International Journal of

Molecular Sciences

Review
Migraine Pharmacological Treatment and Cognitive
Impairment: Risks and Benefits
Mirella Russo 1,2 , Matteo A. De Rosa 1 , Dario Calisi 1 , Stefano Consoli 1 , Giacomo Evangelista 1 , Fedele Dono 1,2 ,
Matteo Santilli 1 , Alberto Granzotto 1,2 , Marco Onofrj 1,2 and Stefano L. Sensi 1,2,3,4, *

1 Department of Neurosciences, Imaging and Clinical Sciences, “G. d’Annunzio” University of Chieti-Pescara,
66100 Chieti, Italy
2 CAST—Center for Advanced Studies and Technology, “G. d’Annunzio” University of Chieti-Pescara,
66100 Chieti, Italy
3 Institute for Mind Impairments and Neurological Disorders-iMIND, University of California, Irvine,
Irvine, CA 92697, USA
4 ITAB—Institute of Advanced Biomedical Technology, “G. d’Annunzio” University of Chieti-Pescara,
66100 Chieti, Italy
* Correspondence: [email protected]

Abstract: Migraine is a common neurological disorder impairing the quality of life of patients.
The condition requires, as an acute or prophylactic line of intervention, the frequent use of drugs
acting on the central nervous system (CNS). The long-term impact of these medications on cognition
and neurodegeneration has never been consistently assessed. The paper reviews pharmacological
migraine treatments and discusses their biological and clinical effects on the CNS. The different anti-
migraine drugs show distinct profiles concerning neurodegeneration and the risk of cognitive deficits.
These features should be carefully evaluated when prescribing a pharmacological treatment as many
migraineurs are of scholar or working age and their performances may be affected by drug misuse.
Citation: Russo, M.; De Rosa, M.A.;
Thus, a reconsideration of therapy guidelines is warranted. Furthermore, since conflicting results
Calisi, D.; Consoli, S.; Evangelista, G.;
have emerged in the relationship between migraine and dementia, future studies must consider
Dono, F.; Santilli, M.; Granzotto, A.;
Onofrj, M.; Sensi, S.L. Migraine
present and past pharmacological regimens as potential confounding factors.
Pharmacological Treatment and
Cognitive Impairment: Risks and Keywords: migraine; dementia; Alzheimer’s disease; neurodegeneration; neuroprotection
Benefits. Int. J. Mol. Sci. 2022, 23,
11418. https://doi.org/10.3390/
ijms231911418
1. Introduction
Academic Editor: Timo T Myöhänen
Migraine is the most prevalent non-communicable neurological disorder in subjects
Received: 8 August 2022 in the 35–60 age bracket, whereas dementia leads the ranking in older individuals [1].
Accepted: 20 September 2022
The two conditions are significantly debilitating and represent a significant burden on
Published: 27 September 2022
health systems [1]. Recent investigations have attempted to assess links between the
Publisher’s Note: MDPI stays neutral two conditions, but, in most cases, the results were conflicting and inconclusive [2]. While
with regard to jurisdictional claims in an increased risk for mid-to-late-life cognitive impairment in migraineurs [3–7] has been
published maps and institutional affil- frequently reported, fewer observations have contradicted the notion [8,9]. Longitudinal
iations. evaluations of the cognitive status of people with migraine (PwM) have shown average
performances [10,11]. In these surveys, the risk of dementia has also been evaluated
according to patients’ features and subtypes, with mixed results. For instance, the increased
risk of dementia has been reported only in female subjects by some authors [5,6], but
Copyright: © 2022 by the authors.
others also indicated the opposite [3,12]. Finally, a recent meta-analysis confirmed the
Licensee MDPI, Basel, Switzerland.
existence of a minor yet significant increased risk for all-cause dementia (RR = 1.33; 95%CI:
This article is an open access article
1.16–1.5) [13].
distributed under the terms and
An unresolved issue concerns the type of dementia associated with cognitive impairment.
conditions of the Creative Commons
Alzheimer’s disease (AD) is the most common cause of dementia in the elderly [14].
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
Thus, the present review will be focused on this pathology. The current understanding of
4.0/).
AD pathophysiology is highly debated. Nevertheless, the disease’s pillars are represented

Int. J. Mol. Sci. 2022, 23, 11418. https://doi.org/10.3390/ijms231911418 https://www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2022, 23, 11418 2 of 27

by the accumulation of brain deposits of β-amyloid and neurofibrillary tangles of hyper-

phosphorylated tau [15,16]. Other dementias include Lewy body dementia (LBD), which
encompasses dementia with Lewy bodies (DLB) and Parkinson’s disease with dementia
(PDD), frontotemporal dementia (FTD) [17], and limbic-predominant age-related TDP-43
encephalopathy (LATE) [18].
Most migraine therapies last several months or years and directly affect the central
nervous system (CNS) [19,20]. Migraine treatment aims to interrupt painful attacks with
abortive drugs and, when needed, prevent new attacks with prophylactic interventions.
Nonsteroidal anti-inflammatory drugs (NSAIDs), such as naproxen, aspirin, diclofenac
potassium, celecoxib, and ibuprofen, are the first-line treatment for migraine attacks [19,20].
Combinations of drugs, such as acetaminophen + aspirin + caffeine, are also employed, as
well as specific second-line or third-line migraine treatments, such as triptans (II), ditans
(III), and gepants (III) [20]. Ergot-derivates are less frequently used (see Section 3.8) [20,21].
Prescription of a preventive treatment has been recommended for ≥4 days of migraine-
related disability per month [21]. However, new guidelines indicate that it should be
employed in the case of ≥2 days of impairment despite optimized first-line therapy [20].
Albeit not mandatory, this indication may lead to widespread and long-term use of com-
pounds that affect the CNS. Migraine prophylaxis is recommended for at least three months
but may be used up to 6–12 months [22]. Beta-blockers, topiramate, and candesartan are
first-line medications. Flunarizine, amitriptyline, and sodium valproate are second-line,
and GRP monoclonal antibodies are third-line treatments [20].
The present work reviews the mechanisms of action of pharmacological treatments
for migraine, including abortive and prophylactic drugs. The goal is also to assess pharma-
codynamic links with cognitive symptoms or AD-related neurodegenerative pathways.

2. Cognitive Profiles in Migraineurs

2.1. Overview
Detailed descriptions of the subclinical neuropsychological features of PwM are be-
yond the scope of the present paper, and comprehensive reviews are already available on
the subject [23–25]. Thus, only the main findings will be reported in this section. Mild
visual and verbal memory impairment, reduced information processing speed, executive
dysfunction, and attention deficits have been reported in PwM [23]. In the ictal phase,
migraineurs may experience cognitive inefficiency and confusion that may be partially
due to the concurrent physical symptoms, such as pain, nausea, and photophobia [26,27].
However, migraine is associated with slight cognitive dysfunctions also during the interic-
tal periods. These appear in tasks involving complex attention and executive functioning,
including set-shifting, spatial cognition, and immediate and delayed memory [24,25,28].
The deficits also affected global cognition, with a more prominent effect in PwM without
aura [24]. They are influenced by the frequency and severity of the attacks [29]. Interest-
ingly, the language domain is spared, whereas conflicting results are available on basic
attention [24,25]. Of note, a negative correlation between mood and cognitive performance
has been posited [25], possibly underlying the presence of shared network derangement.
The overlap also creates a therapeutical window as some antidepressants are used as a
migraine prophylaxis.

2.2. Small-Vessel Disease, Vascular Dementia, and Genetic Conditions

A striking intersection point between cognitive impairment and migraine is repre-
sented by vascular dementia (VaD). Increased cerebrovascular risk is acknowledged in
migraineurs, whose brains typically display white matter changes and may also have small
infarct-like lesions, especially in migraine with aura [30]. While most brain lesions are
silent, a two-fold risk of ischemic attack has also been observed [31]. The ischemic strokes
may be temporally related to the migraine attacks (migrainous infarction) [32] or can also
be disjoined. Accordingly, cognitive impairment is evident immediately after acute brain
infarction. On the other hand, a link between migraine and long-term development of VaD
Int. J. Mol. Sci. 2022, 23, 11418 3 of 27

(e.g., due to chronic small vessel disease) was rarely confirmed [33] and challenged mainly
by subsequent investigations [5,12,34].
Different from sporadic cases, some genetic-driven disorders show major overlap
between migraine and vascular cognitive impairment. Cerebral autosomal dominant
arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), as well as mi-
tochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), are featured
by migraine attacks and cognitive impairment, mostly related to progressive impairment
in the cerebral white matter due to vascular damage [35,36]. Another genetic condition that
encompasses cognitive impairment—mostly due to vascular damage and brain atrophy—
and migraine is represented by retinal vasculopathy with cerebral leukoencephalopathy
(RVCL) [37].
Cerebral amyloid angiopathy (CAA) is a neurodegenerative disorder, sharing patho-
physiological and clinical traits with AD, that also combines cognitive impairment and
migraine, to the point that migraine with aura attacks was proposed as an early biomarker
of the clinical onset of a genetic variant of CAA (Dutch type) [38]. Of note, migraine attacks
are also present in presenilin-1- and amyloid-precursor-protein-related familial AD [39].

