biomolecules

Review
Understanding the Biological Relationship between Migraine
and Depression
Adrián Viudez-Martínez 1 , Abraham B. Torregrosa 2,3,4 , Francisco Navarrete 2,3,4
and María Salud García-Gutiérrez 2,3,4, *

1 Hospital Pharmacy Service, Hospital General Dr. Balmis de Alicante, 03010 Alicante, Spain;
aviudezmartinez@gmail.com
2 Instituto de Neurociencias, Universidad Miguel Hernández, 03550 San Juan de Alicante, Spain;
a.bailen@umh.es (A.B.T.); fnavarrete@umh.es (F.N.)
3 Research Network on Primary Addictions, Instituto de Salud Carlos III, MICINN and FEDER,
28029 Madrid, Spain
4 Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), 03010 Alicante, Spain
* Correspondence: maria.ggutierrez@gmail.com

Abstract: Migraine is a highly prevalent neurological disorder. Among the risk factors identified,
psychiatric comorbidities, such as depression, seem to play an important role in its onset and clinical
course. Patients with migraine are 2.5 times more likely to develop a depressive disorder; this risk
becomes even higher in patients suffering from chronic migraine or migraine with aura. This relation-
ship is bidirectional, since depression also predicts an earlier/worse onset of migraine, increasing the
risk of migraine chronicity and, consequently, requiring a higher healthcare expenditure compared
to migraine alone. All these data suggest that migraine and depression may share overlapping
biological mechanisms. Herein, this review explores this topic in further detail: firstly, by introduc-
ing the common epidemiological and risk factors for this comorbidity; secondly, by focusing on
providing the cumulative evidence of common biological aspects, with a particular emphasis on
the serotoninergic system, neuropeptides such as calcitonin-gene-related peptide (CGRP), pituitary
adenylate cyclase-activating polypeptide (PACAP), substance P, neuropeptide Y and orexins, sexual
hormones, and the immune system; lastly, by remarking on the future challenges required to elucidate
the etiopathological mechanisms of migraine and depression and providing updated information
Citation: Viudez-Martínez, A.;
Torregrosa, A.B.; Navarrete, F.;
regarding new key targets for the pharmacological treatment of these clinical entities.
García-Gutiérrez, M.S. Understanding
the Biological Relationship between Keywords: migraine; major depressive disorder; serotonin; neuropeptides; sexual hormones;
Migraine and Depression. Biomolecules immune system
2024, 14, 163. https://doi.org/
10.3390/biom14020163

Academic Editor: Omar Cauli

1. Introduction
Received: 27 December 2023 Migraine is a complex neurological disorder affecting more than 10% of the general
Revised: 8 January 2024 population, causing a marked loss of productivity and quality of life. In fact, it is placed as
Accepted: 9 January 2024
the sixth most disabling disease worldwide. Its clinical features include intense and pulsat-
Published: 30 January 2024
ing head pain localized unilaterally with a variable duration of up to 72 h that may/may
not be associated with aura, a sequence of visual or sensory disturbances, such as flashing
lights and haphazard lines, that occur shortly before a migraine attack. Additionally, these
Copyright: © 2024 by the authors.
symptoms may be accompanied by nausea, vomiting, and hypersensitivity to acoustic,
Licensee MDPI, Basel, Switzerland.
olfactory, or visual stimuli. Several etiological factors seem to play a part in the develop-
This article is an open access article ment of migraine, including genetic background, climatic region, socioeconomic status,
distributed under the terms and and lifestyle. Genetic, sex-related, and environmental factors seem to contribute the most,
conditions of the Creative Commons with women being approximately three times more likely than men to develop it and with
Attribution (CC BY) license (https:// up to 12% of Caucasians suffering from this neurological condition [1].
creativecommons.org/licenses/by/
4.0/).

