurode-
generative disease and cognitive decline. A few preliminary clinical trials [327,329–331]
showed that regular, but not acute, chlorogenic acid intake improves cognitive function
in humans. Therefore, large-scale longitudinal clinical studies are highly warranted to
provide more insight into the beneficial effects of chlorogenic acid in neurodegenerative
diseases. Further studies are also required to better characterize the pharmacokinetics and
metabolism of chlorogenic acid in humans and to identify its potential adverse effects.

4.3. Neuroprotective Effects of Caffeic Acid

Caffeic acid is produced by many plant species, not only by Coffea sp. Like many
other polyphenols, caffeic acid exerts potent antioxidant and free radical scavenging prop-
erties [332]. Its antioxidant activity appears to be greater than the antioxidant activity
of many other important coffee components including chlorogenic acid [333]. Moreover,
numerous studies showed that caffeic acid has anti-inflammatory, anti-mutagenic, an-
tibacterial, and anti-carcinogenic properties, which could be linked to its high antioxidant
activity [334,335]. There is also a growing body of evidence showing possible neuroprotec-
tive effects of caffeic acid. It is noteworthy that its naturally occurring derivative–caffeic
acid phenyl ester (CAPE) has also been extensively studied for neuroprotective properties.
Chemical versatility and modifiability of caffeic acid caused its phenylpropanoid scaffold to
become a commonly used template for the development of new derivatives with enhanced
pharmacokinetic properties, increased bioactivity, and better safety profile [336].
Preclinical studies. Numerous in vitro studies have demonstrated that caffeic acid
displays a broad-spectrum neuroprotective profile. Several reports showed that caffeic
acid is protective against the H2 O2 -induced oxidative stress. For example, it attenuated the
H2 O2 -induced cell injury in cultured cerebellar granule neurons [291], PC12 cells [337–339],
neuroblastoma SH-SY5Y cells [340], and rat cortical slices [285]. Caffeic acid also suppressed
intracellular ROS accumulation as well as the release of LDH from PC12 cells exposed to
H2 O2 [337,338]. Oboh et al. [290] reported that caffeic acid dose-dependently inhibited the
excessive MDA production in rat brain homogenates following incubation with another
pro-oxidant agents—FeSO4 and SNP (a NO donor). Its beneficial effects against the NO-
induced neurotoxicity were also reported by Taram et al. [291] who showed that caffeic
acid protects cerebellar granule neurons from the SNP-induced death. The effect was
accompanied by reduced NO production indicating that caffeic acid protects neurons
against nitrosative stress via free radical scavenging activity. In the same study, caffeic
acid provided significant protection against the glutamate/glycine-induced neurotoxicity,
which is in line with previous reports showing that this compound protects primary
cultures of rat cortical neurons from the excitoxicity induced by glutamate [296,341,342]. It
is noteworthy that the neuroprotective effect was mediated by inhibition of the glutamate-
induced intracellular Ca2+ influx and subsequent reduction in ROS formation [342]. Caffeic
acid also exhibited anti-apoptotic properties by suppressing the glutamate-induced caspase
activation [296]. Moreover, it ameliorated (via inhibiting 5-LOX activation) the NMDA-
induced early and delayed injuries in PC12 cells [343] and the quinolinic acid-induced
oxidative stress in rat brain homogenates [290] and rat striatal slices [344]. Interestingly,
caffeic acid also attenuated cerebellar granule neurons death induced by brefeldin A–an
ER stressor [291]. In contrast, it did not inhibit SH-SY5Y cell death induced by another
ER stressor—tunicamycin [345]. This could have been due to the fact that these two
Int. J. Mol. Sci. 2021, 22, 107 35 of 64

agents have distinct mechanisms of action. Brefeldin A inhibits transport between the
ER and Golgi apparatus, whereas tunicamycin suppresses protein glycosylation in the
Golgi apparatus [291,345]. Furthermore, caffeic acid displayed protective activity against
caspase-dependent intrinsic apoptosis in cerebellar granule neurons [291]. It seems that the
anti-apoptotic effect of caffeic acid may result from its ability to modulate the anti-apoptotic
and pro-survival pathways in neuronal cells. For instance, it upregulated anti-apoptotic
proteins (Bcl2 and Bcl-XL) and downregulated pro-apoptotic proteins (Bad, PARP, and
cleaved caspase 3) in mouse retinal ganglion cells subjected to the hypoxia-induced damage.
In HT22 mouse hippocampal cells, caffeic acid reduced the acrolein-induced neurotoxicity
by activation of the pro-survival Akt/GSK3β signaling pathway [346]. It is noteworthy that
it also protected cerebellar granule neurons from death evoked by PS-341—a proteasome
inhibitor. Inhibition of proteasome activity induces cell apoptosis by accumulation of
c-Jun and a pro-apoptotic Bim protein [291]. Since caffeic acid was shown to activate
the AKT signaling that promotes cellular survival via inhibition of Bim protein [346], it
seems that this compound confers neuroprotection against PS-341 by inhibition of the
pro-apoptotic Bim protein. Finally, caffeic acid ameliorated the levodopa-induced toxicity
in neuroblastoma SH-SY5Y cells [347] and the Aβ-induced neurotoxicity, by the inhibition
of calcium influx and tau phosphorylation, in PC12 cells [348].
Animal studies have provided further support for neuroprotective effects of caffeic
acid. Yang et al. [349] showed that repeated administration of caffeic acid protected mouse
brain from the aluminum-induced damage. It reversed the learning and memory impair-
ments caused by aluminum overload and antagonized the aluminum-induced increase
in brain MDA levels and decrease in the expression of choline acetyltransferase. It also
decreased overexpression of APP, Aβ, and 5-LOX. Likewise, caffeic acid improved the learn-
ing and memory deficits in the aluminum-treated rats and reduced the aluminum-induced
increase in AChE, catalase, and glutathione-S-transferase activity (GST) as well as GSH
and nitrate levels in the brain [350]. Similar results were obtained by Deshmukh et al. [351]
who reported that caffeic acid ameliorated the streptozotocin-induced neurocognitive
deficits. It improved non-spatial memory performance in the object recognition task and
spatial memory performance in the Morris water maze test. Moreover, it attenuated
streptozotocin-induced oxidative stress and produced dose dependent decrease in AChE
activity. Decreased brain AChE activity was also observed in the Aβ1–40 -induced neu-
rotoxicity in rats [352]. Interestingly, a 30-day treatment with caffeic acid improved the
learning and memory abilities in naïve rats and inhibited significantly the AChE activity
in the cerebral cortex and the striatum but increased the AChE activity in the hippocam-
pus, hypothalamus, and pons [353]. However, data from in vitro studies on the possible
anti-AChE activity of caffeic acid are inconsistent. Oboh et al. [290] reported that this
compound inhibited both the AChE and BChE activity in rat whole brain homogenates.
In other studies, caffeic acid exhibited AChE inhibitory effect in the cerebral cortex of rat
brain, whole brain without the cerebral cortex [354], and whole brain with the cerebral
cortex [350]. In contrast, Anwar et al. [353] reported that caffeic acid significantly increased
the AChE activity in the cerebral cortex, cerebellum, and hypothalamus, while in the
striatum, hippocampus, and pons, it did not alter the enzyme activity. This suggests that
caffeic acid may have the specific selectivity in relation to the AChE from different brain
regions [353].
Neurodegeneration is also a hallmark feature of epilepsy. There are only few reports
on the neuroprotective effects of caffeic acid in animal models of seizure and epilepsy. It
produced an anticonvulsant-like effect in the pilocarpine-induced seizure model in rats and
decreased hippocampal damage caused by seizures. Moreover, it decreased lipid peroxida-
tion level and nitrite content and increased SOD and catalase activity in the hippocampus
following seizures [355]. In addition, caffeic acid prevented the quinolinic acid-induced
behavioral alterations in rats [344,356] and restored the redox status in rat striatum by
increasing the levels of GSH and GSH/GSSG, reversing the rise in oxidized glutathione
level in quinolinic acid-treated animals [356], which add support to the neuroprotective
Int. J. Mol. Sci. 2021, 22, 107 36 of 64