3. Migraine Drugs, Neurodegenerative Pathways, and Cognition: Protection or Risk?

3.1. Anti-Seizure Medications (ASMs)
Data regarding cognitive adverse effects (CAEs) of ASMs have mainly come from
studies performed on epileptic patients. Though some of these effects are undoubtedly the
result of chronic exposure, CAEs onset can also be observed in medium-term administration
as performed in migraine prophylaxis.
Topiramate (TPM), valproic acid (VPA), and gabapentin (GBP) are currently the most
frequently used ASMs in patients with chronic migraine as prophylaxis treatment [40].
TPM exerts its anti-migraine activity by stimulating GABA-A receptors, inhibiting
AMPA and kainate receptors, and blocking cortical spreading depression (CSD), a neuro-
physiological phenomenon characterized by abrupt changes in intracellular ion gradients
and sustained depolarization of neurons [41,42]. In preclinical models, inhibition of AMPA
receptors has been linked to modulation of the Akt/GSK-3β/CREB neuroprotective path-
way [43] and decreased oxidative stress and release of inflammatory mediators [44]. TPM
also promotes neural homeostasis by stimulating the release of brain-derived neurotrophic
factor (BDNF) [44]. CAEs are not uncommon with TPM and usually occur, in a dose-
dependent fashion, during the early phase of the treatment (i.e., within the first 6 weeks).
These side effects include attention deficits, psychomotor slowing, language and compre-
hension difficulties, short-term memory and working memory deficits, poor verbal fluency,
reduced cognitive speed, and altered thinking [45–50]. About 10% of adult patients treated
with TPM as prophylaxis for migraine attacks show mild-to-moderate concentration and
memory difficulties, especially during titration [51,52]. These effects are reversible and
generally disappear after treatment interruption. TPM has been shown to exert more
negative effects on cognition than a range of other antiepileptic drugs [49]. Patients with
pre-existing cognitive dysfunction or a past psychiatric history seem more prone to develop
TPM-related CAEs [53,54]. The mechanism through which TPM may define the onset of
CAEs is unclear. Experimental models suggest that TPM, like other sulfamate compounds
(e.g., zonisamide, ZNS), exhibits a particular tropism for frontal areas, explaining the
worsening in verbal fluency [55].
VPA is a voltage-gated sodium, potassium, and calcium channels blocker, which
also increases GABA levels by inhibiting GABA aminotransferase [56]. VPA exerts its
anti-migraine effects by blocking CSD. VPA administration generates only minor changes
in cognitive functioning regarding attention and visuomotor performances [57]. A random-
ized controlled study in 480 treatment-naïve adult patients with focal epilepsy showed
worse scores in attention and visuomotor tasks in the VPA-treated group compared to
controls [58]. An additional study demonstrated that only a minor percentage of VPA-
treated patients with epilepsy (1.3%) developed Parkinsonism, psychomotor slowing, and
Int. J. Mol. Sci. 2022, 23, 11418 4 of 27

memory difficulties, with a delay of 2.5–10 months after treatment start [59]. These effects
were unrelated to VPA dose, patient age, or epilepsy duration. On the other hand, acute
and chronic VPA administration increase brain levels of taurine and glycine, as well as
serotonin and dopamine in the hippocampus [60], improving cognitive functioning. In
addition, VPA reduced β-amyloid generation and tau hyperphosphorylation, improving
memory deficits of transgenic mouse models of AD [61]. Even though there is a lack of
prospective and controlled studies, the overall available evidence favors the good cognitive
tolerability of VPA.
The precise mechanism through which GBP exerts its therapeutic effects is not well
understood. GBP binds the α2δ-1 subunit of voltage-gated calcium channels, which pro-
motes the transfer of pore-forming α1 subunits of calcium channels from the endoplasmic
reticulum to the cell membrane of pre-synaptic neurons. These subunits play a pivotal
role in the pathophysiology of hyperalgesia. Chronic pain increases the expression of
α2δ subunits and leads to the development of hyperalgesia [62]. Most studies stress the
safety of GBP on cognitive functions, showing only minor or no adverse effects [63–65].
In contrast, just a few underpowered studies reported a possible worsening in attention,
verbal memory, and general executive functioning [66,67] after GBP chronic treatment.
In addition, GBP showed neuroprotective properties, especially in preclinical models of
cerebral ischemia, through activation of the PI3K/Akt/mTOR pathway. The resulting
antioxidant and anti-autophagic effects prevent neuronal loss after ischemic injury [68].
Further ASMs, namely pregabalin (PGB), lamotrigine (LMT), levetiracetam (LEV), and
ZNS, have been occasionally described as therapeutic options for migraine prophylaxis.
PGB is a pre-synaptic voltage-gated calcium channels inhibitor that modulates the release
of several neurotransmitters involved in pain signaling, including glutamate, substance-
P, norepinephrine, and calcitonin-gene-related peptide [69]. In addition, PGB increases
the threshold for CSD, showing a specific mechanism of action against migraine [70].
PGB negatively impacts cognition, especially visuospatial memory, processing speed, and
attention [71], although the effect is generally mild-to-moderate and lower than other ASMs.
On the other hand, PGB has shown neuroprotective effects in experimental models of
diabetes mellitus by reducing oxidative damage and showing anti-apoptotic properties [72].
However, testing PGB in an animal model of AD has provided poor results, questioning
the use of the compound as a possible therapy in neurodegenerative disease [73].
LMT has positive effects on cognition and exhibits neuroprotective properties [74].
LMT, a selective inhibitor of voltage-gated sodium channels, also inhibits presynaptic
glutamate and aspartate release [75]. LMT treatment reduced the number and size of
amyloid plaques in the brain and increased the concentration of BDNF and nerve growth
factor (NGF) in a preclinical model of AD [76]. Similar positive effects have been described
for LEV, which also improves a range of cognitive domains, including attention and short-
term and working memory [77,78]. AMPA receptor blockade explains the neuroprotective
properties of the compound, especially in AD patients [79]. On the contrary, ZNS has
been associated with cognitive profile worsening and the onset of attention and memory
deficits [80]. ZNS is a sulfamate compound that blocks sodium and T-type calcium channels,
which share common CAEs with topiramate [55]. ZNS reduced amyloid deposition and
tau phosphorylation in a mouse model of type-2 diabetes [81].
Conclusions: ASMs may be very effective for migraine prevention, but they carry
more side effects than other drug classes. Topiramate has the heaviest impact on cognition.
Of note, other ASMs proposed for migraine prophylaxis, such as LMT and LEV, show
better tolerability profiles and might be considered for migraineurs at risk for cognitive
impairment (e.g., positive family history).

3.2. Antidepressants
Antidepressants are a broad category of drugs primarily used to treat mood distur-
bances. Despite poorly understood mechanisms of action, their effectiveness for migraine
treatment is also acknowledged. The impact of long-term therapies with serotonergic drugs
Int. J. Mol. Sci. 2022, 23, 11418 5 of 27

on the brain’s amyloid load has been investigated with positron emission tomography
(PET) brain scans. Protective effects on amyloid deposition and a correlation with delayed
conversion time from mild cognitive impairment (MCI) to AD (72) have been reported.
Specific antidepressants are detailed below.