Biomolecules 2024, 14, 163. https://doi.org/10.3390/biom14020163 https://www.mdpi.com/journal/biomolecules

Biomolecules 2024, 14, 163 2 of 37

The International Headache Society classifies migraine into episodic migraine or

chronic migraine, depending on the frequency of outbursts. To add more complexity,
cross-sectional and longitudinal studies indicate a close relationship between migraine and
mood disorders, especially depression, which has been identified as an independent risk
factor for developing migraine earlier and with a worse prognosis [2–4]. This relationship
has been proposed to be bidirectional, with migraine also increasing the risk of developing
depression by 2.5 times [5–7]. Therefore, the comorbidity of migraine and depression is
frequent and, foremost, hinders the diagnosis and treatment of migraine by increasing the
total costs and disability associated with both disorders and diminishing patients’ quality
of life.
Despite this association being attributed to shared genetic factors—an increased risk
of depression in siblings and twins affected by migraine has been demonstrated [8–10]—it
has also been proposed that both entities may share neurotransmission pathways and
neurobiological features; yet, their pathophysiology is complex and has not been fully
characterized. Until a few years ago, depression was mostly believed to involve central
mechanisms and migraine to involve peripheral alterations, such as sensitized perivascular
trigeminal nociceptors [11]; however, in recent studies, migraineurs were also found to
feature abnormal cortical sensory processing [12] and altered central modulation [13]. Thus,
neurotransmitters such as serotonin, hormones, and neuropeptides, and even genetic and
functional brain alterations have been linked with migraine. The immune system seems
to partially explain the etiology of both disorders. Therefore, this review aims to explore
the biological relationship between migraine and depression. The identification of the
mechanisms involved in the occurrence of depression in migraineurs could help identify
key targets that may serve as biomarkers for preventing this comorbidity or develop more
effective pharmacotherapeutic approaches that, ultimately, would help to improve patient
quality of life and the clinical strategies addressed to treat these neuropsychiatric conditions.

2. Materials and Methods

The literature review consisted of a search for scientific information in the Medline
database (PubMed) employing Medical Subject Headings (MeSH) related to the topic of
the review: “migraine”, “depressive disorder”, and “mechanisms”. These terms were com-
bined by the Boolean operator “AND”. Moreover, to maximize the selection of information,
additional search equations were used employing the MeSH “migraine” AND “system
alterations” and “migraine” AND “depressive disorder”.
All the authors critically analyzed all the results for each search to decide upon the
selection of each reference according to the alignment of its content with the subject matter
of the study. No PubMed filters were applied to maximize the selection of all the available
and appropriate information. All original articles, systematic reviews, or meta-analyses
focusing on migraine and depression were accepted. Those articles unrelated to the topic
of interest, not written in English, or to which access was impossible were excluded.

3. Results
3.1. Serotonin
While sufficient evidence has not been provided for any single system/endogenous
substance to explain the bidirectional connection between migraine and depression on its
own, a dysfunction in the serotoninergic system has been continuously considered one of
the major contributors. Brain serotonin imbalance seems to be implicated in both diseases.
Additionally, pharmacological modulation of the serotoninergic system is one of the main
targets in both disorders. In this section, we highlight the findings accumulated over the
years supporting the involvement of the serotonergic system in this comorbidity (Figure 1).
Biomolecules 2024, 14, 163 3 of 37

