International Journal of

Molecular Sciences

Review
Magnesium and the Brain: A Focus on Neuroinflammation
and Neurodegeneration
Jeanette A. M. Maier 1, *, Laura Locatelli 1 , Giorgia Fedele 1 , Alessandra Cazzaniga 1 and André Mazur 2

1 Department of Biomedical and Clinical Sciences, Università di Milano, 20157 Milano, Italy
2 UNH—Unité de Nutrition Humaine, Université Clermont Auvergne, INRAE,
F-63000 Clermont-Ferrand, France
* Correspondence: [email protected]

Abstract: Magnesium (Mg) is involved in the regulation of metabolism and in the maintenance of the
homeostasis of all the tissues, including the brain, where it harmonizes nerve signal transmission and
preserves the integrity of the blood–brain barrier. Mg deficiency contributes to systemic low-grade
inflammation, the common denominator of most diseases. In particular, neuroinflammation is the
hallmark of neurodegenerative disorders. Starting from a rapid overview on the role of magnesium
in the brain, this narrative review provides evidences linking the derangement of magnesium balance
with multiple sclerosis, Alzheimer’s, and Parkinson’s diseases.

Keywords: magnesium; brain; neuroinflammation; blood–brain barrier; neurodegeneration

1. Introduction
Because it efficiently coordinates six oxygen atoms in the first coordination sphere,
magnesium (Mg) was essential in the initial chemical processes resulting in the origin and
evolution of life. Consequently, Mg is vital in all living systems [1], and its concentrations
are tightly and sometimes specifically regulated in tissues and cells. As an example, in the
Citation: Maier, J.A.M.; Locatelli, L.;
brain cytosolic, Mg is lower than in the skeletal muscle, while in the cerebrospinal fluid, it
Fedele, G.; Cazzaniga, A.; Mazur, A. is more elevated than in plasma [2].
Magnesium and the Brain: A Focus To review the relation between Mg in brain health and disease, a search was completed
on Neuroinflammation and using PubMed, MEDLINE, Google Scholar from 2000 to date.
Neurodegeneration. Int. J. Mol. Sci.
2023, 24, 223. https://doi.org/ 2. Magnesium in the Brain
10.3390/ijms24010223 In the brain, beyond its role as a metabolite and its involvement in all biochemical
pathways [3], Mg is fundamental for nerve signal transmission and the maintenance of
Academic Editor: Claudiu
T. Supuran
ionic homeostasis (Figure 1). Since calcium (Ca) plays an important role in the control of
synaptic activity and memory formation, it is relevant that Mg is considered a natural Ca
Received: 6 December 2022 antagonist. Mg controls Ca influx by regulating Ca voltage-dependent channels, while in-
Revised: 19 December 2022 tracellularly, it inhibits Ca release from cytosolic stores through inositol 1,4,5-trisphosphate
Accepted: 20 December 2022 and ryanodine receptors [4]. Moreover, Mg affects the major excitatory and inhibitory
Published: 23 December 2022
neurotransmission pathways. It is an agonist of the ionotropic gamma aminobutyric acid
type A receptor (GABAA -R) [5], known to mediate the anxiolytic and hypnotic actions
of benzodiazepines [6]. In early development, GABAA -R signaling prompts Mg release
Copyright: © 2022 by the authors.
from the mitochondria, and the increase of cytoplasmic Mg activates mTOR, which facili-
Licensee MDPI, Basel, Switzerland. tates the formation of neural networks [7] through ribosome biogenesis [8]. Mg inhibits
This article is an open access article the glutamate N-methyl-D-aspartate receptor (NMDA-R) at the physiological membrane
distributed under the terms and potential, which is around −70 mV, when glutamate only acts on the α-amino-3-hydroxyl-5-
conditions of the Creative Commons methyl-4-isoxazole-propionate (AMPA) receptor, thereby preventing sustained stimulation
Attribution (CC BY) license (https:// of NMDA-R, which leads to neuronal death [8]. The protective action of Mg is also due to
creativecommons.org/licenses/by/ its ability to block the opening of the mitochondrial permeability transition pore and the
4.0/). subsequent release of cytochrome c, which culminates in apoptosis [8]. Mg also protects

Int. J. Mol. Sci. 2023, 24, 223. https://doi.org/10.3390/ijms24010223 https://www.mdpi.com/journal/ijms