3.2.1. Tricyclic Antidepressants

Amitriptyline is a tricyclic antidepressant (TCA) that acts as a mixed serotonin–
norepinephrine reuptake pump inhibitor (SNRI), sodium-channels blocker, and has an-
timuscarinic and antihistaminic effects [82]. It is effective for migraine prevention at a
lower dose than those used in depression, even in the absence of mood disorders [82].
The mechanism by which amitriptyline prevents migraine attacks relies on its activity
as an endogenous pain modulator and suppressor of CSD [83]. Chronic treatment with
amitriptyline inhibits CSD by reducing sodium channel synthesis, desensitizing presynap-
tic receptors, and producing long-lasting monoaminergic neurotransmission changes [84].
Amitriptyline also modulates the noradrenergic descending inhibitory systems, including
α2-adrenoceptor in the spinal dorsal horn, by activating noradrenergic neurons in the locus
coeruleus and enhancing noradrenergic signaling [85]. Overall, clinical studies revealed
detrimental effects on cognition, which are most prominent in elderly subjects and MCI
patients [82,86–88]. Cognitive side effects of amitriptyline are unspecific, but a correlation
with non-amnestic MCI (naMCI) has been posited since the anticholinergic and antihis-
taminic effects primarily affect attention, decision-making, and psychomotor speed [86,87].
Memory deficits are less frequent and appear at higher doses [86].
Due to its anticholinergic properties, a substantial side effect is the worsening of
cognition, as confirmed by a German retrospective study on amitriptyline-treated subjects
with pre-existent cognitive impairment [87]. Amitriptyline is classified as a third-class drug
(the highest) on the Anticholinergic Cognitive Burden scale [87]. Anticholinergic agents
trigger cognitive decline by reducing neuronal connectivity from the basal forebrain to
the hippocampus and cortex [88]. The antihistaminic properties also promote cognitive
impairment by inducing sedation (7) through H1 receptors [89].
On the other hand, neuroprotective properties of amitriptyline have been observed.
Amitriptyline modulates neurotrophin levels [90] and acts as a TrkA and TrkB receptor
agonist, thereby showing beneficial effects by blocking neuronal death and hippocampal
apoptosis [90]. Similarly, in a rotenone rat model of PD, amitriptyline administration
increased BDNF levels and promoted dopaminergic neuron survival [91].

3.2.2. Serotonin and Norepinephrine Reuptake Inhibitors and Selective Serotonin

Reuptake Inhibitors
Serotonin and norepinephrine reuptake inhibitors (SNRIs) are antidepressant drugs
frequently employed in clinical practice [92]. These medications are also used for migraine
prevention and are particularly useful in comorbid depressed patients [83,93]. The mecha-
nism of action is related to modulation of descending pain pathways, mainly due to the
potentiation of norepinephrine transmission [92,93]. SNRIs—particularly duloxetine—are
highly effective as anti-migraine drugs in subjects showing “descending pronociceptive”
features [92]. Pronociceptive migraineurs are less responsive to NSAIDs than centrally
acting pain modulators [92].
Venlafaxine is an SNRI with a high safety profile, even in the elderly, due to no affinity
for adrenergic, muscarinic, or histaminergic receptors [94,95]. Venlafaxine was found as
effective as amitriptyline for migraine prevention [96] by modulating descending pain
pathways [92]. Little is known about the effects of venlafaxine on cognition. However,
results from preclinical studies indicate neuroprotective activity [92,97,98] in terms of
myelin integrity [97] associated with improved working memory performances. This
finding was not correlated with mood symptom improvement [97].
Duloxetine is an SNRI also effective for migraine prevention, especially in depressed
and fibromyalgia patients [83,93]. Preclinical models showed that duloxetine exhibits
Int. J. Mol. Sci. 2022, 23, 11418 6 of 27

antioxidant properties that can counteract free radical generation and apoptosis [92], as
well as anti-glutamatergic and pro-cholinergic actions [99]. In chronic immobilization
stress-induced mice, duloxetine inhibited hippocampal degeneration by up-regulating
BDNF-driven neurogenesis, synaptic plasticity [99], and neurite outgrowth [100]. In de-
pressed patients, the clinical effects of duloxetine on cognition are positive. Duloxetine
improved attentional deficits in PD [92], as well as behavioral symptoms and memory
deficits [92,101]. The compound also improves psychomotor processing, set-shifting, and
working memory [101]. Of note, the positive effects were also found in non-depressed
subjects [101]. In conclusion, duloxetine seems effective in promoting neuroprotective and
precognitive effects.
Although selective serotonin reuptake inhibitors (SSRI) are a second-line migraine treat-
ment, they effectively reduce the frequency and pain intensity of monthly episodes [83,93].
Fluoxetine blocks serotonin reuptake in the synaptic cleft and has an inhibitory effect on
5-HT2C receptors [83,93]. Higher doses also increase norepinephrine levels and modu-
late central opioid receptors [83,93]. The compound promotes hippocampal neurogen-
esis [102,103] and has neuroprotective effects by increasing BDNF levels [104,105] and
counteracting amyloid-driven neuronal toxicity [106,107]. Fluoxetine supplementation is
protective in neuronal cultures challenged with synthetic human amyloid oligomers. A
small randomized placebo-controlled trial in non-depressed MCI patients showed that
8 weeks of fluoxetine treatment improves performances on the MMSE test and immediate
and delayed logical memory tests [108].
Escitalopram’s effect on amyloid load has been tested on APP/presenilin 1 mice.
The compound significantly reduced (about 30%) the amyloid plaque load in a dose-
dependent fashion by increasing the expression of α-secretases and thus enhancing the
non-amyloidogenic pathway [109]. In humans, escitalopram administration was associated
with mild, non-significant, short-term verbal memory deficits that worsened and became
significant after pindolol (5-HT1A partial agonist) add-on administration. Furthermore,
spatial working memory deficits were observed upon intake of escitalopram + ketanserin
(a 5-HT2A antagonist) [110], thus highlighting that serotonin pharmacological modulation
could affect performances at memory tests. According to the authors, high CNS levels
of serotonin could induce cognitive impairment as well as low levels in a bell-shaped
curve [110]. These findings align with the notion that, in PD patients, administration of
pro-serotoninergic medications leads to better cognitive trajectories [111], possibly due to
restoring normal serotonin levels after the neurodegenerative depletion of serotonergic
transmission. The impact of SSRI and SNRI medications may differ according to subjects’
previous serotonin levels.
Conclusions: All the anti-depressants seem to have a favorable biological impact in
terms of neuroprotection. Nonetheless, amitriptyline—deemed the most effective com-
pound for migraine prevention—carries significant CAEs due to its anti-cholinergic and
anti-histaminergic properties. The serotonergic asset must be considered before prescribing
anti-depressants for migraine prevention.

3.3. Beta-Blockers
Several antihypertensive drugs are effective in slowing cognitive decline [112], al-
though it remains unclear if the protective effects observed are linked to cardiovascular
protection or modulation of neurodegenerative processes. Beta-blockers are the first-line
drugs for hypertension [113]. Propranolol, metoprolol, atenolol, and bisoprolol are also first-
line preventive therapies for migraine [20]. Although the use of beta-blockers is common in
elderly individuals, it is still unclear whether this class of drugs impacts the development of
cognitive conditions. Studies on beta-blockers as a group mostly found, in elderly subjects,
an increased risk of vascular dementia (after correction for confounders, such as atrial fibril-
lation, incident coronary event, stroke, and heart failure) but not for all-cause, AD, or mixed
dementia [114]. However, these results primarily focus on older adults taking beta-blockers
to manage hypertension. Thus, it is likely that many other confounders could interfere.
Int. J. Mol. Sci. 2022, 23, 11418 7 of 27

Of note, only long-term use of beta-blockers affects cognition [115]. Nonetheless, each
compound has a different capacity for crossing the blood–brain barrier (BBB) and thus may
differently impact the CNS. On one hand, cognitively impaired subjects taking CNS-active
beta-blockers exhibited a consistent trend to worsen memory retrieval and MMSE scores
when compared to untreated patients [116]. On the other hand, highly BBB-permeable
compounds (e.g., propranolol or carvedilol) decreased the risk of developing AD compared
to low permeable compounds (e.g., atenolol, sotalol, or bisoprolol) according to a large
nation-wide retrospective cohort from Denmark [117]. The effect was significant after a
minimum of 1.5 years of treatment and was attributed to improved clearance of AD-related
neurotoxic molecules [117]. Since each compound has unique biochemical properties, a
separate evaluation of each anti-migraine beta-blocker is still warranted.
Propranolol is a lipophilic non-cardioselective beta-blocker with membrane-stabilizing
properties [118]. Besides managing hypertension, angina pectoris, myocardial infarction,
and cardiac arrhythmias [118], propranolol is also used as migraine prophylaxis [20].
The noradrenergic system is essential in modulating memory processes and inhibiting
beta-noradrenergic receptors interfering with emotional memory reconsolidation [119].
Accordingly, propranolol has been used to treat post-traumatic stress disorder and is most
effective when administered before extinction of the stimulus. This evidence has shifted
the attention to the existence of a propranolol-driven cognitive bias that affects decision-
making [120]. Furthermore, compared to atenolol (a hydrophilic compound), a single dose
of propranolol increased the manipulation costs of a working memory task in young sub-
jects [121]. However, no differences in terms of memory maintenance were observed. More
comprehensive clinical investigations revealed no significant cognitive and psychological
alterations in propranolol-treated patients with hypertension [122–124], except for one
study showing mild long-term impairment in sustained attention [124].
Propranolol has shown neuroprotective effects in a preclinical AD model by reducing
Aβ1-42 hippocampal accumulation and decreasing tau hyperphosphorylation through
modulation of the GSK3β/JNK1 pathway [125]. Propranolol also inhibits Aβ1-42-driven
increase in cAMP levels and decreases ApoE expression [125]. This evidence suggests the
potential association between propanol and ApoE homeostasis in astrocytes, which could
counter Aβ neurotoxicity.
Metoprolol is a selective beta1-adrenergic antagonist with moderate BBB permeability,
recommended for episodic migraine prevention [126]. Metoprolol reduces cardiovascular
events and mortality in patients with hypertension and coronary heart disease [127]. From
a cognitive viewpoint, metoprolol improves proofreading, visual–motor performance,
and several measures of complex managerial competence [128]. However, metoprolol
has also exhibited immunomodulatory effects, increases pro-inflammatory conditions,
and attenuates anti-inflammatory signaling [129]. In addition, chronic use of metoprolol,
while impairing synaptic phagocytosis, potentiated synaptic degeneration and acceleration
of neurodegeneration in CNS disorders [129]. Whereas the pro-inflammatory effects of
acute beta-blocker administration have been observed only in the CNS in the amyloidosis
model, chronic effects of metoprolol warrant additional research with potential relevance
to human health.
Atenolol is a hydrophilic, generally well-tolerated selective adrenoceptor antago-
nist [130]. Unlike propranolol, atenolol treatment does not significantly affect cognitive
performance [131,132]. However, two case reports demonstrated cognitive improvement
after atenolol withdrawal [133]. Finally, atenolol treatment may be associated with a higher
number of errors in a visual–motor task and with impairment in one measure of complex
management [134].
Bisoprolol is a long-acting selective blocker of beta1-adrenergic receptors used for
management of congestive heart failure and prevention of episodic migraine attacks [135].
Despite its widespread use in clinical practice, there is no evidence linking the drug to
cognitive impairment or neurodegeneration.
Int. J. Mol. Sci. 2022, 23, 11418 8 of 27