The role of serotonin (5-HT) in the pathophysiology of migraine has been a matter of
study for decades. The first evidence was provided in the early 1960s by Sicuteri et al. [14].
In this study, increased levels of the 5-hydroxyindoleacetic acid, the main metabolite
of 5-HT, were found in the urine of patients during migraine attacks. This elevation is
representative of higher plasma levels of serotonin. Subsequent investigations found that
plasma levels of 5-HT decrease between attacks and increase during attacks [15,16]. These
findings laid the foundations for the theory that postulates that migraine is a syndrome of
chronically low interictal levels of 5-HT with a transient increase during attacks [17,18].
Considering that 5-HT is a crucial neurotransmitter for the coherent modulation of
peripheral and central pain signaling [19–21], the abnormalities observed in migraine
patients have been considered as an indicator of pain-modulating system dysfunction.
Moreover, 5-HT is involved in excitatory (hyperalgesia) as well as in inhibitory (analgesia)
mechanisms [22]; yet, its role is determined by location, cell type, and serotonin recep-
tor subtype, among other factors. Before and after migraine attacks, patients present an
increased sensitivity to visual (light), auditory (sound), or somatic stimuli (allodynia).
The investigations focused on this phenomenon have shown that patients present a ‘de-
ficient habituation’ during the pain-free period. Interestingly, habituation changes with
the proximity of an attack, during the attack, and the course of migraine (episodic or
chronic), which is characterized by the occurrence of the sensitization phenomena [23].
The conversion from episodic to chronic migraine is not well understood; however, two
putative mechanisms that seem to play a remarkable part are the increased excitability
of neurons in central nociceptive pathways and a dysfunctional pain modulation, both
regulated by 5-HT. In this sense, decreased serotonin availability has been associated with
abnormal habituation in episodic migraine [24–27]. Moreover, it has been proposed that
the low levels of 5-HT induce a disinhibition of pain signals from the peripheral nociceptor,
resulting in a decrease of nociceptive thresholds and increased responsiveness to sensory
or somatic stimuli, making patients more susceptible to stimuli [28–35]. Serotonin surges
during migraine attacks would increase and maintain pain [19].
Solid evidence supporting the involvement of 5-HT in the pathophysiology of mi-
graine is linked to the efficacy of 5-HT2 antagonists, such as methysergide and pizotifen,
as prophylactic drugs and 5-HT1B/D agonists, such as triptans, for acute management.
Triptans, the pillar of migraine therapy, increase serotonin signaling in cranial blood vessels
and nerve endings [36], relieving pain by inducing vasoconstriction and reducing the
release of vasoactive peptides, such as the calcitonin-gene-related peptide (CGRP) and
substance P (SP), among others [37,38].
The relevance of 5-HT in migraine has also been assessed by studying polymorphisms
in the gene SLC6A4, coding for the serotonin transporter (SERT), involved in the removal
of serotonin from the synaptic cleft back to the presynaptic neuron. Genetic alterations in
SERT can partially explain changes in serotonin levels. More precisely, two polymorphisms
in SERT have been linked with migraine, VNTR STin2 and 5-HTTLPR. The VNTR STin2
12/12 genotype is linked with migraine susceptibility in those of European descent [39]
and in the general population [40]. In the case of the 5-HTTLPR polymorphism, the short
variant (S) is associated with slower clearing of 5-HT from the synaptic cleft, increasing the
risk of migraine development [41–43], having some negative results [44,45].
More recently, genetic studies have shown that migraine is a polygenetic disorder,
since more than 38 loci have been linked to a higher susceptibility to migraine [46]. Locus
1p36 for the 5-HT1D receptor and functional polymorphism rs3813929 of the promoter
region of the gene for the 5-HT2C receptor have also been associated with migraine [47,48].
Additionally, the T allele of this gene impacts the transcription rate of the 5-HT2C receptor
and was found in Turkish population with migraine [48].
Biomolecules 2024, 14, 163 4 of 37