properties of this coffee compound against the excitotoxic damage. In the kainic acid-
induced excitotoxicity model in rats, caffeic acid prolonged the latency to seizures and
reduced neuronal loss in the CA3 hippocampal field [357]. Further studies, however, did
not confirm the anticonvulsant-like properties of caffeic acid. It was not effective against
the pentylenetetrazole- and pilocarpine-induced seizures in mice [358] and did not produce
antiepileptogenic effect in the kindling model of epilepsy [359]. Nonetheless, caffeic acid
presented neuroprotective effect against the pilocarpine-induced genotoxic damage in
the mouse hippocampus [358]. It also showed neuroprotective action against DNA dam-
age and oxidative stress in the cerebral cortex caused by the pentylenetetrazole-induced
kindling in mice [359].
Several reports demonstrated that caffeic acid has protective effects on focal [360–363]
and global [364] cerebral ischemia/reperfusion injury in rodents. Caffeic acid signifi-
cantly reduced infarct volume and improved neurological deficit scores in mice [361] and
rats [362,363] after induction of focal cerebral ischemia. It also decreased cell damage in the
ischemic hippocampal CA1 region of Mongolian gerbils [360] and attenuated hippocampal
neurons injury induced by global cerebral ischemia-reperfusion in rats [364]. Moreover,
Pinheiro Fernandes et al. [361] showed that caffeic acid protects against ischemia-induced
cognitive impairments. It attenuated working, spatial, and long-term aversive memory
deficits in mice with focal cerebral ischemia. A beneficial effect of caffeic acid on cognitive
decline following ischemia was also reported by Liang et al. [364]. In rats with global
cerebral ischemia, it attenuated learning and memory deficits. There is evidence of mi-
croglia activation in ischemic stroke, and it appears that the neuroprotective effects of
caffeic acid against ischemic injury may result, at least in part, from its ability to attenuate
astrocyte proliferation and microglia activation. It was demonstrated that caffeic acid
inhibited astrocyte proliferation 14 days after focal cerebral ischemia in rats [363] and
decreased microglia activation and its protein level in ischemic gerbils [360]. The protec-
tive effects of caffeic acid in ischemia models may be also related to its ability to inhibit
5-LOX activity as it suppressed the production of leukotrienes (i.e., 5-LOX metabolites)
in the rat brain after focal ischemia induction [363] as well as in the PC12 cells exposed
to oxygen-glucose deprivation/reperfusion (OGD/OGD-R) insult—an in vitro model of
ischemia/reperfusion [362]. Furthermore, caffeic acid downregulated the 5-LOX mRNA
and protein overexpression in rats with global cerebral ischemia-reperfusion injury [364].
A declined expression of 5-LOX after caffeic acid treatment was also observed in rats with
focal cerebral ischemia [362]. In OGD/OGD-R PC12 cells, caffeic acid suppressed the
production of arachidonic acid by lipoxygenase metabolism, maintained the ultrastructure
and integrated function of mitochondria, decreased ROS generation, and finally protects
the cells from ischemia [362]. It is also worth mentioning that caffeic acid decreased caspase
3 immunoreactivity [361], reduced NF-κBp65 overexpression, decreased the brain MDA
level and increased SOD activity [364], which further suggests that it may also ameliorate
inflammation and oxidative stress following global cerebral ischemia-reperfusion injury.
Interestingly, caffeic acid was also shown to inhibit the reduction of synaptophysin expres-
sion after ischemic insult in mice. Of note, synaptophysin is a membrane-associated protein
that is an important marker of synaptogenesis, synaptic density, and neural development.
Its expression decreases following ischemia, which is correlated with memory deficits [361].
Caffeic acid attenuated the lesion and neuron loss after cryoinjury in mice, which
suggests its neuroprotective effect against traumatic brain injury. It inhibited astrocytes
activation and thereby attenuating their proliferation and glial scar formation in the late
phase of cryoinjury. Moreover, it inhibited the decrease in SOD activity and the increase
in MDA content in the brain after cryoinjury [365]. In an in vivo model of Alzheimer’s
disease, it ameliorated the Aβ1–40 -induced learning and memory impairment, increased
synaptophysin expression and weakened the cerebral damage in rats. The effect was
accompanied by inhibition of AChE activity, suppression of oxidative stress and reduced
inflammation [352].
Int. J. Mol. Sci. 2021, 22, 107 37 of 64