 and the subsequent release of cytochrome c, which culminates in apoptosis [8]. Mg als
protects the integrity and function of the blood–brain barrier (BBB) [9], the impenetrab
cellular scaffold that regulates central nervous system (CNS) homeostasis, and therefor
maintains
Int. J. Mol. Sci. 2023, 24, 223 healthy neurological function [10]. The BBB also protects the brain 2against of 14 tox
ins and pathogens and bidirectionally controls the passage of molecules between th
blood and the CNS. It is also a relevant source of various neurotrophins, among which
the integrity and function of the blood–brain barrier (BBB) [9], the impenetrable cellular
brain-derived neurotrophic
scaffold factor
that regulates central(BDNF), which
nervous system contributes
(CNS) homeostasis,toand
neuronal
therefore, plasticity
maintains and
essential for healthy
learning and memory
neurological function[11].
[10].ItThe
is reported that Mg
BBB also protects the supplementation
brain against toxins and augmen
pathogens and bidirectionally controls the passage of molecules between
serum BDNF in patients with depression [12], and the addition of Mg pidolate (5 mM) t the blood and the
CNS. It is also a relevant source of various neurotrophins, among which is brain-derived
a co-culture neurotrophic
model of BBB/cerebral organoids
factor (BDNF), which increases
contributes theplasticity
to neuronal expression
and is of BDNF
essential for[13]. Fo
cusing on memory, increasing
learning and memory [11].brain Mg through
It is reported diet enhances
that Mg supplementation neuronal
augments serumplasticity
BDNF an
in patients
long-term memory inwith
youngdepression
and aged[12], and the addition
rodents of Mgin
[14] and pidolate (5 mM) to
Drosophila a co-culture
[15] through diffe
model of BBB/cerebral organoids increases the expression of BDNF [13]. Focusing on mem-
ent mechanisms.
ory, increasing brain Mg through diet enhances neuronal plasticity and long-term memory
in young and aged rodents [14] and in Drosophila [15] through different mechanisms.

Figure 1. The role of magnesium in the brain. Magnesium in the brain plays a fundamental role in
Figure 1. The the
role of magnesium
modulation inpathways.
of different the brain. Magnesium in the brain plays a fundamental role i
the modulation of different pathways.
Mg in the brain also has a role in counteracting oxidative stress and inhibiting the
release of vasoactive molecules, among which is substance P (SP) [2]. Moreover, Mg admin-
Mg in the brain
istration also in
is useful has a role in
attenuating counteracting
spasms and autonomic oxidative stress
instability in and
tetanus, inhibiting th
eventually
acting as anmolecules,
release of vasoactive anti-toxin [16].among which is substance P (SP) [2]. Moreover, Mg ad
Not surprisingly, a deficit of Mg in the brain unbalances neural function and has been
ministration linked
is useful in attenuating spasms and autonomic instability in tetanus, eventu
to neuroinflammation and neurodegeneration.
ally acting as an anti-toxin [16].
3. Magnesium and Neuroinflammation
Not surprisingly, a deficit of Mg in the brain unbalances neural function and has bee
Mg deficiency is also linked to chronic low-grade inflammation in the brain [4]. Neu-
linked to neuroinflammation and neurodegeneration.
roinflammation shares common primary features with peripheral inflammation, such as the
activation of resident macrophages, i.e., microglia, the increase of inflammatory mediators,
3. Magnesium
the and Neuroinflammation
recruitment of peripheral immune cells, and local tissue injury [17]. Recently, it was
shown that Mg deficiency induces neuroinflammation in the mouse brain by upregulating
Mg deficiency is also
the expression linked to chronic low-grade
of neuroinflammation-associated genes in inflammation
the hippocampusinand thecortex
brain [4]. Neu
[18].
roinflammation sharesestrogen
Accordingly, common primary
decline featuresrats
in ovariectomized with peripheral
causes extracellular inflammation,
and intracellular such a
Mg deficiency, which in turn engenders neuroinflammation by upregulating inflammatory
the activation of resident macrophages, i.e., microglia, the increase of inflammatory me
cytokines and by activating microglia, events that are mitigated by the administration of
diators, the recruitment
Mg [19]. Moreover,of peripheral immune
in primary microglia, Mgcells,
inhibitsand local tissue injury
lipopolysaccharides [17]. Recently
(LPS)-induced
it was shownactivation
that Mg deficiency
of nuclear induces
factor kappa neuroinflammation
B (NF-κB), the master regulatorin the mouse [20].
of inflammation brain by up
regulating the3.1. expression
Magnesium andof neuroinflammation-associated
Inflammatory Mediators in the Brain genes in the hippocampu
and cortex [18]. Accordingly, estrogen
The chronic elevation of the decline
levels of in ovariectomized
inflammatory mediators, rats causes
among which extracellula
are
and intracellular Mg deficiency, which in turn engenders neuroinflammation by upregu
cytokines, nitric oxide (NO), prostanoids, and SP, profoundly affects the CNS [4]. In the
brain, thesecytokines
lating inflammatory molecules are released
and by the cellularmicroglia,
by activating components events
of the BBB and are
that by cerebral
mitigated b
cells, or they are delivered to the CNS through afferent nerves.
the administration of most
SP, the Mg abundant
[19]. Moreover,
tachykinin in inthe
primary microglia,
brain, is mainly secretedMg inhibits
by neurons and lipopolysa
acts
charides (LPS)-induced
after binding itsactivation
receptor, the ofG-protein-coupled
nuclear factor neurokinin
kappa B (NF-κB),
1 receptor, the
whichmaster
is highly regulato
expressed
of inflammation [20]. by neurons and glial cells [21]. SP acts as a neurotransmitter and a modulator of
pain perception, mediates the cross-talk between neurons and immune cells, and promotes
inflammation [22]. SP is an early contributor to Mg deficiency-dependent neuroinflamma-
3.1. Magnesium and Inflammatory Mediators in the Brain
The chronic elevation of the levels of inflammatory mediators, among which are cy
tokines, nitric oxide (NO), prostanoids, and SP, profoundly affects the CNS [4]. In th
Int. J. Mol. Sci. 2023, 24, 223 3 of 14