Neuroimaging studies have also examined the relevance of 5-HT in migraine. PET
studies have found increased 5-HT synthesis and elevated 5-HT turnover, which result in
decreased brain 5-HT levels [49]. However, in other studies, no differences were observed
regarding the rates of 5-HT synthesis [50]. Several variables appear to influence the
discrepancies of these results, namely, the time elapsed since the last attack as well as
clinical and demographic variables (age, sex, diagnosis, and chronicity). Further studies
have found lower 5-HT4 receptor binding, which was interpreted as higher interictal brain
5-HT levels [51,52]. However, increased 5-HT1A binding was found in the brainstem of
patients during migraine attacks, a change that has been associated with decreased 5-HT
availability [53]. Curiously, sumatriptan appears to reverse the increase in 5-HT synthesis
in the brain during migraine attacks [27]. These results suggest that the brain’s serotonin
synthesis rate may be altered in migraineurs and that triptans are effective in modulating
pain pathways by decreasing brain serotonin synthesis.
The role of serotonin in depression is well documented, with low 5-HT levels being
considered one of the most validated biological causes of mood disorders [54,55]. Thus,
5-HT levels in the cerebrospinal fluid are associated with the severity of depression in
major depressive disorder (MDD) patients [56]. Moreover, as described in the case of
migraine, the 5-HTTLPR polymorphism has also been associated with depression and the
efficacy of antidepressants. Lee et al. found a positive correlation of this polymorphism
with depression [57]. Accordingly, additional studies showed that this polymorphism
displays a role in modulating the onset of mood disorders [6,58]. The s/s genotype is
linked with worse antidepressant response, reduced serotonin expression and function,
and increased fear and anxiety [59,60]. Additionally, depressed patients with l/l or l/s
genotypes showed better responses to selective serotonin reuptake inhibitors (SSRIs) [61,62].
A few studies have analyzed the 5-HTTLPR polymorphism in migraine patients with
depressive symptoms, observing no association with the onset of migraine combined
with depression [63,64]. However, the sample size was small, making further large-scale
studies necessary.
Patients affected by mood disorders also present alterations in 5-HT1D , the pharma-
cological target of triptans, including reduced sensitivity, density, and binding of central
5-HT1D receptors [65,66]. Noticeably, the cessation of long-term excessive triptan use is
associated with the onset of severe major depression [67]. Therefore, it is hypothesized that
the chronic excessive use of triptans may induce persistent changes in the serotoninergic
system, including the desensitization of 5-HT1 receptors [68].
Magnetic resonance imaging (MRI) showed that the comorbidity of migraine and
depression is associated with a more pronounced reduction in brain volume [69]. This study
provided the first evidence providing that migraineurs with depression may represent
a clinical phenotype with different long-term sequelae. Additional regions affected by
migraine–depression comorbidity are the thalamus and the fusiform gyrus [70]. Patients
suffering from this comorbidity showed a marked decrease in the intrinsic brain activity
in the thalamus [71]. Moreover, the activity of the medial prefrontal cortex is altered in
both diseases, which can influence the activation of the dorsal raphe nucleus, leading to
depressive symptoms and headaches [71,72]. By using transcranial sonography (TCS), a
real-time imaging technique, reduced echogenicity has been identified in the midbrain
raphe (MBR) of MDD patients [73]. This alteration is representative of structural changes
in the MBR, which can explain the monoamine deficiency hypothesis in depression [74].
Interestingly, the reduced echogenicity in the MBR has also been associated with depressive
symptoms, migraine attack frequency, or overuse of analgesics in migraine patients [75–78].
Interestingly, the microarchitecture of the cerebral cortex is different in patients with MDD
and migraine compared to patients diagnosed with only one of them [70,79]. Altogether,
this evidence firmly supports the involvement of 5-HT in migraine–depression comorbidity.
Biomolecules 2024, 14, x FOR PEER REVIEW 5 of 39
Biomolecules 2024, 14, 163 5 of 37