It was showed that caffeic acid may be also a preventive agent against the progression
of Parkinson’s disease. In vitro, caffeic acid provided protection against the 5-S-cysteinyl-
dopamine-induced neurotoxicity in mouse cortical neurons [366]. Li et al. [367] showed
that this compound protects against dopaminergic neurodegeneration in in vivo model. In
the LPS-treated rats, it attenuated the loss of nigral dopaminergic neurons and microglia
activation [367]. Next studies showed that caffeic acid reversed the paraquat-induced move-
ment impairment (i.e., climbing capability) in Drosophila melanogaster–a valid model of
Parkinson’s disease [368]. In the same model, caffeic acid reduced fly mortality, restored
mitochondrial activity, and attenuated the paraquat-induced oxidative stress [369]. More-
over, Tsai et al. [370] reported the neuroprotective effect of this compound in the MPTP
mouse model of Parkinson’s disease. It decreased the MPTP-caused inflammatory stress
by suppressing the production of inflammatory cytokines (i.e., IL-1β, IL-6, TNFα, IL-4
and IL-10), lowering the production of NO and prostaglandin E2, and the activity of total
NOS and COX-2. Caffeic acid intake also declined the expression of iNOS, nNOS, and
COX-2 as well as retained the expression and production of BDNF, GDNF, and tyrosine
hydroxylase in the striatum of the MPTP-treated mice. Although caffeic acid failed to affect
dopamine transporter expression, it restored dopamine, DOPAC and HVA levels [370]. In
rotenone-injected mice, chlorogenic acid attenuated degeneration of dopaminergic neu-
rons in the substantia nigra and increased the expression of metallothionein-1 and 2 in
striatal astrocytes [321]. In another study, caffeic acid produced neuroprotective effects
in the α-synuclein-induced models of Parkinson’s disease. α-Synuclein is a presynaptic
neuronal protein that is implicated in the pathophysiology of this disease. In SH-SY5Y
cells overexpressing A53T α-synuclein, caffeic acid alleviated the cell damage caused by
overexpression of A53T α-synuclein, suppressed the accumulation of A53T α-synuclein,
and induced the JNK/Bcl-2-mediated cell autophagy to degrade A53T α-synuclein. In
next experiments, caffeic acid administered for 8 weeks alleviated motor deficits, induced
autophagy, decreased the accumulation of A53T α-synuclein, and ameliorated the loss of
dopaminergic neurons in the substantia nigra of A53T transgenic mice (i.e., mice expressing
the human A53T mutant of α-synuclein) [371]. Recently, caffeic acid was also reported to
improve survival and motor performance in wild type Caenorhabditis elegans exposed to
dopaminergic toxin 6-OHDA, which was in line with data obtained from in vitro studies.
Specifically, caffeic acid prevented the loss of reductive capacity, cell damage, and the
oxidative damage induced by 6-OHDA in rat cortical slices. Additionally, similar neuro-
protective effects of caffeic acid were observed in both Caenorhabditis elegans and rat cortical
slices treated with FeSO4 and quinolinic acid. Based on further molecular studies, it was
concluded that caffeic acid confers neuroprotection against different toxic insults via the
Nrf2/ARE pathway in the mammalian cortical tissue and the orthologous skn-1 pathway
in the worms [372].
CAPE, a caffeic acid derivative, was also reported to exhibit neuroprotective effects
in numerous in vitro studies. For example, it prevented the glutamate-induced excitotoxi-
city by inhibiting phosphorylation of p38 and caspase-3 activation in cerebellar granule
neurons [373]. CAPE also protected T22 mouse hippocampal cells from acrolein-induced
neurodegeneration through modulating MAPKs and Akt/GSK3b signaling pathways [346].
Moreover, it was shown to be a potent inducer of HO-1 in astroglial cells and neurons [374].
Interestingly, inhibition of NF-kB by CAPE downregulated the release of pro-inflammatory
miRNAs from primary human neuronal–glial cells stressed with the brain tissue-derived
extracellular fluid from patients with Alzheimer’s disease [375]. In an animal model of
Alzheimer’s disease, CAPE decreased Aβ1–42 –induced neuronal apoptosis and neuroin-
flammation and improved learning and memory [376]. Furthermore, CAPE was effective
against the MPP+ - [377,378] and 6-OHDA-induced [379,380] neurotoxicity in vitro and at-
tenuated the dopaminergic neuronal loss induced by 6-OHDA in mice [381] and rats [382]
as well as by MPTP in mice [378], which makes it a potential therapeutic candidate for the
prevention and/or treatment of Parkinson’s disease. CAPE was also reported to produce
neuroprotective effects in animal models of ischemia. It reduced focal cerebral ischemia
Int. J. Mol. Sci. 2021, 22, 107 38 of 64

injury in both mice and rats possibly through its antioxidant and anti-inflammatory effects
and/or via the upregulation of NO production [383–385]. In addition, it inhibited apoptotic
cell death in ischemic rats by downregulating caspase 3 and upregulating anti-apoptotic
protein Bcl-xL [385]. CAPE also exhibited a preventive effect on early brain injury after
subarachnoid hemorrhage in rats [386]. In other studies, this compound reversed cognitive
impairment induced by streptozotocin [387], D-galactose [388], and cadmium [389].
Taken together, in vitro studies show that caffeic acid protects neurons from a wide
range of cell death-inducing agents. Moreover, data from animal studies (Table 5) indicate
that this compound may prevent neuronal damage/death caused by different stressors
suggesting that caffeic acid is a promising neuroprotective compound for the prevention
and treatment of neurodegenerative diseases. Unfortunately, there are no human interven-
tion studies or clinical trials on this matter. Nevertheless, based on the above-mentioned
reports, it appears that the neuroprotective properties of coffee may be largely attributed to
the presence of caffeic acid.