tion. Low Mg inhibits the principal SP-degrading enzyme, neprilysin, and consequently,
SP increase precedes the changes in redox balance and the enhanced production of NO,
typically associated with Mg deficit [23]. SP activates the microglia to release cytokines,
prostaglandin E2 (PGE2), NO, and reactive oxygen species (ROS), which maintain and
amplify the inflammatory response [24]. SP also promotes BBB hyperpermeability, thus
unbalancing the brain microenvironment. Consequently, it is implicated in vasogenic
edema [25] because in the very early phases of traumatic brain injuries and in various
pathologic processes, SP induces cerebral endothelial cells to overexpress caveolin-1, the
main component of caveolae, thus increasing protein transport from the blood to the brain
by transcytosis. Because of the consequent osmotic gradient, water enters the brain through
acquaporin-4 expressed by the perivascular astrocytic processes. Mg administration down-
regulates aquaporin-4 and reduces the severity of cerebral edema in a murine experimental
model [26]. SP also contributes to tight junction opening [25], partly through the induction
of tumor necrosis factor (TNF)α and angiopoietin-2, which induce the redistribution zonula
occludens-1 and claudin-5, resulting in BBB impairment [27].
NO, a ubiquitous gaseous cellular messenger, has pleiotropic effects in the brain, where
it is synthesized mainly by neuronal nitric oxide synthases (nNOS) [28]. Additionally, brain
endothelial cells synthesize NO through endothelial nitric oxide synthases (eNOS), primar-
ily influencing resting vascular tone but also modulating neuronal signaling and protecting
the CNS from ischemic injury [29]. Accordingly, in a model of vascular dementia, the
knock-out of eNOS exacerbates cognitive impairment and brain damage [30]. NO modu-
lates neurotransmission and neuronal metabolism and regulates learning, memory, and
sleep, among others [31]. Its overproduction is detrimental, as NO post-translationally
modifies many proteins by S-nitrosylation, which has a role in glutamate excitotoxicity;
impairs mitochondrial function; reacts with superoxide to generate peroxynitrite, which
damages lipids, proteins, and nucleic acids; and increases BBB permeability [32]. Under
low Mg conditions, NO is overproduced [33] and damages the brain [34]. Accordingly,
elevating Mg in the cerebrospinal fluid is neuroprotective through the inhibition of NO pro-
duction [35]. Further, Mg inhibits high NOS activity in cortical neurons after ischemia [36].
In a rat model, Mg prevents maternal inflammation-induced fetal brain injury partly by
inhibiting nNOS [37].
Prostaglandins (PG), lipid mediators derived from arachidonic acid, are local regula-
tors of brain functions, such as synaptic plasticity. The levels of PGE2 and PGD2 in the brain
are maintained at appropriate low levels also through the clearance pathway of the BBB [38].
PG are massively produced in inflammation by neurons and glial cells and released into
the cerebrospinal fluid. PG derange the neuronal network and neuro-glial interactions and
impairs microglial function [39]. The most abundant prostaglandin in the brain is PGD2,
which is rapidly dehydrated to the biologically active PGJ2. In addition to generating and
maintaining inflammation, PGJ2 also impairs mitochondrial function, resulting in oxidative
stress and apoptosis [40]. It has been proposed that one of the neuroprotective actions of
Mg after brain injury might be related to its inhibitory effect on PG synthesis [20].
Because of its high oxidative metabolism that consumes approximately 20% of the total
basal oxygen, the brain produces ROS [41]. At low concentrations, ROS act as signaling
molecules and plays a role in controlling the growth of neural stem cells, axonal outgrowth
and regeneration, and intracellular Ca concentrations. In response to tissue damage or
pathogens being activated, microglia overproduce ROS [17], which plays a role in brain
aging and neurodegeneration. Mg mitigates the production of ROS in various tissues,
including the CNS. In the brain of different experimental models, Mg has been shown
to contrast oxidative damage after hypoxia [42], counter maternal inflammation-induced
oxidative stress [37], and protect against carbon monoxide-induced brain damage [43].
Because low Mg concentrations activate NF-kB [4,44], it is not surprising that Mg
deficiency is associated with increased levels of pro-inflammatory cytokines, pleiotropic
signaling proteins participating in various vital processes (Figure 2). Over the past decades,
it emerged that cytokines serve a wide array of physiological functions in the CNS, where
 [43].
Because low Mg concentrations activate NF-kB [4,44], it is not surprising that Mg
deficiency is associated with increased levels of pro-inflammatory cytokines, pleiotropic
signaling proteins participating in various vital processes (Figure 2). Over the past dec-
ades, it emerged that cytokines serve a wide array of physiological functions in the CNS,
Int. J. Mol. Sci. 2023, 24, 223 4 of 14
where neurons, microglia, and astrocytes release TNFα, interleukins (IL)-1, and γ-inter-
feron, all controlling synaptic transmission and playing a role in learning and memory
[45]. In contrast, elevated levels of cytokines are detrimental and lead to neuronal death
neurons, microglia, and astrocytes release TNFα, interleukins (IL)-1, and γ-interferon, all
and cognitivesynaptic
controlling impairment. Moreover,
transmission and high amounts
playing oflearning
a role in cytokines andgenerate
memorya[45].
self-sustain-
In
ingcontrast,
loop because they perpetuate the activation of NF-κB. Cytokines
elevated levels of cytokines are detrimental and lead to neuronal death released by and
activated
microglia
cognitiveinduce
impairment. neurotoxic astrocyte
Moreover, reactivity,
high amounts whichgenerate
of cytokines promotes oligodendrocyte
a self-sustaining loop and
neuronal
because cell
theydeath [46]. the
perpetuate In LPS-stimulated
activation of NF-κB.BV2Cytokines
microglial cells, by
released Mgactivated
reducesmicroglia
LPS-induced
induce neurotoxiccytokines,
pro-inflammatory astrocyte reactivity,
includingwhichTNF-α, promotes oligodendrocyte
IL-1α, IL-1β, and neuronal
and IL-6, promotes the mac-
cell death
rophage M2[46]. In LPS-stimulated
polarization, BV2 microglial
and mitigates cells, Mg reduces
neuroinflammation LPS-induced
in LPS-injected micepro-
[20,47].
inflammatory cytokines, including TNF-α, IL-1α, IL-1β, and IL-6, promotes
In humans, MgSO4 treatment significantly reduces the levels of cytokines in the peripheral the macrophage
M2 polarization, and mitigates neuroinflammation in LPS-injected mice [20,47]. In humans,
blood through the inhibition of NF-κB activation and nuclear localization, events medi-
MgSO4 treatment significantly reduces the levels of cytokines in the peripheral blood
ated by the
through theincreased
inhibition of constitutive levelsand
NF-κB activation of nuclear
its inhibitor IĸBα [44].
localization, eventsItmediated
is relevant that the
by the
administration
increased constitutive levels of its inhibitor IkBα [44]. It is relevant that the administration and
of Mg constrains inflammation and reduces the risk of cerebral palsy
major
of Mgmotor dysfunction
constrains in preterm
inflammation neonates
and reduces the[48].
riskIn
ofneonate
cerebral mice
palsyexposed
and majorto motor
hypoxia/is-
chemia, a single
dysfunction dose of neonates
in preterm Mg reduces[48]. inflammation
In neonate mice and is neuroprotective
exposed by transiently
to hypoxia/ischemia, a
single dosegene
modulating of Mgexpression
reduces inflammation
and affecting and mitochondrial
is neuroprotective by transiently
function [49]. modulating
gene expression and affecting mitochondrial function [49].