Conclusions: The effect of beta-blocker administration on cognition and neurodegen-

erative processes seems more controversial than other drug classes, and further studies
are needed.

3.4. Calcium Channel Blockers

According to the Italian guidelines for primary headaches, the calcium channel block-
ers cinnarizine and flunarizine are recommended as preventive treatments for disabling
migraine [21]. However, the use of these drugs, especially in elderly patients, often results
in common side effects such as drowsiness, sedation, weakness, and depression [136]. In
addition, they may induce extrapyramidal symptoms and drug-induced Parkinsonism
(DIP) [137] due to their pre-synaptic and post-synaptic effects. In particular, the D2 receptor
blockade and the loss of tyrosine hydroxylase in the monoaminergic presynaptic can lead
to movement disorders [138,139]. Less well-known are the neurocognitive effects of these
drugs, particularly their long-term tolerability.
Calcium acts as a second messenger and regulates numerous biological processes, such
as muscle contraction, neuronal plasticity, cell migration, cell growth, and excitability [140].
Calcium is also implicated in releasing neurotransmitters, including glutamate, via voltage-
gated channels (N-type and P/Q-type) located at the presynaptic terminals. Once released,
glutamate promotes calcium entry through NMDA receptors and, indirectly, through L-type
calcium channels. Excessive glutamatergic stimulation can lead to excessive ion flux into
the cell (particularly sodium and calcium), resulting in oxidative stress, neuronal damage,
and subsequent cell death [141–144]. This process, termed excitotoxicity, participates in
many neurodegenerative disorders [145], including headache, epilepsy, AD, and vascular
disorders [144,146].
Cinnarizine is a calcium channel blocker (CCB) that inhibits vascular smooth muscle
cell contractions by blocking voltage-gated L- and T-type calcium channels. Cinnarizine
antagonizes dopamine D2 receptors, histamine H1 receptors, and muscarinic acetylcholine
receptors (weak anticholinergic activity) [147]. Antihistaminic and antimuscarinic drugs
are known to impair cognitive processes [148], but D2 antagonism also plays an important
role in impairing working memory [149]. The dopaminergic system is involved in memory
processes and the proper functioning not only of the hippocampus but also the striatal
(caudate) dopaminergic system, intermingled in numerous cognitive networks [150,151].
Cases of cinnarizine overdose have been reported in pediatric and adult children [152],
with effects including a range of symptoms such as drowsiness, coma, vomiting, hypotonia,
stupor, and seizures. In addition, a study reported that, when compared to the pre-
intake status, cinnarizine administration significantly impaired psychomotor performance,
information processing, and vigilance [153]. The maximum effect occurred 5–6 h after drug
administration and lasted for 10 h, an effect linked to drug-mediated blockade of CNS H1
receptors. However, a recent study showed that cinnarizine does not affect psychomotor
speed, attention, vigilance, and working memory [154].
Other studies reported no adverse effects or even a protective role of cinnarizine. A
placebo-controlled trial on pediatric PwM [155] showed no serious adverse effects. No
cognitive adverse effects were reported—but neither specifically assessed. Finally, in a
preclinical model of haloperidol-induced cognitive impairment, cinnarizine reduced brain
oxidative stress and prevented memory deficits [156].
Flunarizine is a selective CCB with calmodulin-binding properties also exhibiting his-
tamine H1 blocking activity. Flunarizine has structural and pharmacological commonalities
with cinnarizine [157]. However, it has a longer plasmatic half-life and can be used in a sin-
gle daily administration. Flunarizine reduces excessive calcium entry into the cell, thereby
preventing cation overload without affecting physiological calcium homeostasis [158,159].
Flunarizine reduces systemic oxidative stress in patients with migraine. It also regulates
changes in cerebral blood flow, thus protecting the cerebral endothelium from oxidative
insults [158]. Through its antioxidant potential, it plays a role in blocking membrane lipid
bilayer peroxidation [160]. Finally, flunarizine also modulates cholinergic transmission by
Int. J. Mol. Sci. 2022, 23, 11418 9 of 27

promoting acetylcholine (Ach) release and by altering the expression/affinity of muscarinic

receptors [161,162].
Flunarizine also relieved cerebral ischemia-reperfusion-related cognitive and motor
deficits through increased tissue calcium and AchE level [163]. The effect was due not
only by the calcium channel blockade, but also antioxidative, lipid anti-peroxidation, and
anticholinesterase activities.
Flunarizine is generally well tolerated and rarely causes major side effects. The
main adverse effect experienced by patients is drowsiness, which can be avoided by slow
titration of the drug and taking it in the evening [164]. Few clinical studies are available
on the specific effect of flunarizine on cognitive function. A randomized controlled trial
of flunarizine as adjunctive ASM in children with infantile spasms [165] did not reveal
a protective effect of flunarizine on cognitive outcomes. However, subgroup analysis
indicated that it might further improve cognitive outcomes in children with no clear
disease etiology.
Conclusions: Calcium channels blockers carry important side effects that can, indi-
rectly, impair cognition (e.g., sedation and depression) and motor abilities (DIP). Despite
limited evidence suggesting potential neuroprotective effects, the anti-histaminergic and
anti-dopaminergic CAEs seem to prevail.

3.5. Inhibitors of the Renin–Angiotensin System (RAS)

Candesartan is an anti-hypertensive medication acting as an angiotensin (AT) II recep-
tor blocker (ARB). The primary anti-migraine mechanism of action is related to modulation
of the intrinsic RAS of the CNS, which is largely independent of the systemic one [166], and
to the inhibition of nitric oxide release by microglia [167]. Activation of the AT receptors
is a risk factor for AD; therefore, central-acting RAS inhibitors might represent promising
pharmacological aids [168]. The hypothesis is supported by the observation that MCI indi-
viduals receiving RAS inhibitors show slower cognitive decline [169] and a reduced risk of
developing AD [170]. The protective effect is mediated by the anti-inflammatory activity of
the compound, exerted through AT receptor blockade. Mechanistically, candesartan inhibits
the release of inflammatory mediators, such as TNF-α and TGF-β1, and counteracts the
expression of COX-2 and iNOS [167]. In a preclinical AD model, intranasal administration
of candesartan reduces Aβ deposition [167]. Interestingly, the effect is unrelated to changes
in Aβ metabolism but occurs through enhanced microglial phagocytosis of Aβ deposits.
Other ARBs (irbesartan and telmisartan) also display promising anti-inflammatory features,
primarily driven by agonism of the transcription factor PPARγ, and could also be asso-
ciated with reduced risk of diabetes [171,172], a known predisposing factor for cognitive
impairment. Candesartan exhibited anti-inflammatory and anti-neurodegenerative prop-
erties also in a post-stroke experimental model [173], possibly preventing mixed forms of
dementia. Administration of candesartan was not only associated with a reduced degree of
reactive post-ischemic gliosis but also with reduced deposition of β-amyloid in dense hip-
pocampal plaques and reduced Aβ1-42 -related toxicity [173]. A modest anti-amyloid effect
was also documented, after candesartan treatment, in mice carrying the Swedish or Indiana
APP mutation compared to untreated animals [174]. In the same experiment, candesartan
significantly decreased APP-related neuroinflammation, as expressed by GFAP-positive
astrocytes and Iba-1-activated microglial cells, and promoted hippocampal neurogenesis
by increasing BDNF levels [174].
From a clinical viewpoint, candesartan administration did not show a major ef-
fect on global cognition, assessed by MMSE, in the SCOPE (Study on Cognition and
Prognosis in the Elderly) trial, conducted on elderly subjects with hypertension [175].
However, a sub-study showed that treated patients had better performances in terms of
attention and episodic memory, whereas no longitudinal differences were observed in
executive functions, working memory, and cognitive speed [176]. The HOPE3 clinical
trial, however, where candesartan was administered with hydrochlorothiazide (HCT),
showed that scores on the Montreal Cognitive Assessment (MoCA), Digit Symbol Sub-
Int. J. Mol. Sci. 2022, 23, 11418 10 of 27