4.4. Neuroprotective Effects of Trigonelline

Trigonelline, the second most abundant alkaloid in coffee beans, exerts a wide range
of pharmacological effects including an anti-hyperglycemic, anti-hyperlipidemic, antibacte-
rial, antiviral, and anti-tumor activity [390,391]. In contrast to caffeine or chlorogenic acid,
neuroprotective effects of trigonelline have not been so extensively studied. However, there
are several preliminary in vitro and in vivo studies showing that trigonelline provides
neuroprotection and may be beneficial in the management of some neurodegenerative
conditions. Few reports focused on the possible protective effects of trigonelline against
Alzheimer’s disease. Molecular docking study showed that it has high affinity to the Aβ1-42
peptide altering its structure and thereby inhibiting its aggregation [392]. In rat cortical
neurons, trigonelline prevented dendritic and axonal atrophy induced by administration of
Aβ25–35 . It also reversed the Aβ25–35 -induced impairment of spatial memory in mice [393].
Moreover, trigonelline produced neuroprotective effect in a rat model of Alzheimer’s
disease induced by administration of Aβ1–40 . Pretreatment of Aβ1–40 -microinjected rats
with trigonelline significantly improved spatial recognition memory in the Y maze test
and performance in the novel object recognition task. Importantly, histological analysis
showed that trigonelline prevented Aβ1–40 -induced loss of hippocampal CA1 neurons.
Furthermore, it decreased oxidative stress parameters; augmented antioxidant defensive
system; reduced hippocampal levels of glial fibrillary acidic protein (GFAP), S100b, COX-2,
TNF-α, and IL-6; and improved mitochondrial membrane potential. Thus, it appears
that the neuroprotective effect could be mediated by the reduction of oxidative stress,
neuroinflammation, astrocyte activity, and preservation of mitochondrial integrity [394]. In
another study, trigonelline ameliorated LPS-induced cognitive decline in mice in the Morris
water maze task and Y maze test, which suggests that it can improve both spatial and
working memory. The behavioral effects were accompanied with reduced oxidative stress
parameters, decreased level of pro-inflammatory cytokines, decreased AChE activity, and
upregulated BDNF level in both the hippocampus and cortex [395]. Similar results were
obtained by Khalili et al. [396] who reported that trigonelline diminished the LPS-induced
learning and memory disturbances via suppression of hippocampal oxidative stress, neu-
roinflammation, and AChE activity. In addition, they showed that the anti-inflammatory
effect of trigonelline could be mediated by the NF-κB and TLR4 signaling pathways.
Int. J. Mol. Sci. 2021, 22, 107 39 of 64

Table 5. Summary of in vivo studies on the neuroprotective effects of caffeic acid.

Animals Treatment Model Behavioral Tests Main Outcomes Ref.

(1) Attenuation of the aluminum-induced
impairment of learning and memory, (2)
10 and 30 mg/kg (p.o.) 30 min
Aluminum-induced Passive avoidance task, decreased MDA level, (3) increased choline
Mice (KM strain) before aluminum injection and [349]
neurotoxicity water maze test acetyltransferase expression, (4) decreased
then for 10 consecutive days
expression of amyloid precursor protein of Aβ,
and 5-LOX
(1) Improved memory; (2) reduced AChE,
Aluminum-induced
Male Wistar rats 100 mg/kg (p.o.) for 11 days Morris water maze test catalase, and GST activity; (3) reduced GSH and [350]
neurotoxicity
nitrite levels
(1) Attenuation of the streptozotocin -induced
Object recognition test, learning and memory impairments; (2) increase
Streptozotocin- induced
Wistar rats 10–40 mg/kg (p.o.) for 21 days Morris water maze test, in AChE activity; (3) increase in MDA, nitrite, [351]
dementia
locomotor activity test and protein carbonyl levels; and (4) decrease in
GSH level
(1) Improved cognitive deficits, (2) decreased
AChE activity and nitrite generation, (3)
increased activity of catalase and GSH, (4)
Sprague–Dawley rats 100 mg/kg (i.p.) for 2 weeks Aβ1–40 -induced neurotoxicity Morris water maze test reduced IL-6 and TNF-α levels, (5) decreased [352]
NF-κB-p65 protein expression and caspase-3
activity, and (6) decreased p53 and p-p38 MAPK
protein expression
(1) Improved learning and memory; (2)
decreased AChE activity in the cerebral cortex
Step-down inhibitory
Wistar rats 10–100 mg/kg (p.o.) for 30 days – and striatum; and (3) increased AChE activity in [353]
avoidance test, open field test
the cerebellum, hippocampus, hypothalamus,
and pons
Seizure assessment (latency (1) Anticonvulsant-like effect, (2) decreased
4 mg/kg (i.p.) 30 min before
Wistar rats Pilocarpine-induced seizures to the first seizure, % lipid peroxidation level and nitrite content, (3) [355]
pilocarpine injection
seizures) increased SOD and catalase activity
20 mg/kg (i.p.) for 5 days before Quinolinic acid-induced Circling behavior test, Attenuation of the quinolinic acid-induced
Wistar rats [344]
quinolinic acid administration neurotoxicity cylinder test behavioral alterations
Int. J. Mol. Sci. 2021, 22, 107 40 of 64

Table 5. Cont.

Animals Treatment Model Behavioral Tests Main Outcomes Ref.