Figure 1. Representative figure of the involvement of the serotoninergic system in migraine and
Figure 1. Representative
depression. figure
TNC: trigeminal of thecomplex;
nuclear involvement
5-HTof the serotoninergic system in migraine and
1B : serotonin receptor 1B; 5-HT1D : serotonin
depression. TNC: trigeminal nuclear complex; 5-HT1B: serotonin receptor 1B; 5-HT1D: serotonin re-
receptor 1D; 5-HT1F : serotonin receptor 1F; CGRP: calcitonin gene-related peptide; 5-HTTLPR
ceptor 1D; 5-HT1F: serotonin receptor 1F; CGRP: calcitonin gene-related peptide; 5-HTTLPR poly-
polymorphism: functional polymorphism in serotonin transporter; mPFC: medial prefrontal cortex;
morphism: functional polymorphism in serotonin transporter; mPFC: medial prefrontal cortex;
MBR:
MBR: midbrain
midbrain raphe.
raphe. Figure
Figure adapted
adapted from
from [80].
[80].
3.2. Neuropeptides
3.2. Neuropeptides
3.2.1. Calcitonin-Gene-Related Peptide
3.2.1. Calcitonin-Gene-Related Peptide
Calcitonin gene-related peptide (CGRP) is a 37-amino acid, vasoactive, neuroendocrine
peptideCalcitonin gene-related
that belongs peptide family.
to the calcitonin (CGRP)Both is a of
37-amino
its isoformsacid,(α,vasoactive, neuroendo-
β) are closely related
crine peptide
peptides encodedthat by
belongs
tandem to the
genescalcitonin
expressed family. Both ofchromosome
in human its isoforms 11 (α, (CALCA
β) are closelyand
related peptides
CALCB, encoded
respectively) andby tandem
only differgenes
in a fewexpressed
amino in human
acids, chromosome
dependent upon 11 the(CALCA
species.
and CALCB,
Thus, though respectively)
CGRPα and CGRPβ and onlypeptides
differ inare a few amino acids,
differentially dependent
regulated, theyupon
havethe spe-
nearly
cies. Thus, though
indistinguishable activitiesCGRPα and CGRPβ peptides are differentially regulated,
are expressed in an overlapping pattern [81,82] in the they have
nearly indistinguishable
nervous, cardiovascular, activities
immune,and are expressed
hematopoietic, andin an overlapping pattern
gastrointestinal systems[81,82] in the
[81,83–85].
nervous, cardiovascular,
Regarding the nervousimmune,
system,hematopoietic,
CGRP is expressedand gastrointestinal systemsganglia
in the peripheral [81,83–85]. and
Regarding
the central nervousthe nervous system,
system (CNS) CGRP
[85]. In theis expressed
periphery,in the peripheral
CGRP is releasedganglia and the
from primary
central nervous
afferents system (CNS)
of the trigeminal nerve [85].
intoInthe
theperivascular
periphery, CGRP spaceisofreleased from primary
the meninges, as well af-as
ferentsthe
within of ganglia,
the trigeminal
inducing nerve into thethat
a crosstalk perivascular
involves CGRP, space purinergic
of the meninges,
receptors, as nitrous
well as
oxide
within(NO), and inflammatory
the ganglia, cytokines
inducing a crosstalk that[86]. This CGRP,