stitution Test (DSST), or Trail Making Test part B (TMT-B) did not differ between the
candesartan + HCT group and the placebo group [177]. However, when administered
alone, candesartan improved executive functions in MCI subjects [178,179]. Candesartan
has recently landed in one phase-two double-blind placebo-controlled randomized clinical
trial (CEDAR—Candesartan’s Effects on Alzheimer’s Disease and Related Biomarker), in
which MCI subjects were administered the maximum tolerated dose of the drug [180].
Although the enrollment phase was concluded, the results are still not available.
Conclusions: Compared to other migraine preventive treatments, including beta-
blockers, candesartan seems to show the most promising profile to counteract neurodegen-
eration and neuroinflammation-driven cognitive impairment.

3.6. Anti-CGRP and Gepants

The calcitonin-gene-related peptide (CGRP) is a 37-aa neuropeptide ubiquitously
expressed from alternative splicing of the CALCA gene, mostly in the peripheral nervous
system and CNS [181]. CGRP regulates smooth muscle cells of the peripheral vasculature
and also modulates vasodilation through non-endothelial mechanisms by activation of
adenylate cyclase and generation of intracellular cyclic adenosine monophosphate [182].
CGRP modulates the neuronal activity in the trigeminocervical complex [183] and the
transmission of pain signals to the thalamus and cortical brain regions [184]. The role of the
trigeminal system and CGRP is profoundly intertwined in the pathophysiology of migraine,
as confirmed by the expression of CGRP receptors on trigeminal C- and A- nociceptive
fibers. Moreover, CGRP is known to be released into the cranial venous system during
migraine attacks.
These findings led to the development of anti-migraine therapies that inhibit CGRP
action. Small-molecule α-CGRP receptor antagonists, gepants, and fully humanized mon-
oclonal antibodies towards CGRP and the α-CGRP receptor showed beneficial effects in
reducing migraine symptoms in clinical trials [19,185]. The Gepant class now includes
ubrogepant and rimegepant [19], whereas monoclonal antibodies against CGRP include
fremanezumab, galcanezumab, and eptinezumab [185]. Only one monoclonal antibody
directed against the receptor complex (erenumab) is commercially available [185]. While
gepants are approved as abortive drugs that reduce attack frequency [19], monoclonal
antibodies are considered third-line prophylactic therapies [185]. Monoclonal antibodies
and gepants have only recently been made commercially available, and there is now limited
evidence on the long-term effects of the drugs.
CGRP is physiologically expressed in brain regions connected to memory, attention,
autonomic, and behavioral functions [186]. Many preclinical studies indicate that the
peptide profoundly affects behavior [187,188] and biological processes related to mood
and cognition. CGRP, by enhancing IGF-1 production, promotes hippocampal neuro-
genesis and synaptic plasticity, resulting in improved spatial learning performances in
mice [189–191]. An analog effect has been reported after donepezil administration [192].
Overall, several observations point towards CGRP involvement in neuroprotection in
different conditions, including ischemia-reperfusion injury and experimental allergic en-
cephalomyelitis [193,194]. CGRP also activates amylin type 1α receptors, and amylin is
thought to play a protective role in AD [195,196]. Accordingly, lower CGRP concentra-
tions in the cerebrospinal fluid (CSF) and worse neuropsychological profiles, albeit in
specific domains, such as selective attention and visuoperceptual functions, have been
reported [186].
CGRP has also been suggested to participate in AD pathogenesis. In a preclinical AD
model, the 5XFAD mouse, treatment with an α-CGRP receptor blocker (BIBN) reduced the
pathology-related phenotype [197] by enhancing the expression of PSD95, a synaptic protein
involved in synaptic plasticity [198]. BIBN administration also decreased α-synuclein
expression and aggregation in the AD mouse model. Finally, BIBN reduced the cortical and
hippocampal Aβ burden and tau phosphorylation [197]. Inhibition of the α-CGRP receptor
counteracted the pro-inflammatory p38-MAPK-NFκB pathway, supporting the CGRP role
Int. J. Mol. Sci. 2022, 23, 11418 11 of 27

in inflammation. The peptide exerts a bimodal effect on the immune system by exhibiting
anti- and pro-inflammatory properties [199,200]. However, the pro-inflammatory effects in
neurological disorders such as migraine are more prominent [201,202].
No cognitive side effects have been reported with antagonists of the CGRP system.
Of note, monoclonal antibodies do not cross the BBB [203], whereas gepants have limited
access [204] and could exert some activity on the CNS.
Conclusions: Most studies suggest a neuroprotective role for the peptide. However,
some conflicting evidence from a preclinical model prompts further research to confirm
the hypothesis.

3.7. Triptans and Ditans

Triptans are selective 5-hydroxytryptamine1B/1D (5-HT1B/1D ) receptor agonists used
as abortive drugs for migraine attacks, usually when FANS are ineffective [20]. Triptans
(sumatriptan, zolmitriptan, almotriptan, eletriptan, frovatriptan, naratriptan, and rizatrip-
tan) have replaced ergot-derived compounds [205]. Both 5-HT1B and 5-HT1D receptors are
expressed within the trigeminal nerve and ganglion. They counteract migraine-related
vasodilation through different mechanisms [205]. Further, 5-HT1B receptors are localized
within smooth muscle cells of blood vessels and inhibit vascular contraction [205]. The
process is also facilitated by pharmacological agonism on 5-HT1D receptors. These are
located in the efferent trigeminal fibers that innervate the dural vessels and inhibit release of
vasoactive peptides [205]. Despite some initial controversies [206], triptans can effectively
cross the BBB and influence the expression of serotonergic receptors [206,207].
In physiological conditions, 5-HT1B receptors are most densely expressed within the
thalamus (especially in the ventromedial nucleus, VMN) and the basal ganglia, followed
by the cerebral cortex and, in particular, within the precentral and postcentral gyri [208].
Further, 5-HT1D receptor expression shows several topographical overlaps (thalamus and
basal ganglia), but it is also expressed within the midbrain (dorsal and medial raphe
nuclei) [208]. At the cortical level, 5-HT1D receptors are mainly located within the piriform
cortex [208]. The VMN is a primary target for nociception control and acts as a gate for
the transmission of noxious stimuli to the cortex [209]. Furthermore, modulation of VMN
neurons can have a significant and widespread impact on cortical activity [210], particularly
the frontal cortex [211], thanks to their extensive connections.
Alterations in the serotonergic system, including a significant reduction in 5-HT1B/1D
receptors, were found post-mortem in AD brains compared to controls [212]. The reduction
was observed in the prefrontal (BA10, 25%) and temporal (BA20, 37%) cortices [212]. Ex-
pression levels of 5-HT1B/1D receptors in the frontal lobe positively correlate with cognitive
decline in the patient’s lifetime. In contrast, no differences in receptor affinity for the ligand
were observed [212]. This is not surprising as BA10 has a key role in memory retrieval [213].
As 5-HT1B/1D receptors at pre-synaptic terminals inhibit Ach release, their downregulation
could represent a compensatory mechanism [212,214–216]. Accordingly, the agonism on
5-HT1B/1D receptors—such as the one exerted by triptans—could impair memory con-
solidation processes [217–221]. While in vivo studies documented a down-regulation of
5-HT1B receptors after administration of sumatriptan in migraine, effects on cognition have
not been thoroughly investigated [207].
From a clinical viewpoint, memory impairment is listed among the potential (infre-
quent) neurological side effects of rizatriptan [222]. Anecdotic reports suggest that acute or
chronic exposure to triptan-driven vasoconstriction induces transient global amnesia-like
symptoms, possibly due to reversible ischemia [223,224]. Preliminary results also suggest
reversibility of 5-HT1B/1D -driven memory impairment by administering 5-HT1B/1D an-
tagonists and ultimately restoring cholinergic-driven learning consolidation [221,225,226].
Further studies are needed to assess the actual effectiveness and safety of these compounds.
However, it is important to remember that sumatriptan administration restores cognitive
functioning when disturbed by migraine-related pain, providing short-term benefits [227].
Int. J. Mol. Sci. 2022, 23, 11418 12 of 27