(1) Improvement of locomotor activity and
Quinolinic acid-induced Locomotor activity test,
Male Wistar rats 5 and 10 mg/kg (p.o.) for 21 days motor coordination, (2) restored redox status in [356]
neurotoxicity rotarod test
striatum
Kainic acid-induced Seizure assessment (latency (1) Prolonged latency to seizures, (2) reduced
Fisher rats 50 mg/kg (i.p.) 4 injections [357]
neurotoxicity to seizures, seizure severity) neuronal loss in the CA3 hippocampal field
Pilocarpine- and Seizure assessment (latency (1) No anticonvulsant-like effect, (2) protection
4 and 8 mg/kg (i.p.) 30 min
CF1 mice pentylenetetrazole-induced to the first seizure, % against pilocarpine-induced genotoxic damage [358]
before seizure induction
seizures seizures) in the hippocampus
1–8 mg/kg (i.p.) 30 min before Seizure assessment (latency (1) No antiepileptogenic-like effect, (2)
pentylenetetrazole injection, once Pentylenetetrazole -induced to the first seizure and the protection against kindling-induced genotoxic
CF1 mice [359]
every three day, for a total of kindling occurrence of clonic forelimb damage in cerebral cortex, (3) decreased ROS
6 injections seizures) production
(1) Decreased cell damage in the ischemic
10 and 20 mg/kg (p.o.) for 3 days Transient cerebral ischemia
Mongolian gerbils hippocampal CA1 region, (2) inhibition of [360]
before ischemia induction injury
microglia activation
(1) Reduced infarcted area and improved
neurological deficit scores, (2) improvement of
Neurological deficit scoring,
working, spatial, and long-term aversive
passive avoidance test,
Swiss mice 2–60 mg/kg (i.p.) for 5 days Focal cerebral ischemia injury memory deficits, (3) attenuation of the [361]
Y-maze test, water maze test,
ischemia-induced reduction in synaptophysin
open field test
expression, and (4) increase in caspase
3 expression
50 mg/kg (i.p.) immediately after (1) Improved neurological deficit scores, (2)
Cerebral
Sprague–Dawley rats ischemia induction and then Neurological deficit scoring reduced infraction volume, (3) decreased 5-LOX [362]
ischemia/reperfusion injury
repeatedly for 12 h expression
50 mg/kg (i.p.) 30 min before (1) Reduction of neurological deficits, (2)
ischemia induction and 0, 1, 2 h Focal cerebral Neurological deficit scoring, decreased neuron loss, infarct volume, brain
Sprague-Dawley rats [363]
after reperfusion in 1st day, and ischemia/reperfusion injury inclined board test atrophy, and astrocyte proliferation, (3)
twice daily in the 2nd to 5th day inhibition of leukotriene production
Int. J. Mol. Sci. 2021, 22, 107 41 of 64

Table 5. Cont.

Animals Treatment Model Behavioral Tests Main Outcomes Ref.

(1) Attenuation of the ischemia-induced spatial
learning and memory deficits, (2) reduced
10–50 mg/kg (i.p.) 30 min before Global cerebral
Sprague–Dawley rats Morris water maze test hippocampal neurons injury, (3) decreased [364]
ischemia induction ischemia-reperfusion injury
MDA level, (4) increased SOD activity, and (5)
suppressed 5-LOX overexpression
10 and 50 mg/kg (i.p.) 30 min, 2 (1) Reduced astrocyte proliferation and glial scar
and 6 h after cryoinjury on the wall formation, (2) decreased expression of
ICR mice Brain cryoinjury – [365]
1st day and twice daily on days 2 GFAP protein, (3) decreased SOD activity and
to 7 (4) increased MDA level
Attenuation of the LPS-induced loss of
50 mg/kg (p.o.) 10.5, 5.5, and 0.5
Sprague-Dawley rats LPS-induced neurotoxicity – dopaminergic neurons and microglial activation [367]
h before LPS injection
in the substantia nigra
(1) Decreased inflammatory cytokines levels; (2)
suppressed NO, prostaglandin E2, and GFAP
C57BL/6 mice 0.5–2% in diet, for 4 weeks MPTP-induced neurotoxicity _ production; (3) reserved BDNF, GDNF, and [370]
tyrosine hydroxylase levels; (4) improved
synthesis of dopamine
50 mg/kg (p.o.) for 1 week
(1) Prevented degeneration of dopaminergic
before rotenone exposure, and Rotenone-induced
C57BL/6J mice – neurons in the substantia nigra, (2) upregulated [321]
then 5 days/week during the neurotoxicity
metallothionein-1 and 2 in striatal astrocytes
4 weeks of rotenone treatment
Int. J. Mol. Sci. 2021, 22, 107 42 of 64