involves scenario generatesreceptors,
purinergic a perfectnitrous
storm
combining
oxide (NO),vasodilatation
and inflammatory and positive
cytokines feedback
[86]. Thisloops, sensitizing
scenario generates trigeminal
a perfectganglia
storm com-(TG)
neurons, ultimately contributing
bining vasodilatation and positive to pain exacerbation
feedback and peripheral
loops, sensitizing sensitization,
trigeminal ganglia as in
(TG)
migraine
neurons, [81].ultimately contributing to pain exacerbation and peripheral sensitization, as in
In fact,
migraine different animal models and clinical studies have established a direct correla-
[81].
tion between an augmentation
In fact, different of CGRP
animal models andblood concentrations
clinical studies haveand the onset/worsening
established a direct correla- of
symptoms in migraine-like models and migraineurs [86]. Firstly,
tion between an augmentation of CGRP blood concentrations and the onset/worsening of indirect approaches, such
as electrical in
symptoms stimulation of themodels
migraine-like TG, theand dural surface of the
migraineurs dura
[86]. matter,
Firstly, or the approaches,
indirect administra-
tion
suchofasnitroglycerine, a precursor
electrical stimulation of theof TG,
NO,the caused
durala surface
noticeable of therelease
duraofmatter,
CGRP,or which in
the ad-
turn caused vasodilation,
ministration of nitroglycerine,increased meningeal
a precursor blood
of NO, flow [87,88],
caused a noticeableand trigeminal
release of system
CGRP,
sensitization
which in turnincausedanimalvasodilation,
models [89,90]. These meningeal
increased results consolidate
blood flow the[87,88],
crosstalkandbetween
trigeminalthe
CGRP, NO, TG, and meninges stated above and are coherent with
system sensitization in animal models [89,90]. These results consolidate the crosstalk be- the increase in CGRP
levels
tweenobserved
the CGRP, in NO,
patients
TG, with chronic migraine
and meninges [91–93],
stated above and though this feature
are coherent with is
the not found
increase
in all migraineurs.
in CGRP levels observed in patients with chronic migraine [91–93], though this feature is
Secondly,
not found in alldirect administration of CGRP has been proven to provoke peripheral
migraineurs.
and central sensitization, depending of
Secondly, direct administration onCGRP
the administration
has been proven route to selected
provoke[86]. Moreover,
peripheral and
direct
centralinfusion of CGRP
sensitization, causes aon
depending dilation of the cortical
the administration pial selected
route arteries and
[86]. arterioles
Moreover,and di-
of theinfusion
rect middle of meningeal
CGRP causesartery.a This vasodilatation
dilation of the corticalincreases local cortical
pial arteries cerebral and
and arterioles blood of
Biomolecules 2024, 14, x FOR PEER REVIEW 6 of 39