Figure 2. The effects of low magnesium in the brain. Magnesium deficiency is responsible for the
Figure 2. The effects of low magnesium in the brain. Magnesium deficiency is responsible for the
increase of neuroinflammation and BBB dysfunction.
increase of neuroinflammation and BBB dysfunction.
3.2. Magnesium and Other Contributors to Neuroinflammation
3.2. Magnesium and Other Contributors
Mg is a well-characterized to Neuroinflammation
Ca antagonist [50], with obvious consequences on neuro-
transmission and cell function. InCa
Mg is a well-characterized theantagonist
microglia, Ca signaling
[50], is mediated
with obvious by the activation
consequences on neuro-
of many metabotropic receptors or store-operated Ca channels,
transmission and cell function. In the microglia, Ca signaling is mediated by and changes in the
theintra-
activation
of cellular Ca concentration are required for these cells to execute their sensor and effector
many metabotropic receptors or store-operated Ca channels, and changes in the intra-
functions [51]. The increase of intracellular Ca has a role in stimulating mitochondrial ROS
cellular Ca concentration are required for these cells to execute their sensor and effector
production and inducing the release of cytokines. It is by antagonizing Ca entry through the
functions [51].
purinergic The increase
channels that Mgof intracellular
curtails microglialCaacquisition
has a role ofinastimulating mitochondrial
neurotoxic phenotype after ROS
production
exposure to andLPSinducing the also
[51,52]. Mg release of cytokines.
regulates It isdependence
the voltage by antagonizing Ca entry
of NMDA-R, through
which
theispurinergic
essential in channels that Mg and
synaptic plasticity curtails
in themicroglial
integrationacquisition
of synaptic of a neurotoxic
activity phenotype
with neuronal
after exposure
activity to LPS
[53]. While [51,52]. function
the reduced Mg alsoofregulates
NMDA-R is the voltage
linked dependence
to cognitive of NMDA-R,
impairment, its
overactivation
which is essentialresults in excitotoxicity
in synaptic plasticity[54].and
Whenin extracellular
the integration Mg isofreduced,
synapticNMDA-R
activity with
is overactivated by Ca with consequent hyper-excitation, leading neurons
neuronal activity [53]. While the reduced function of NMDA-R is linked to cognitive im- to excitotoxic
cell death [2]. In cultured primary neurons, low extracellular Mg causes fluctuations of
pairment, its overactivation results in excitotoxicity [54]. When extracellular Mg is re-
intracellular Ca, electrographic epileptiform events, mitochondrial depolarization, and,
duced, NMDA-R is overactivated by Ca with consequent hyper-excitation, leading neu-
in the end, NMDA-R-dependent cell death [55]. NMDA-R activation also stimulates the
rons to excitotoxic
release cell death
of SP and induces [2]. In cultured
neuroendocrine primary
changes, eventsneurons, low extracellular
which determine Mg causes
oxidative stress
and inflammation [4]. Accordingly, the administration of Mg exerts neuroprotective effects
in various animal models after cerebral ischemia or trauma. This beneficial action is partly
due to the fact that Mg protects against metabolic failure caused by excitotoxic glutamate
exposure [56]. It has also been shown that Mg traverses the NMDA-R channel pore and
activates the cAMP-response-element binding protein (CREB) in neurons [57]. CREB is a
transcription factor that modulates the expression of many genes affecting the function of
the human brain, principally those involved in the production of dopamine [12]. Of interest,
it has recently been shown that high Mg reduces the expression of NMDA-R in cerebral
Int. J. Mol. Sci. 2023, 24, 223 5 of 14