A new class of drugs has been recently approved, ditans, with prototypal drug las-
miditan [19]. Ditans activate trigeminal 5-HT1F receptors and block the release of CGRP
and other vasoactive peptides. Ditans do not affect 5-HT1B receptors and, therefore, do not
directly promote vasoconstriction, thereby limiting the cardiovascular- and cerebrovascular-
related side effects [228]. Interestingly, 5-HT1F agonists such as lasmiditan block the release
of glutamate and neuronal hyperexcitability, a process related to pain sensitization and
AD neurodegeneration [228]. Lasmiditan has easy access to the CNS due to the high
lipophilicity of the molecule and, although it may provoke somnolence or fatigue, no
clear-cut adverse cognitive effect has been reported [229], possibly due to a relatively low
expression of 5-HT1F receptors in the brain tissue [208]. Interestingly, the hippocampus is
one of the regions more enriched in 5-HT1F receptors [230]. Thus, any potential drug effect
in terms of neuroprotection would be exerted in a key structure for memory processes.
Conclusions: The current evidence suggests a potential null-to-positive effect for
lasmiditan on neurodegenerative pathways and cognition, whereas triptans show potential
interference with memory processes due to presynaptic inhibition of Ach release.

3.8. Ergots
Ergotamine and dihydroergotamine (DHE) efficacy profiles are similar to triptans.
However, these compounds are progressively out-phased due to the more frequent adverse
events and cases of abuse [20,21]. To date, DHE is rarely employed for severe refractory
attacks that are unresponsive to other abortive medications, whereas ergotamine or other er-
gots carry lower levels of indication [19,21]. Ergot alkaloids bind—as agonists—5-HT1B/1D
receptors, such as triptans, 5-HT1F -like ditans with lower affinity, D2 dopaminergic, and
α-adrenergic receptors [231]. Ergots exert anti-migraine activity by promoting intense
vasoconstriction and interfering with the trigeminovascular system [231].
Increased latency of the N2 component in an event-related potentials (ERP) study
indicated potential impairment in cognitive processes and pre-attentive stimulus evaluation
about two hours after ergotamine intake [232]. The finding was attributed to changes
in the “automatic memory updating” system that participates in the earliest stages of
cognitive processing for unpredictable stimuli, possibly relying on abnormal hippocampal
functioning [232]. Furthermore, in ergotamine abusers, a significant cognitive impairment
was documented for complex reaction time tasks, cognitive flexibility tests, and verbal
memory [233]. However, the dose-dependency of the effect still needs clarification.
Overall, the clinical evidence indicates a detrimental effect of ergotamine on cognition,
but the actual impacts of ergots on neurodegenerative or neuroprotective pathways are
still inconclusive. For instance, a previous study evaluating the potential neuroprotective
effect of alkaloid derivates in AD [234] found that dihydroergocristine, but not ergotamine
or dihydroergotamine, inhibits γ-secretase and interferes with β-amyloid deposition [234].
Further evidence indicates that plasma levels of Aβ1-42 do not differ in ergot-users [235],
but it should be stressed that this measure is not an established biomarker for AD and is
only used for research purposes [16]. Furthermore, drug-driven cognitive impairment may
depend upon different neurodegenerative pathways that have not been explored yet.
Conclusions: The use of ergots should be limited to selected cases due to several
adverse effects, including potential CAEs.

3.9. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

Several studies have investigated the potential effects of NSAIDs on neurodegenera-
tion. NSAIDs’ mechanism of action depends primarily on the inhibition of cyclooxygenases
that convert arachidonic acid into pro-inflammatory mediators, such as prostaglandins,
prostacyclins, and thromboxanes. The application of COX-inhibitors to migraine treat-
ment is mainly due to the inhibition of neurogenic inflammation and trigeminal nocicep-
tion, as well as modulation of the brainstem and thalamic antinociceptive systems [236].
Growing evidence indicates that neuroinflammatory processes contribute to AD patho-
Int. J. Mol. Sci. 2022, 23, 11418 13 of 27

physiology [237,238], suggesting that NSAID-based anti-inflammatory interventions are

neuroprotective [239,240].
Several NSAIDs (e.g., nimesulide, indomethacin, and ibuprofen) up-regulate the
expression of α-secretase, promoting the non-amyloidogenic processing of APP [241].
Similarly, compelling evidence indicates that NSAIDs can lower Aβ1-42 levels in vitro and
in vivo by modulating γ-secretase cleavage activity [242,243]. NSAIDs also act downstream
from Aβ1-42 metabolism by inhibiting the formation of amyloid fibrils and destabilizing
those already aggregated [244].
Conflicting evidence has been found while evaluating NSAIDs in clinical settings.
While many observational studies supported the protective role of NSAIDs in AD [240,241],
other studies showed opposite results [245–247].
On a final note, the Food and Drug Administration has recently allowed one phase-
three study on rofecoxib (COX-2 inhibitor) as an acute treatment for migraine attacks [248].
Close monitoring of cerebrovascular adverse events is warranted due to a previous report
about an increased risk of ischemic stroke upon taking this medication [249] and the higher
stroke risk in migraineurs (see Section 2.1).
Conclusions: The biological activity of NSAIDs suggests an overall neuroprotective
role, confirmed by some clinical observations. The conflicting results may depend on the
intra-class variability among the compounds’ features or the clinical trial designs.

4. Discussion
4.1. Migraine and Dementia—The Missing Link
Observational studies and meta-analyses support the idea that migraine attacks and
their frequency are associated with risk of dementia. However, the combined effects
exerted by different classes of anti-migraine compounds on cognition and neurodegener-
ation are still largely unexplored. As summarized in Table 1, some anti-migraine drugs
display an overall positive effect, others negatively impact dementia-related pathologies,
and a few exhibit conflicting properties (e.g., they are neuroprotective but also impair
cognitive processes).

Table 1. Summary of findings on the role of anti-migraine therapies on cognition and neurodegeneration.

Migraine Treatment Indication Biological Effect Clinical Impact on Cognition References

ASMs
- mild-to-moderate impairment in
- ↑ Akt/GSK-3β/CREB attention, psychomotor abilities,
pathway [§] language, and comprehension,
- ↓ inflammation mediators including verbal fluency, short-term
TPM Prophylaxis [41–55]
(IL-1β, TNF-α) [§] episodic and working memory,
- ↓ oxidative stress [§] processing speed. Abnormal
- ↑ BDNF [§] thinking. TPM is the ASM with the
heaviest impact on cognition.
- ↑ taurine, glycine, serotonin, and
dopamine in the hippocampus [§] - mild attention, memory, and
VPA Prophylaxis [56–61]
- ↓ Aβ generation and tau visuomotor deficits
hyperphosphorylation [#]
- overall good tolerability. Few
- antioxidative and anti-autophagy
reports indicated deficits in attention,
GBP Prophylaxis properties by activating the [62–68]
verbal memory, and executive
PI3K/Akt/mTOR pathway [§]
functions after chronic use.
Antidepressants
- antimuscarinic (↓ cholinergic
pathways from the basal forebrain - sedation
to the hippocampus and - promotes cognitive impairment
cortex) [♦] with a non-amnestic phenotype
Amitriptyline Prophylaxis [82–91]
- antihistaminic [♦] - impairs attention, decision-making,
- neuroprotection through TrkA and psychomotor speed
and TrkB receptor agonism [#] and - memory deficits at higher doses
increase in BDNF levels [§]
Int. J. Mol. Sci. 2022, 23, 11418 14 of 27

Table 1. Cont.