It appears that trigonelline may also produce neuroprotective effects due to its antigly-
cating properties. In in vitro experiments, it suppressed formation of advanced glyca-
tion end products (AGEs), pentosidine compounds, and Amadori compounds (i.e., early
markers of protein glycation). This is an important observation as AGEs contribute to
amyloidosis in Alzheimer’s disease suggesting that glycoxidation plays a crucial role in
the pathogenesis of this disease. It was demonstrated that chronic administration of D-
galactose impairs learning and memory, induces oxidative damage, elevates the AGEs
levels, and increases AChE activity in mice. It is noteworthy that trigonelline treatment
significantly improved cognitive performance in the Morris water maze and Y-maze tests,
reduced oxidative stress, and decreased AGEs and AChE levels in D-galactose-treated
animals [397].
Neuroprotective properties of trigonelline were also reported in experimental models
of Parkinson’s disease. In unilaterally 6-OHDA-lesioned rats, it reduced apomorphine-
induced rotations, increased the viability of neurons in the substantia nigra pars compacta,
prevented apoptosis, and restored the MDA level [398]. Gaur et al. [399] showed however
that trigonelline (but only at low doses) increased the number of ipsilateral rotations
in the 6-OHDA-lesioned rats, indicating dopamine releasing action. In the same study,
trigonelline pretreatment also reversed the MPTP-induced motor dysfunctions in mice.
Additionally, it was demonstrated that this coffee compound is devoid of anticholinergic
effects and does not inhibit MAO-B activity [399].
It is also worth mentioning that trigonelline was neuroprotective in ischemic stroke [400]
and oxygen-glucose deprivation-induced neural injury [391]. Trigonelline injected immedi-
ately following ischemia induction produced neuroprotection in rats by reducing cerebral
infarct, which was accompanied with improvement in motor and neurodeficit scores. More-
over, it reduced the glutathione-mediated expression of myeloperoxidase in the cortical
brain region and augmented the antioxidant status. Consistent with in vivo findings,
trigonelline increased the PC12 cell viability following hypoxia induction in in vitro ex-
periments [400]. Qiu et al. [391] demonstrated that trigonelline protected hippocampal
neurons from the oxygen-glucose deprivation/reperfusion-induced injury. It also amelio-
rated oxidative stress, attenuated inflammatory response, and inhibited cell apoptosis in
hippocampal neurons. Of note, the neuroprotective effect was probably mediated by the
activation of PI3K/Akt signaling pathway.
Taken together, the above-mentioned reports (Table 6) consistently demonstrated that
trigonelline may be a promising neuroprotective agent mainly due to its antioxidant, anti-
inflammatory, and anti-apoptotic properties. However, the exact molecular mechanisms
underlying the neuroprotective effects of trigonelline need to be established. Some studies
showed possible involvement of the TLR4/NF-κB [396] and PI3K/Akt [391] signaling path-
ways, but these are preliminary findings only. It is noteworthy that a recent study showed
trigonelline exerts an antidepressant-like effect in mice via reduction of NMDA receptor
activity [401], which deserves further investigation as the NMDA-mediated glutamatergic
transmission is also implicated in the pathophysiology of neurodegenerative disorders. It
has been postulated that coffee may exert health promoting effects, including neuropro-
tective ones, via dampening inflammation-induced NF-κB activity and activation of the
Nrf2 system with subsequent enhancement of the cell defense response [402,403]. Indeed,
several coffee constituents (i.e., chlorogenic acids, caffeic acid, kahweol, and cafestol) have
been reported to act as inducers of the Nrf2 pathway. In contrast, trigonelline is a potent
inhibitor of the Nrf2 transcription factor and the inhibitory effect is observed at physiologi-
cally relevant concentrations. Importantly, roasting of coffee beans increases their ability to
activate the Nrf2/ARE pathway. This is related to the formation of new potent activators
of the Nrf2 transcription factor during roasting process (e.g., N-methylpyridinium ion). A
lower content of trigonelline in roasted coffee may also contribute to the stronger activa-
tion of Nrf2/ARE pathway [402–404]. Thus, the question also arises whether trigonelline
significantly contributes to the beneficial effects of coffee beverages consumption in neu-
rodegenerative diseases.
Int. J. Mol. Sci. 2021, 22, 107 43 of 64

Table 6. Summary of in vivo studies on the neuroprotective effects of trigonelline

Animals Treatment Model Behavioral Tests Main Outcomes Ref.

Aβ25–35 -induced memory
ddY mice 500 mg/kg (p.o.) for 15 days Morris water maze test Attenuated memory impairment [393]
impairment
(1) Attenuated learning and memory
impairment; (2) alleviated hippocampal
neuronal loss; (3) improved mitochondrial
Aβ25–35 induced Y maze test,
Wistar rats 100 mg/kg (p.o.) for 3 days membrane potential; (4) restored MDA, protein [394]
neurotoxicity novel object recognition task
carbonyl, and GSH levels; (5) reduced SOD and
LDH activity; (6) reduced GFAP, S100b, COX-2,
TNF-α, and IL-6 level in the hippocampus
(1) Attenuated learning and memory
disturbances, (2) decreased AChE activity, (3)
50 and 100 mg/kg (p.o.) for Morris water maze test,
Swiss Albino mice LPS-induced neurotoxicity restored SOD activity, (4) restored GSH and [395]
28 days Y maze test
lipid peroxidation levels, (5) decreased TNF-α
and IL-6 levels, and (6) increased BDNF level
(1) Attenuated learning and memory
Y maze test, disturbances; (2) decreased MDA level and
Wistar rats 20–80 mg/kg (p.o.) for 7 days LPS-induced neurotoxicity Novel object discrimination AChE activity; (3) increased SOD and catalase [396]
test, passive avoidance test activity; (4) reduced GSH level; and (5)
decreased NF-κB, TLR4, and TNF-α levels
(1) Attenuated learning and memory
D -Galactoseinduced Morris water maze test, disturbances, (2) decreased AChE activity, (3)
Swiss Albino mice 20–80 mg/kg (p.o.) for 6 weeks [397]
cognitive impairment Y maze test decreased AGEs and MDA levels, (4) increased
SOD activity and GSH level
(1) Reduced rotational behavior, (2) increased
50 and 100 mg/kg (i.p.) for 6-OHDA-induced Apomorphine-induced viability of neurons in substantia nigra, (3)
Wistar rats [398]
3 days neurotoxicity rotation test prevented apoptosis, (4) reduced MDA and
nitrite levels, and (5) increased GSH level
Trigonella foenum-graecum extract
(82% trigonelline) 30–100 mg/kg 6-OHDA-induced Apomorphine-induced
Wistar rats Increased number of ipsilateral rotations [399]
(p.o.), 2 weeks after 6-OHDA neurotoxicity rotation test
injection
Int. J. Mol. Sci. 2021, 22, 107 44 of 64

Table 6. Cont.

Animals Treatment Model Behavioral Tests Main Outcomes Ref.

Trigonella foenum-graecum extract
(82% trigonelline) 30 mg/kg Improved spontaneous locomotor activity in the
C57BL/6 mice MPTP-induced neurotoxicity Open field test [399]
(p.o.), 60 min before or after pre-treatment schedule
MPTP
(1) Improved motor coordination and
25–100 mg/kg (i.p.) twice neurodeficit scores, (2) decreased cerebral
Cerebral Neurological deficit scoring,
Sprague–Dawley rats (30 min before and immediately infarction volume, (3) reduced nitrite and MDA [400]
ischemia/reperfusion injury rotarod test
after ischemia induction) levels, (4) increased GSH level, and (5)
decreased expression of myeloperoxidase
Int. J. Mol. Sci. 2021, 22, 107 45 of 64