organoids, miniature structures mirroring the brain [13]. As mentioned before, in this
experimental model, high Mg also upregulates BDNF, a neurotrophin with a widespread
distribution in the CNS; it is involved in the growth, maturation, and maintenance of neu-
rons and synapses [11]. Consistently, in an experimental model of depression in rodents,
Mg exerted anti-depressant activity through the BDNF pathway [58]. A recent randomized
clinical trial showed that supplementing Mg and vitamin D increased the circulating levels
of BDNF and reduced serum TNFα and IL-6 in obese women. These findings correlate with
the positive effect on mood disorders [59]. It is noteworthy that inflammation inhibits the
expression of BDNF and its receptor tropomyosin receptor kinase B (TrkB) [60]. Therefore,
the increase of BDNF reported in [59] might be due to the reduction of neuroinflammation.
Another feature associated with neuroinflammation is the impairment of the BBB,
which not only allows the transport of plasma proteins and immune cells to the brain, but
also amplifies neuroinflammation because the endothelial cells and the reactive astrocytes
of the BBB release inflammatory mediators [61]. It is known that Mg prevents BBB hy-
perpermeability induced by the plasma of women with preeclampsia [62], restores BBB
permeability after traumatic brain injury or ischemia in rodents [63,64], and in in vitro
models of the BBB, protects against LPS-induced damage [9].
Since alterations of Mg levels might favor SARS-CoV-2 dissemination and further ag-
gravate neurological signs and symptoms, it has recently been proposed that derangements
of Mg levels might be involved in neuro-COVID and its clinical manifestation [65].

4. Magnesium and Neurodegeneration

Neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and
multiple sclerosis, are among the most prevalent disorders with a high burden to the
patients, their families, and society. They share a common denominator, i.e., neuroinflam-
mation, which has a relevant role in their pathogenesis and progression. Of interest, Mg
levels are often deranged in neurodegenerative diseases and might therefore favor their
onset and aggravation [34]. We briefly summarize current knowledge on the connection
existing between altered Mg levels and Alzheimer’s and Parkinson’s diseases, as well as
multiple sclerosis.