Migraine Treatment Indication Biological Effect Clinical Impact on Cognition References

Venlafaxine Prophylaxis - enhances myelin integrity [#] - improves working memory * [92,94–97]
- antioxidative effects [#] - improvement in
Duloxetine Prophylaxis - anti-glutamatergic effects [#] neurodegeneration-driven attention, [83,92,93,99–101]
- pro-cholinergic effects [#] memory, and behavioral symptoms
- ↑BDNF levels and hippocampal
- improvement in global cognitive
neurogenesis [†]
level (MMSE score), and immediate
Fluoxetine Prophylaxis - ↓ amyloid neuronal toxicity [83,93,102–108]
and delayed logical memory
through the expression of TGF-β1
performances in MCI
and MMP-2 in the astroglia [§]
- ↑ α-secretase (non-amyloidogenic
- mild short-term verbal memory
Escitalopram Prophylaxis processing of APP) [#] [109–111]
exacerbated by add-on of pindolol
- ↓ amyloid load [#]
Beta-blockers
- cognitive bias in decision-making
- ↑ working memory
- ↓ of Aβ-driven cAMP levels and
Propranolol Prophylaxis manipulation costs [118–125]
ApoE expression [#]
- no long-term evident changes in
cognition or behavior
- ↑ pro-inflammatory mediators [#]
- ↑ abilities in proofreading,
- ↓ anti-inflammatory mediators [#]
Metoprolol Prophylaxis visual–motor tasks, and [126–129]
- ↓ synaptic phagocytosis →
complex management
synaptic degeneration [#]
- does not significantly affect
global cognition
Atenolol Prophylaxis - unknown - impairs visual–motor performances [130–134]
and complex
management components
Bisoprolol Prophylaxis - unknown - Unknown [135]
Calcium-channel blockers
- sedation
- anti-muscarinic, anti-histaminic,
- conflicting results about the impact
Cinnarizine Prophylaxis and anti-dopaminergic effects [♦] [147–156]
on psychomotor speed, attention,
- antioxidant [#]
vigilance, and working memory
- antioxidant [♦†]
- ↓ lipid peroxidation [†]
- modulates Ach transmission: - sedation, increased risk
Flunarizine Prophylaxis [157–165]
↑ Ach release [§] of Parkinsonism
↓ M receptor expression [§]
↑ M receptor affinity (Kd) [§]
ARB
- ↓ release of neuroinflammatory - positive effect on episodic memory
mediators by microglial cells [§#†] and attention in cognitively normal
Candesartan Prophylaxis - ↑ cell-mediated Aβ clearance [§#] elderly subjects [166–180]
- ↑ BDNF-driven hippocampal - positive effect on executive
neurogenesis [#] functions in MCI subjects
Monoclonal antibodies
- unknown (low CSF levels of CGRP
Erenumab, - inhibition of CGRP-related
have been linked to impaired
Fremanezumab, Prophylaxis effects, which seem mainly [19,181–204]
selective attention and
Galcanezumab neuroprotective [♦]
visuo-perceptual functions).
Gepants
- inhibition of CGRP-related
effects, which seem mainly
Rimegepant, neuroprotective [♦]
Acute treatment - unknown [19,181–204]
Ubrogepant - another receptor antagonist
(BIBN) showed neuroprotective
effects [#]
Triptans
- agonism on 5-HT1B/D may
Almotriptan, Eletriptan,
impair cholinergic
Frovatriptan, Naratriptan, - on rare occasions, memory deficits
Acute treatment transmission [♦] [20,205–227]
Rizatriptan, Sumatriptan, have been reported after R use.
- S administration →
Zolmitriptan
Down-regulation of 5-HT1B [♦]
Int. J. Mol. Sci. 2022, 23, 11418 15 of 27

Table 1. Cont.

Migraine Treatment Indication Biological Effect Clinical Impact on Cognition References

Ditans
Lasmiditan Acute treatment - via 5-HT1F: ↓Glu release [§] - unknown [19,228–230]
NSAIDs
- ↓ inflammation [♦]
Aspirin, ibuprofen, - ↑ α-secretase [†]
- conflicting results in terms of
diclofenac, Acute treatment - ↓ Aβ aggregation [†] [237–247]
protection/risk of AD.
indomethacin, and others - favorable modulation of
γ-secretase [†]
Ergots
- cognitive impairment at complex
- similar effects to triptans and
reaction time tasks, cognitive
Ergotamine, DHE Acute treatment ditans (modulation of 5-HT1B/1D, [19–21,231–235]
flexibility tests, and verbal memory
5-HT1F) [♦]
in ergotamine abusers.
Abbreviations: Aβ, β-amyloid peptide; AD, Alzheimer’s disease; Akt/GSK-3β/CREB, protein kinase B/glycogen
synthase kinase-3β/cAMP response element binding protein; ApoE, apolipoprotein E; APP, amyloid precur-
sor protein; ARB, angiotensin (AT) II receptor blocker; ASMs, anti-seizure medications; BIBN, CGRP receptor
antagonist; BDNF, brain-derived neurotrophic factor; cAMP, cyclic adenosine monophosphate; CGRP, calcitonin-
gene-related peptide; DHE, dihydroergotamine; GBP, gabapentin; IL-1β, interleukin 1 beta; Kd, dissociation
constant; MCI, mild cognitive impairment; MMP-2, matrix metallopeptidase 2; MMSE, Mini-Mental State Ex-
amination; PI3K/Akt/mTOR, phosphatidylinositol 3-kinase/protein kinase b/mammalian target of rapamycin;
TGF-β1, transforming growth factor beta 1; TNF-α, tumor necrosis factor alpha; TPM, topiramate; TrkA and
TrkB, tyrosine protein kinase (neurotrophin) receptors A and B; VPA, valproic acid; 5-HT HT1B/1D/1F, serotonin
receptor subtypes. * cognitive effects tested on animal models. Investigations on samples from: [§] rats, [#] mice,
[†] or other species/media. Clinical studies are indicated by the symbol [♦].

Additional investigation is needed. Promising mechanisms to be explored concern

the disruption of BBB integrity (see Figure 1). Migraine-related nociceptive molecules can
enter the BBB [250]. BBB breakdown is also an early event that precedes brain atrophy in
AD and other neurodegenerative conditions [251]. Thus, BBB is a potential trait d’union
between migraine and dementia. However, recent imaging studies of BBB integrity in
migraineurs or in vivo evaluation of migraine-inducing substances on BBB permeability
have challenged this notion [250]. The poor sensitivity of the employed methods might be
the root of the lack of positive correlations. Improved imaging techniques and/or focus on
alternative biomarkers could, in future studies, resolve the issue [250].
The functioning of the glymphatic system offers another intriguing link. The system
encompasses a network of perivascular channels that, during sleep, clean the interstitial
brain space, removing neurotoxic molecules and other debris [252].
The system’s impairment is implicated in headache disorders [253,254]. In particular,
CSD-driven migraine aura is accompanied by a temporary closure of paravascular spaces
and the build-up of nociceptive molecules [255]. The sleep-driven activity of the glymphatic
system in migraineurs provides the rationale for the empirical observation that sleep halts
headache attacks while insomnia increases their frequency [254].
Sleep disturbances and glymphatic system dysfunction are common features in neu-
rodegenerative settings, including AD, where system impairment contributes to enhancing
Aβ and tau pathology [256,257]. However, whether headache-related glymphatic alter-
ations participate in AD pathogenesis is still unknown.
However, the meningeal lymphatic system can participate in the onset of a migraine
attack [258,259] by carrying nociceptive molecules [260]. Although poorly investigated,
meningeal lymphatics ablation alters the balance of pro- and anti-inflammatory factors
involved in migraine [260]. On the other hand, a growing body of evidence indicates that
impairment in meningeal lymphatics and brain inflammation participate in AD pathogene-
sis [259,261].
 However, the meningeal lymphatic system can participate in the onset of a migraine
attack [258,259] by carrying nociceptive molecules [260]. Although poorly investigated,
meningeal lymphatics ablation alters the balance of pro- and anti-inflammatory factors
involved in migraine [260]. On the other hand, a growing body of evidence indicates that
Int. J. Mol. Sci. 2022, 23, 11418 impairment in meningeal lymphatics and brain inflammation participate 16 of in
27 AD
pathogenesis [259,261].

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where it itisis collected
collectedalong alongwith neurotoxic
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neurotoxic and drained
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composition (BBB).
the blood–brain
The layers properly filter the arterial blood, and only selected molecules may cross.
barrier (BBB). The layers properly filter the arterial blood, and only selected molecules may cross. (d) Disruption
(d) of the BBB and
Disruption of related
the BBB pathological
and related changes. Abbreviations:
pathological changes. ArAbbreviations:
= arachnoid; AVAr = arterial vessel; AV =
= arachnoid;
arterial
CSF =vessel; CSF = cerebrospinal
cerebrospinal fluid; DM = dura fluid; DML==dura
mater; mater; L
lymphatics; LB= =lymphatics; LB =PM
lamina basalis; lamina basalis; PM
= pia mater;
= pia
SAmater; SA = subarachnoid
= subarachnoid space; SM =space;
smoothSM = smooth
muscle; muscle; V = vein.
V = vein.