4.5. Neuroprotective Effects of Kahweol and Cafestol

Kahweol and cafestol are two coffee-specific diterpenes present in unfiltered coffees
such as Scandinavian-style boiled coffee, Turkish-style coffee, French press coffee, and
espresso. Although these two compounds are known mainly from their hypercholes-
terolemic effects, a growing body of evidence shows that kahweol and cafestol also have
many beneficial effects such as anti-inflammatory, antioxidant, hepatoprotective, anti-
diabetic, and anti-carcinogenic activities [405,406]. However, data on the neuroprotective
properties of these two compounds are quite limited.
Kahweol is a potent antioxidant agent with cytoprotective properties [407,408], which
suggests that it should also produce neuroprotection. Indeed, Hwang and Jeong [409]
demonstrated the protective effect of kahweol against the 6-OHDA-induced oxidative
stress in the dopaminergic SH-SY5Y neuronal cells indicating its possible neuroprotective
effects in Parkinson’s disease. They showed that kahweol significantly increased cell sur-
vival following 6-OHDA treatment and reduced 6-OHDA-induced ROS production. It
also induced heme oxygenase-1 expression and Nrf2 nuclear translocation in dopamin-
ergic neuronal cells. Next experiments demonstrated the involvement of PI3K/Akt and
p38 signaling in kahweol-induced heme oxygenase-1 upregulation [409]. Kahweol was
also protective in the human neuroblastoma SH-SY5Y cells exposed to methylglyoxal.
It decreased the methylglyoxal-induced loss of mitochondrial membrane potential, pre-
vented the mitochondria-related bioenergetics decline, and suppressed production of
ROS and RNS [407]. Likewise, kahweol promoted mitochondrial protection in SH-SY5Y
cells exposed to H2 O2 , decreased the level of oxidative stress markers, and reduced the
production of ROS [410]. In both of the aforementioned studies, the protective effect of
kahweol was mediated via activation of the PI3K/Akt and p38 MAPK/Nrf2 signaling
pathways [407,410], which is in line with previous findings by Hwang and Jeong [409].
It is also worth mentioning that kahweol was protective against the H2 O2 -induced DNA
damage [408]. This is an important observation in view of the fact that oxidative DNA
damage is one of the earliest changes in neurodegenerative diseases.
It is noteworthy that there is one in vivo study showing a possible protective ef-
fect of kahweol on brain neurons. In mice, acute systemic administration of kahweol
ameliorated the traumatic brain injury-induced brain parenchymal damage and reversed
short- and long-term functional outcomes. These effects were accompanied by reduced
production of cytokines (IL-1β, MIP-1α, MIP-2, and TIMP-1) in the brain, decreased mi-
croglia/macrophage activation, and reduced neutrophil and leukocyte infiltration. In
addition, continuous administration of kahweol potentiated the protective effects of a
single-dosage treatment [411]. This is an important finding as the traumatic brain injury is
associated with an increased risk of neurodegenerative diseases, though the mechanism
underlying this association is not clear [412].
To date, only one study focused on the possible neuroprotective properties of cafestol.
Trinh et al. [413] studied its protective effect in Drosophila models of Parkinson’s disease.
They showed that cafestol conferred neuroprotection in both α-synuclein transgenic and
parkin null mutant flies. Moreover, it was demonstrated that the effect was mediated
through the Nrf2-dependent mechanism [413]. Similarly to kahweol, cafestol was also
demonstrated to produce antioxidant and anti-inflammatory effects. Other studies showed
that cafestol may activate the Nrf2/ARE signaling pathway, increase the expression of HO-1,
eliminate excessive ROS production, and protect against oxidative DNA damage [406,408].
All these effects may contribute to its potential neuroprotective action.
Summarizing, there are some initial evidence suggesting neuroprotective effects of
kahweol and cafestol. However, the possible protective effects of the two coffee diterpenes
have to be confirmed in animal models of neurodegenerative diseases. More insight into
the absorption and metabolism of kahweol and cafestolis also needed. A special attention
should be given to the ability of kahweol and cafestol (and/or their active metabolites)
to cross the BBB as their brain penetration has not been studied so far. Moreover, since
 Int.
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FORSci.
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REVIEW 46 of 63 46 of 64

coffee diterpenes are known to raise serum cholesterol level, it will be necessary to care-
fully evaluate the risk/benefit ratio of using them for neuroprotection.
the coffee diterpenes are known to raise serum cholesterol level, it will be necessary to
carefully evaluate the risk/benefit ratio of using them for neuroprotection.
5. Summary and Conclusions
Extensive 5.
in Summary
vitro and in vivo
and studies have demonstrated that coffee and its bioactive
Conclusions
compounds exert neuroprotective
Extensive in vitro effects
and suggesting
in vivo studiestheirhave
preventive and/orthat
demonstrated therapeutic
coffee and its bioactive
potential for different neurodegenerative conditions (Figure 3). Among
compounds exert neuroprotective effects suggesting their preventive and/orthem, caffeine has therapeutic
been the most potential
extensively investigated and the beneficial effects of coffee consumption
for different neurodegenerative conditions (Figure 3). Among them, caffeine has
can be largely been
(but not solely)
the most attributedinvestigated
extensively to caffeine. andHowever, numerous
the beneficial reports
effects show
of coffee consumption can
that other coffee
becompounds
largely (butmay not independently
solely) attributed produce neuroprotective
to caffeine. However, effects
numerousindicat-
reports show that
ing that decaffeinated coffeecompounds
other coffee could be also very
may effective in neurodegenerative
independently produce neuroprotectiveconditions.
effects indicating
Polyphenolic acids
that (i.e., chlorogenic
decaffeinated acidscould
coffee and caffeic
be alsoacid)
veryand trigonelline
effective appear to be
in neurodegenerative conditions.
the most promising, but in contrast
Polyphenolic to caffeine,
acids (i.e., chlorogenicthere is a and
acids lack caffeic
of epidemiological studies appear to be
acid) and trigonelline
or clinical reports
theon their
most protectivebut
promising, effects in neurodegenerative
in contrast to caffeine, therediseases.
is a lackThere are only
of epidemiological studies or
preliminary data on the
clinical possible
reports on beneficial effectseffects
their protective of chlorogenic acid on cognitive
in neurodegenerative func- There are only
diseases.
tion in humans.preliminary
Thus, large-scale
data onobservational and clinical
the possible beneficial studies
effects are highly acid
of chlorogenic warranted
on cognitive function
to provide more in insight
humans. into the large-scale
Thus, neuroprotective effects ofand
observational caffeine, coffee
clinical polyphenols,
studies are highly warranted to
provide
and trigonelline. more insight
Each compound into the
should be neuroprotective
studied separately effects of caffeine,
as each one hascoffee polyphenols, and
its own
trigonelline.
unique properties and can haveEachdifferent
compound should
effects be studied
depending on separately
the disease. asMoreover,
each one hastheits own unique
properties
exact mechanism(s) and can
by which eachhave differentconfers
component effects neuroprotection
depending on the disease.
should Moreover, the exact
be eluci-
mechanism(s)
dated. Their bioavailability andbylong-term
which each component
adverse effectsconfers neuroprotection
also warrant should be elucidated.
further investiga-
tion. Their bioavailability and long-term adverse effects also warrant further investigation.