4.1. Magnesium and Alzheimer’s Disease

Alzheimer’s disease is a neurodegenerative disorder that primarily affects cognitive
function and accounts for 60–70% of all dementia cases [66]. It is characterized by a
diffuse atrophy of the brain, which starts from the hippocampus and spreads to the rest
of the brain. While the pathogenesis of the disease is complex and, in part, unveiled, a
role seems to be played by the deposition of the amyloid β (Aβ) peptide as the result of
the proteolytic cleavage of the β-amyloid precursor protein (APP) through the action of
α and γ-secretases [67]. On the contrary, when α and β secretases cleave APP, soluble
fragments are released. In the extracellular space, aggregates of Aβ peptide form the
amyloid plaques, while in neurons, abnormal precipitates of the phosphorylated tau protein
accumulate as neurofibrillary tangles. Aggregated proteins activate microglia and trigger
neuroinflammation, which plays a role in the severity of the disease [68]. Accordingly,
high levels of pro-inflammatory cytokines are detected in the brain and cerebrospinal fluid
of Alzheimer’s disease patients. Additionally, inducible nitric oxide synthase (iNOS) is
overexpressed in the brain, and iNOS knock-out mice are protected against the disease [69].
Additionally, PGD2 levels are higher in the cortex of Alzheimer’s disease patients than in
healthy individuals. Inflammatory alterations, together with Aβ deposits, also occur in the
vessels, thus impairing blood flow. Mg deficiency contributes to Alzheimer’s disease and
reduced amounts of Mg have been detected in the brain of the patients [70–72]. While it
is likely that a BBB dysfunction might alter Mg transport, no causative mechanisms have
been demonstrated yet. A recent metanalysis of 21 studies published in the last 20 years
reported that circulating Mg levels in Alzheimer’s patients were significantly lower than in
healthy people [73]. Considering that the content of Mg in the Western diet is low [74], it is
 it is likely that a BBB dysfunction might alter Mg transport, no causative mechanisms
been demonstrated yet. A recent metanalysis of 21 studies published in the last 20 y
reported that circulating Mg levels in Alzheimer’s patients were significantly lower
in healthy people [73]. Considering that the content of Mg in the Western diet is low
Int. J. Mol. Sci. 2023, 24, 223 6 of 14
it is interesting that high dietary Mg intake is inversely correlated with the risk of d
oping cognitive impairment [75,76]. Accordingly, Mg supplementation in an an
model of Alzheimer’s
interesting disease
that high dietary Mg supports the relevance
intake is inversely ofwith
correlated appropriate concentrations o
the risk of developing
mineral in reducing
cognitive impairment neuroinflammation,
[75,76]. Accordingly, Mg preventing Aβ deposition,
supplementation in an animal and improving
model of le
Alzheimer’s disease supports
ing abilities and memory [77]. the relevance of appropriate concentrations of this mineral in
reducing neuroinflammation, preventing Aβ deposition, and improving learning abilities
These protective effects of Mg are explained by the fact that Mg downregulate
and memory [77].
1β, thereby
Theseinhibiting inflammation;
protective effects it reduces
of Mg are explained the
by the synthesis
fact of the Aβ peptide
that Mg downregulates IL-1β, by sw
ingthereby
β- to α-secretase cleavage, facilitates
inhibiting inflammation; it reduces thethesynthesis
clearance of Aβ
of the Aβpeptide
fibrils by
byswitching
controlling the
β- to α-secretase
meability cleavage,
of the BBB, andfacilitates
preventsthe clearance
the of Aβ fibrils by
phosphorylation of controlling
tau [77–79] the(Figure
perme- 3).
ability of the BBB, and prevents the phosphorylation of tau [77–79] (Figure 3).

Figure 3. Low Mg in Alzheimer’s and Parkinson’s diseases. Magnesium deficiency promotes

Figure 3. Low Mg in Alzheimer’s and Parkinson’s diseases. Magnesium deficiency promotes
common events involved in Alzheimer’s and Parkinson’s diseases.
mon events involved in Alzheimer’s and Parkinson’s diseases.
Mg deficiency might represent the common denominator explaining, at least in part,
theMgrelationship
deficiencyexisting
might between diabetes
represent thetype 2 and Alzheimer’s
common denominator disease [80]. It is well-
explaining, at least in
known that Mg balance is impaired in diabetes and contributes to glucose intolerance and
the relationship existing between diabetes type 2 and Alzheimer’s disease [80]. It is
insulin resistance [81]. The resulting hyperinsulinemia and hyperglycemia increase Aβ
known that Mgand
accumulation balance is impaired
exacerbate in diabetes
neuroinflammation and Correcting
[80,82]. contributes Mgto glucose
might intolerance
therefore
insulin resistance
represent [81].with
a “two birds Theone resulting hyperinsulinemia and hyperglycemia increas
stone” intervention.
Mg homeostasis depends on the
accumulation and exacerbate neuroinflammation activity of several [80,82].
transporters. TransientMg
Correcting receptor
might ther
potential melastatin (TRPM) 7, a ubiquitously expressed ion channel coupled with an
represent a “two birds with one stone” intervention.
α kinase domain, is essential in maintaining intracellular Mg concentrations [83]. It has
Mginhomeostasis
a role neurodevelopmentdepends onembryonic
at early the activity ofand
stages several transporters.
coordinates Transient
the maturation of rece
potential melastatin (TRPM) 7, a ubiquitously expressed ion channel
neuronal networks at later postnatal stages [84] and the loss of this channel is involved coupled with
kinase
in thedomain, is essentialdiseases
onset of neurological in maintaining
[85]. At theintracellular Mg concentrations
cellular level, TRPM7 controls the pro- [83]. It h
liferation and differentiation of neuronal cells and regulates the growth
role in neurodevelopment at early embryonic stages and coordinates the maturatio and migration of
astrocytes [8]. TRPM7 has also been implicated in mediating neuronal death in response to
neuronal networks at later postnatal stages [84] and the loss of this channel is involv
various triggers [86]. Accordingly, in the rat hippocampus, TRPM7 knock-down prevents
theneuronal
onset ofdeath
neurological diseases
after ischemia, [85]. At cognitive
thus preserving the cellular level,
function and TRPM7
memorycontrols
tasks [87].the pro
ation and differentiation
Moreover, the evidence that ofTRPM7
neuronal shapescells and regulates
immune the growth
system function and migration
[88,89] indicates it o
might [8].
trocytes playTRPM7
an indirect
hasrole in neuroinflammation
also been implicated in and neurodegeneration.
mediating neuronalOf interest,
death in respon
TRPM7 kinase transactivates SMAD2-dependent genes, thus promoting T cell differentia-
various triggers [86]. Accordingly, in the rat hippocampus, TRPM7 knock-down prev
tion toward the pro-inflammatory Th17 lymphocyte [90]. IL17, the signature cytokine of
neuronal death
Th17 cells, afterthe
promotes ischemia,
activationthus preserving
of astrocytes cognitive
and microglia, function
heightens the and memory tasks
inflammatory
Moreover, theand
cascade [91], evidence thatintegrity
impairs BBB TRPM7[92]. shapes immune
All these system
events occur function [88,89]
in Alzheimer’s disease, indica
might play an indirect role in neuroinflammation and neurodegeneration.
and IL17 promotes the classical Alzheimer’s disease neuropathology [92]. Circulating TH17 Of inte
cells are markedly increased in the early stages of the disease and are associated with the
extent of amyloidopathy [93]. Antibodies against IL17 mitigate cognitive impairment and
reduce amyloid β-induced neuroinflammation in mice [94].