Biomolecules 2024, 14, 163 6 of 37

the middle meningeal artery. This vasodilatation increases local cortical cerebral blood
flow, provoking migraine-like symptoms in rodent models [91–93]. These effects have also
flow, reported
been provoking in migraine-like
patients. Aftersymptomsintravenous in infusion
rodent models of CGRP [91–93]. These
at a dose ableeffects have
to induce
also been reported in patients. After intravenous infusion
vasodilation, 66% of migraineurs experienced a migraine-like headache [94–96]; yet, pa- of CGRP at a dose able to
induce vasodilation, 66% of migraineurs experienced a
tients with no previous history of migraine only suffered mild headaches [97].migraine-like headache [94–96]; yet,
patients with
All the no previous
effects history of
and symptoms migraineabove
expressed only suffered mildor
are partially headaches [97].
totally abolished after
All the effects and symptoms expressed above are partially
the administration of indirect CGRP modulators that exert 5-HT1B/1D receptors agonist or totally abolished after
the administration of indirect CGRP modulators
properties in the serotoninergic pathway, such as triptans [98], and that exert 5-HT 1B/1D receptors agonist
drugs that directly
properties in the serotoninergic pathway, such as
complex CGRP or block its receptors, such as gepants [99] and anti-CGRP triptans [98], and drugs that directly
monoclonal
complex CGRP
antibodies [100–102]. or block its receptors, such as gepants [99] and anti-CGRP monoclonal
antibodies [100–102].
Regarding depression, CGRP disturbances have also been observed in several animal
Regarding depression, CGRP disturbances have also been observed in several animal
models. For example, Shao et al. reported increased CGRP levels in the CSF and hippo-
models. For example, Shao et al. reported increased CGRP levels in the CSF and hip-
campus (HIPP) of rats, showing more prominent depressive-like behavior in a model of
pocampus (HIPP) of rats, showing more prominent depressive-like behavior in a model of
post-stroke depression [103]. CGRP could also play a part in depression onset, as shown
post-stroke depression [103]. CGRP could also play a part in depression onset, as shown by
by Jiao et al., who reported increased depressive-like behavior in mice after the central
Jiao et al., who reported increased depressive-like behavior in mice after the central admin-
administration of CGRPα. Moreover, these findings were counteracted after the admin-
istration of CGRPα. Moreover, these findings were counteracted after the administration of
istration of CGRP antagonists [104].
CGRP antagonists [104].
These results are controversial, since other authors have found CGRP-overexpressing
These results are controversial, since other authors have found CGRP-overexpressing
mice to show stress-resistant behavior [105,106] or normal sensitivity to stress [107]. Nev-
mice to show stress-resistant behavior [105,106] or normal sensitivity to stress [107]. Never-
ertheless, recent published work seems to confirm that increased brain levels of CGRP are
theless, recent published work seems to confirm that increased brain levels of CGRP are
present
present in in well-established
well-established animal animal models
models of of depression;
depression; yet, yet, these
these are
are not
not modified
modified by by
SSRIs or tricyclic antidepressants
SSRIs or tricyclic antidepressants (TCAs) [108].(TCAs) [108].
Accordingly,
Accordingly, an an increase
increase in in CGRP
CGRP levels
levels has
has been
been found
found in in women
womenwith withMDD MDDcom-com-
pared
pared to healthy subjects, suggesting a potential role for CGRP as a biomarker [109]. Some
to healthy subjects, suggesting a potential role for CGRP as a biomarker [109]. Some
studies
studies even
evensuggested
suggestedthat thatthe thefold
foldelevations
elevations of of
CGRPCGRP could
couldbe be
related to symptom
related to symptom se-
verity
severity rather than disease classification per se [110]. Interestingly, recently publishedre-
rather than disease classification per se [110]. Interestingly, recently published re-
sults
sults from
from aa prospective
prospective cohort
cohortshow showhow howthethetreatment
treatmentwith withsome
someanti-CGRP
anti-CGRP monoclo-
monoclonal
nal antibodies
antibodies led led to improvement
to improvement in depressive
in depressive symptoms
symptoms in individuals
in individuals withwith migraine,
migraine, with
with independence
independence of migraine
of migraine reduction reduction [111]. Altogether,
[111]. Altogether, these findings
these findings support
support the the
rationale
rationale behind the potential role of CGRP in both entities (Figure
behind the potential role of CGRP in both entities (Figure 2), migraine and depression; 2), migraine and de-
pression; though
though further further
studies arestudies
required, are this
required, this could
could provide anprovide
innovative an innovative
approach for approach
patients
for patients that could benefit from undergoing
that could benefit from undergoing treatment targeting CGRP. treatment targeting CGRP.

Figure 2. The involvement of the CGRP and PACAP in migraine and depression. CGRP: calcitonin-
Figure 2. The involvement of the CGRP and PACAP in migraine and depression. CGRP: calcitonin-
gene-related peptide; PACAP: pituitary adenylate cyclase-activating polypeptide; MDD: major de-
gene-related peptide; PACAP: pituitary adenylate cyclase-activating polypeptide; MDD: major de-
pressive disorder;
pressive disorder; Ab:
Ab: monoclonal
monoclonal antibody;
antibody; VPAC1-R:
VPAC1-R: vasoactive
vasoactive intestinal polypeptide receptor
intestinal polypeptide receptor1;1;
VPAC2-R: vasoactive intestinal polypeptide receptor 2; PAC1-R: pituitary adenylate cyclase-activating
polypeptide type I receptor; CGRP-R: calcitonin-gene-related peptide. Figure adapted from [112].
Biomolecules 2024, 14, 163 7 of 37