Figure 3. Summary of the neuroprotective

Figure effects
3. Summary of the of coffee.
neuroprotective effects of coffee.

On the other hand,

On the theother
effects of coffee
hand, in neurodegenerative
the effects diseases may result
of coffee in neurodegenerative diseases may result
from a synergistic
fromaction of many active
a synergistic actioncompounds.
of many activeTherefore, epidemiological
compounds. Therefore,and clin-
epidemiological and
ical studies should be continued to fully evaluate the association between regular coffee
clinical studies should be continued to fully evaluate the association between regular coffee
beverageand
beverage consumption consumption and the risk of neurodegenerative
the risk of neurodegenerative diseases.
diseases. It should It should be, however,
be, however,
emphasized that emphasized
such studiesthatface
such studies of
a variety face a variety of
challenges, andchallenges,
one of theand oneimportant
most of the most important is
a highin
is a high variability variability
the final in the final composition
composition of coffee beverage
of coffee beverage that depends
that depends on manyon many factors
factors such as such
coffeeasbeans
coffeeorigin,
beans origin, roasting
roasting level,
level, and and brewing
brewing techniques
techniques [182]. [182].
In addi-In addition, since
tion, since bioavailability of ingredients may depend on each individual’s metabolism, the
Int. J. Mol. Sci. 2021, 22, 107 47 of 64

bioavailability of ingredients may depend on each individual’s metabolism, the response

to coffee intake can vary substantially across individuals [183], which should also be taken
into account when studying the effect of coffee intake in neurodegenerative diseases.

Funding: This research received no external funding.

Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations
Aβ Amyloid beta
AChE Acetylcholinesterase
AGEs Advanced glycation end products
Akt Protein kinase B
APP Amyloid precursor protein
APPsw Swedish mutation mice, mice carrying the mutant APPK670N, M671L gene
ATP Adenosine-50 -triphosphate
Bax Bcl-2-associated X protein
BBB Blood brain barrier
BChE Butyrylcholinesterase
Bcl2 B-cell lymphoma protein 2
BDNF Brain-derived neurotrophic factor
CAPE Caffeic acid phenyl ester
CBF Cerebral blood flow
CD31 Platelet/endothelial cell adhesion molecule-1
CNS Central nervous system
COX-2 Cyclooxygenase 2
CSF Cerebrospinal fluid
CYP Cytochrome P450
DAT Dopamine transporter
ER Endoplasmic reticulum
ERK1/2 Extracellular signal-regulated kinase-1 and -2
GABA Gamma-aminobutyric acid
GDNF Glial cell line-derived neurotrophic factor
GFAP Glial fibrillary acidic protein
GSK3β Glycogen synthase kinase 3 beta
GSH Reduced glutathione
GSH-Px Glutathione peroxidase
GST Glutathione-S-transferase
HI Hypoxia-ischemia
HIF1α Hypoxia-inducible factor 1 alpha
HO-1 Heme oxygenase 1
ICAM-1 Intercellular adhesion molecule 1
IL-1β Interleukin 1 beta
IL-2 Interleukin 2
IL-4 Interleukin 4
IL-6 Interleukin 6
IL-13 Interleukin 13
i.n. Intranasal
iNOS Inducible nitric oxide synthase
i.p. Intraperitoneally
i.v. Intravenously
LDH Lactate dehydrogenase
5-LOX 5-Lipoxygenase
LPS Lipopolysaccharide
Int. J. Mol. Sci. 2021, 22, 107 48 of 64

MAPK Mitogen-activated protein kinase

MB Manganese bisethylenedithiocarbamate
MDA Malondialdehyde
mGluR1 Metabotropic glutamate receptor type 1
mGluR5 Metabotropic glutamate receptor type 5
MMP-2, -9 Metallomatrixprotease-2,-9
MPTP 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
MRI Magnetic resonance imaging
mTOR Mammalian target of rapamycin
NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells
NGF Nerve growth factor
NMDA N-methyl-D-aspartate
nNOS Neuronal nitric oxide synthase
NO Nitric oxide
NOS-2 Nitric oxide synthase-2
NQO-1 NAD(P)H quinone oxidoreductase
Nrf2 Nuclear factor erythroid 2-related factor 2
6-OHDA 6-Hydroxydopamine
p53 Tumor protein p53
p65 Transcription factor p65
PARP-1 Poly [ADP-ribose] polymerase 1
p-JNK C-Jun N-terminal kinases
p.o. Orally
PQ 1,10 -Dimethyl-4,40 -bipyridinium dichloride hydrate
RNS Nitrogen reactive species
ROS Reactive oxygen species
rpS3 Ribosomal protein
S100b S100 calcium-binding protein B
SNP Sodium nitroprusside
SOD Superoxide dismutase
SOD2 Superoxide dismutase 2
TFEB Transcription factor EB
TH+ Tyrosine hydroxylase immunoreactivity
TLR4 Toll-like receptor 4
TNF-α Tumor necrosis factor α
TrkB Tirosine kinase receptor
UDP Uridine 50 -diphosphate
VCAM-1 Vascular cell adhesion protein 1

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