4.2. Magnesium and Parkinson’s Disease

Parkinson’s disease is the second most common neurodegenerative disorder, and
its prevalence has risen rapidly in the last 20 years. It is characterized by cardinal motor
postural instability, rigidity, involuntary body movements, bradikynesia, rest tremor- and
Int. J. Mol. Sci. 2023, 24, 223 7 of 14

non-motor symptoms, such as cognitive impairment, depression, autonomic dysfunction,

and disorders of sleep [95]. Parkinson’s disease results from the complex combination of
various pathological events, among which are abnormal protein aggregation, altered lyso-
some function, mitochondrial dysfunction, endoplasmic stress, glutaminergic excitotoxicity,
oxidative stress, and neuroinflammation. These all promote neuronal death, targeting the
dopaminergic neurons of the basal ganglia in particular. Mg might exert beneficial effects
by contrasting oxidative stress, neuroinflammation, and exaggerated NMDA-R activity.
Further, Mg increases BDNF, which is a trophic factor for dopaminergic neurons, including
those that degenerate in the disease [96]. Moreover, by acting on the mTOR pathway, Mg
reduces the formation of α-synuclein, the main protein involved in the pathogenesis of
Parkinson’s disease [97]. Mg also inhibits α-synuclein aggregation by directly binding
the protein and preventing interaction with pro-aggregant metals, such as Fe [2]. These
mechanisms might explain why a multicenter case-control study in Japan reported that
higher Mg intake was associated with a reduced risk of Parkinson’s disease [98]. Moreover,
since nitrative stress has a high etiopathogenic relationship with the disease [99], it should
be recalled that Mg downregulated iNOS and attenuated the loss of dopaminergic neurons
in a murine Parkinsonian model [100].
Mg in the cerebrospinal fluid is lower in Parkinson’s disease patients and in Parkin-
son’s disease animal models than in controls [101,102]. Moreover, using spectroscopic
methods, lower Mg levels were detected in postmortem brains from Parkinson’s disease
patients compared to the controls [103]. A low Mg dietary intake over generations damages
the mitochondria, the endoplasmic reticulum, ribosomes, and nuclear DNA, as well as
induces the loss of the dopaminergic neurons in the substantia nigra [104]. That altered Mg
balance has a role in Parkinson’s disease is further supported by the evidence that muta-
tions of the Mg transporting protein solute carrier family 41 member 1 (SLC41A1) were
reported in familial Parkinson’s disease patients [105,106], and SLC41A1 downregulation
occurs in a Parkinsonian animal model [107]. Looking at TRPM7, it has been proposed as a
candidate susceptibility gene for familial Parkinson’s disease [108]. TRPM7 has a funda-
mental role in the survival of dopaminergic human neuroblastoma SH-SY5Y cells [109],
and the suppression of TRPM7 inhibits Mg content and mitochondrial function, inducing
cell death [85]. On the contrary, in an experimental model of Parkinson’s disease induced
by 6-hydroxy-dopamine, the total amounts of TRPM7 are increased [110], and the silencing
TRPM7 is neuroprotective in pheochromocytoma PC12 cells [111].