4.2. Migraine Therapies, Cognitive Deficits, and Neurodegenerative Pathways—Final Remarks

Cognitive adverse effects may be triggered by migraine treatments with short latency
through several mechanisms, including direct modulation of neurotransmitters’ systems.
As illustrated in Figure 2, some ASM therapies, amitriptyline [86–88], and ergots [232,233]
produce the heaviest burden on cognitive performances [45–50,57,58], along with calcium
antagonists, which significantly increase sedation [137,165]. Escitalopram [110], propra-
nolol [120,121], atenolol [134], or triptans [222] rarely generate mild symptoms. These
iatrogenic symptoms may resemble naMCI features, whereas memory deficits are less
common. Of note, positive effects are found after administration of SNRIs [92,97,101],
metoprolol [129], or candesartan [176,178,179].
Long-term changes in cognition, however, may arise due to slower biological effects
of the compounds on the CNS, which might play a role in the increased risk for late-onset
dementia in some migraineurs. Metoprolol [129] was found to increase inflammation,
whereas TPM [43,44], GBP [68], duloxetine [92], fluoxetine [107], cinnarizine [156], flunar-
izine, NSAIDs [236], and candesartan [167,173] either showed antioxidant capacities or
favorably modulate the microglia–astrocyte axis. Neuroinflammation plays a pivotal role
in AD and migraine pathogenesis [262] and represents a key therapeutical target.
The “core” AD neurodegenerative processes (β-amyloid oligomers and fibrils in
plaques, and accumulation of hyperphosphorylated tau in neurofibrillary tangles) [16] are
directly modulated by VPA [61], fluoxetine [106,107], escitalopram [109], propranolol [125],
candesartan [167,173,174], and NSAIDs [241–244].
Furthermore, active enhancement in the brain’s recovery from damage was found
upon administration of TPM [44], amitriptyline [90,91], LMT [76], duloxetine [99,100], fluox-
etine [104,105], or candesartan [174]. The drugs stimulate, through increased expression of
BDNF and other neurotrophins, neurogenesis, which is increased in chronic degeneration
Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 17 of 29

Int. J. Mol. Sci. 2022, 23, 11418 17 of 27

4.2. Migraine Therapies, Cognitive Deficits, and Neurodegenerative Pathways—Final Remarks
Cognitive adverse effects may be triggered by migraine treatments with short latency
through several
to neutralize mechanisms,
tissue including
damage [263]. direct modulation
Accordingly, long-term use of neurotransmitters’
of these compoundssystems.
can offer
As illustrated in Figure 2, some
substantial neuroprotective effects.ASM therapies, amitriptyline [86–88], and ergots [232,233]
produce In the heaviest the
conclusion, burden on cognitive
anti-migraine performances
efficacy [45–50,57,58],
of the compounds along
should bewith calcium
carefully bal-
antagonists,
anced with the negative impact on the patients’ daily and work performances in the[110],
which significantly increase sedation [137,165]. Escitalopram short-
propranolol
term and with[120,121], atenolol
potential [134], or triptans
neurodegenerative [222]
sequelae in rarely generate
the long mild symptoms.
term, especially given the
These iatrogenic
availability symptoms
of several may resemble
therapeutical naMCI
options features,
that may whereas
counteract memory deficits are
neurodegeneration and
less common. Of note, positive effects are found after administration of SNRIs [92,97,101],
neuroinflammation (summarized in Figure 3). Future research should focus on the intersec-
metoprolol
tions shared[129], or candesartan
by dementia [176,178,179].
and migraine to develop safe and possibly protective treatments.

Cognitiveeffects
Figure2.2.Cognitive
Figure effectsofofmigraine
migrainetreatments.
treatments.InInthe
thegreen
greensection:
section:compounds
compoundswith withpositive
positive
effects on cognition; in the yellow section: compounds with mild negative effects; in the
effects on cognition; in the yellow section: compounds with mild negative effects; in the orange–red orange–red
section:
section:compounds
compoundswithwiththe
theworst
worstimpact
impactononcognitive
cognitiveperformances.
performances.Abbreviations:
Abbreviations:ASMs
ASMs = anti-
= anti-
Int. J. Mol. Sci. 2022, 23, x FOR PEERseizure
REVIEW medications, type 1: lamotrigine, levetiracetam, type 2: valproic acid, topiramate, 18 of 29
seizure medications, type 1: lamotrigine, levetiracetam, type 2: valproic acid, topiramate, gabapentin,
gabapentin,
pregabalin,pregabalin,
zonisamide,zonisamide, CCBschannel
CCBs = calcium = calcium channel blockers.
blockers.

Long-term changes in cognition, however, may arise due to slower biological effects
of the compounds on the CNS, which might play a role in the increased risk for late-onset
dementia in some migraineurs. Metoprolol [129] was found to increase inflammation,
whereas TPM [43,44], GBP [68], duloxetine [92], fluoxetine [107], cinnarizine [156],
flunarizine, NSAIDs [236], and candesartan [167,173] either showed antioxidant capacities
or favorably modulate the microglia–astrocyte axis. Neuroinflammation plays a pivotal
role in AD and migraine pathogenesis [262] and represents a key therapeutical target.
The “core” AD neurodegenerative processes (β-amyloid oligomers and fibrils in
plaques, and accumulation of hyperphosphorylated tau in neurofibrillary tangles) [16] are
directly modulated by VPA [61], fluoxetine [106,107], escitalopram [109], propranolol
[125], candesartan [167,173,174], and NSAIDs [241–244].
Furthermore, active enhancement in the brain’s recovery from damage was found
upon administration of TPM [44], amitriptyline [90,91], LMT [76], duloxetine [99,100],
fluoxetine [104,105], or candesartan [174]. The drugs stimulate, through increased
expression of BDNF and other neurotrophins, neurogenesis, which is increased in chronic
degeneration to neutralize tissue damage [263]. Accordingly, long-term use of these
compounds can offer substantial neuroprotective effects.
In conclusion, the anti-migraine efficacy of the compounds should be carefully
balanced with the negative impact on the patients’ daily and work performances in the
short-term and with potential neurodegenerative sequelae in the long term, especially
given the availability of several therapeutical options that may counteract
neurodegeneration
Thediagram
Figure3.3.The diagramandillustrates
neuroinflammation (summarized
migrainetherapies
therapies in Figure
thatpositively
positively impact3).CNS
Future researchby
homeostasis
Figure illustrates migraine that impact CNS homeostasis by
should focus on the
promoting neurogenesis intersections
neurogenesis or shared by dementia and migraine to develop safe and
promoting or counteracting
counteractingneuroinflammatory
neuroinflammatoryoror neurodegenerative
neurodegenerativeprocesses. Ab-
processes.
possibly protective
breviations:
Abbreviations:ADAD = treatments.
= Alzheimer’s
Alzheimer’sdisease;
disease;Cand
Cand= =candesartan;
candesartan;Fluo
Fluo= =fluoxetine.
fluoxetine.

SupplementaryMaterials:
Supplementary Features,study
Materials: Features, studydesign,
design,and
andmain
mainfindings
findingsofofthe
themost
most
relevantclinical
relevant clinicaltrials
trialsare
aresummarized
summarizedininSupplementary
SupplementaryTable
Table S1.
S1.

Supplementary Materials: The following supporting information can be downloaded at

www.mdpi.com/xxx/s1.
Author Contributions: M.R. conceptualized the manuscript. M.R., M.A.D.R., D.C., S.C., G.E. and
F.D. revised the literature. M.R., M.A.D.R., D.C., S.C., G.E., F.D., M.S., A.G. and S.L.S. wrote the
Int. J. Mol. Sci. 2022, 23, 11418 18 of 27

Supplementary Materials: The following supporting information can be downloaded at https:

//www.mdpi.com/article/10.3390/ijms231911418/s1.
Author Contributions: M.R. conceptualized the manuscript. M.R., M.A.D.R., D.C., S.C., G.E. and
F.D. revised the literature. M.R., M.A.D.R., D.C., S.C., G.E., F.D., M.S., A.G. and S.L.S. wrote the
manuscript. M.O. and A.G. critically revised the manuscript. All authors have read and agreed to the
published version of the manuscript.
Funding: Prof. Stefano Sensi is supported by the Italian Ministry of Health, the AIRAlzh Onlus
(ANCC-COOP), the Alzheimer’s Association—Part the Cloud: Translational Research Funding for
Alzheimer’s Disease (18PTC-19-602325), and the Alzheimer’s Association—GAAIN Exploration to
Evaluate Novel Alzheimer’s Queries (GEENA-Q-19-596282).
Acknowledgments: Figure 1 was created with BioRender.com. Panel 1a was adapted from “Cranial
Meninges”, and panels 1c and 1d from “Brain Vascular System”, all by BioRender.com (2022).
Retrieved from https://app.biorender.com/biorender-templates (accessed on 8 August 2022).
Conflicts of Interest: The authors declare no conflict of interest.

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