4.3. Magnesium and Multiple Sclerosis

Multiple sclerosis is a common disabling disease in young adults and is manifested by
a variety of signs and symptoms, including vision loss, weakness, and spasms. Hallmarks
of multiple sclerosis are the demyelination and axonal degeneration in different areas of
the brain and spinal cord, as well as the disruption of the BBB, events sustained by the
activation of inflammation [112]. Cytokines, NO, and mitochondrial dysfunction are major
determinants in the onset, recurrence, and progression of the disease. Considering the anti-
inflammatory action of Mg and its role in maintaining mitochondrial function, the potential
protective role of a correct intake of Mg is feasible. As in Alzheimer’s disease, Th17 cells
are key effectors in multiple sclerosis, and accordingly, IL17 is highly expressed in the brain
of patients [113]. Moreover, because of its antagonist action on Ca, Mg supplementation
improved the severe spastic paraplegia in a young multiple sclerosis patient [114]. Further,
since vitamin D deficiency seems to play a causal role in the disease, it is worth noting
that Mg is required for vitamin D metabolism, and Mg supplementation is recommended
in vitamin D deficiency [115,116]. Notably, patients with multiple sclerosis treated with
Mg and vitamin D experienced significantly less exacerbations than untreated ones [117].
Conflicting results are available about the levels of serum Mg. A study reported that
patients with normal serum Mg had a more favorable clinical course than patients with
low circulating Mg [118]. Another investigation demonstrated reduced concentrations of
several minerals, among which were Mg, in the blood of multiple sclerosis patients [119].
Int. J. Mol. Sci. 2023, 24, 223 8 of 14

However, according to a recent metanalysis, no significant differences of magnesemia

emerged between multiple sclerosis patients and healthy controls [120].
TRPM7 is overexpressed in astrocytes isolated from patients with multiple sclerosis,
and this dysregulation seems to be involved in the early and late steps of multiple sclerosis.
Initially, upregulated TRPM7 might drive the accumulation of Th17 lymphocytes, thus
favoring inflammation [89]. Then, it might favor the progression of the disease because
TRPM7 overexpression is linked to the formation of the gliotic scars [121].

5. Unanswered Questions in Mg, Neuroinflammation and Neurodegeneration

Some aspects that might correlate with altered Mg levels and neurodegenerative
diseases still need to be unveiled. First, Mg deficiency accelerates cellular senescence
and aging [122,123], events that translate to reduced adaptation to stressors, as typically
reported in the elderly. Moreover, senescent cells, including astrocytes, release a wide
range of inflammatory cytokines and chemokines, thus generating and maintaining inflam-
mation with detrimental effects on the brain [124]. Looking at the increasing interest in
senotherapeutic approaches to prevent or treat age-associated disorders [125], it is rational
to investigate whether Mg deficiency might also promote neurodegeneration by hastening
the senescence of brain cells. Second, Mg is a regulator of the circadian rhythm of cellular
metabolism and function [126]. Indeed, circadian control of oxidative stress, proteostasis,
and inflammatory pathways plays a role in neurodegeneration. Therefore, it is likely that
alterations of Mg balance are reflected into circadian dysfunction, which results in the
accumulation of neurotoxic proteins. Accordingly, circadian rhythm disruptions, which are
common in the elderly, are more severe in patients with a wide range of neurodegenerative
diseases, including Parkinson’s and Alzheimer’s diseases [127]. Third, Mg supports the
integrity of the intestinal barrier. Mg deficiency causes intestinal dysfunction that increases
the paracellular transport of LPS, a component of the cell wall of Gram-negative bacteria,
into systemic circulation [128,129], thus promoting inflammation. Therefore, Mg deficiency
also increases neuroinflammation by altering gut microbiota, which influences the ner-
vous system through the activation of the vagal nerve, the production of cytokines, and
the release of neuropeptides and neurotransmitters [130]. Accordingly, low Mg intake
unbalances the gut microbiota–brain axis, which leads to depression in mice [130,131].
Moreover, because of the growing interest in the implications of TRPM7, a cation channel
with kinase function, in neurological and neurodegenerative disorders, there is a need to
better understand the role of this channel in the direct (on target cells) or indirect (e.g., via
systemic inflammation) impact on nervous system alterations.
Another aspect that requires attention is the choice of Mg salt that more efficiently
traverses the BBB to be utilized in case of Mg deficiency to harmonize the levels of brain
Mg. While preclinical reports are rather numerous, more clinical trials should be fostered
to address this issue.
A correct and, if possible, personalized dietary intake of Mg might represent a preven-
tive measure, whereas supplementing Mg might be an adjunct option in neurodegeneration.

6. Conclusions
Neuroinflammation drives tissue damage in neurodegeneration. Solid evidence sug-
gests a role of Mg in taming neuroinflammation and in retarding some neurodegenerative
diseases. Therefore, a correct and, if possible, personalized dietary intake of Mg might
represent a preventive measure, whereas supplementing Mg might be an adjunct option
in neurodegeneration.
Int. J. Mol. Sci. 2023, 24, 223 9 of 14

Author Contributions: Review, conception, and design: J.A.M.M. and A.M.; critical analysis of
literature: J.A.M.M., L.L., G.F., A.C., A.M.; manuscript preparation: J.A.M.M.; reviewing the final
version of the manuscript: J.A.M.M., L.L., G.F., A.C., A.M. All authors have read and agreed to the
published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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