3.2.2. Pituitary Adenylate Cyclase-Activating Polypeptide

Pituitary adenylate cyclase-activating polypeptide (PACAP), which is found as a
38-amino-acid peptide (PACAP-38) and its truncated 27-amino-acid form (PACAP-27),
belongs to the vasoactive intestinal polypeptide (VIP)–secretin–growth hormone-releasing
hormone–glucagon superfamily [113]. Both isoforms act on the same receptors and are
encoded by exon 4 of the ADCYAP1 gene, located in chromosome 18, with PACAP27
being the only one that suffers post-translational shortening at the C-terminus site. Despite
having similar affinities and functions, PACAP-38 is the predominant peptide, representing
more than 90% of the total PACAP content in most tissues, including the CNS [112].
PACAP38 is also expressed in migraine-related anatomical structures located in the
peripheral nervous system, such as the sphenopalatine ganglion, parasympathetic perivas-
cular nerve fibers, and sensory nerve afferents of the cranial arteries. Despite being co-
localized with CGRP-immunoreactive neurons in the TG and trigeminal nucleus caudalis,
PACAP38 has a larger parasympathetic distribution and a smaller trigeminal distribution
than GCRP [112,114,115]. Thus, it could be hypothesized that PACAP38 functions primarily
as a neuropeptide in the parasympathetic pathways underlying migraine, while CGRP acts
predominantly in the sensitization process [112].
In addition, the available evidence confirms that PACAP38 triggers a migraine-like
response similar to CGRP administration in some animal models of migraine [116,117].
However, it is important to notice that the PACAP38 pathway seems to be distinct and
independent from other migraine pathways [112,116,117], contrasting previous observa-
tions [118]. In this sense, multiple potential mechanisms have been proposed to explain
the migraine-inducing effect of PACAP38, including: vasodilatation, modulation of the
parasympathetic nervous system, mast cell degranulation, activation of sensory afferents,
and central effects [112].
Several animal studies have demonstrated that PACAP38 can activate the trigemi-
novascular system, causing perivascular neurogenic inflammation mediated by mast cell
degranulation [119,120]. Its peripheral injection has also been shown to induce hyperalge-
sia [121] and light aversive behavior in wild-type mice, which is absent in PACAP knockout
mice [122]. Despite exerting vasodilatory effects [123], it has been suggested that the ability
of PACAP-38 to induce migraine may not be related to this feature but to its excitatory role
in pain transmission [124,125].
In humans, the administration of PACAP38 caused headaches in healthy volun-
teers [126,127], and plasma levels of PACAP38 seemed to be elevated during spontaneous
migraine attacks compared to the interictal phase. However, blood levels decreased dur-
ing the interictal phase compared to healthy volunteers, a phenomenon attributed to the
chronic depletion of PACAP38 caused by an excessive consumption during migraine cri-
sis [128,129]. A double-blind, randomized, placebo-controlled study found that intravenous
administration of PACAP38, but not placebo, caused headache in healthy subjects and
migraineurs without aura. Moreover, in 58% of migraineurs without aura, a migraine-like
attack was observed, while only 16% of patients in the placebo-controlled group experi-
enced migraine-like symptoms [130]. Therefore, it could be hypothesized that PACAP38
antagonists may be a therapeutic tool.
Nevertheless, in a phase 2a, randomized, double-blind, placebo-controlled, three-arm
clinical trial aimed to evaluate the efficacy and safety of AMG 301 (a PACAP38 antagonist)
in migraine prophylaxis, no statistically significant differences were found between AMG
301 and placebo [131]. Even though no favorable results were obtained, more promising
results have been reported regarding ALD1910, a monoclonal antibody 4000-fold more
selective for PACAP38 and PACAP27 than VIP, in an umbellulone-induced rat model of
headache [132]. More recently, Lu AG09222, a humanized monoclonal antibody directed
against the PACAP ligand, successfully inhibited PACAP38-induced cephalic vasodilation
while reducing concomitant headache, so is thus a potential therapy against migraine [133].
When it comes to the CNS, PACAP38 is most abundant in the hypothalamus (likewise
for CGRP), cerebral cortex, cerebellum, and brain stem [134]. Curiously, its receptors
Biomolecules 2024, 14, 163 8 of 37

have a widespread distribution, some of them being particularly abundant in the cerebral
cortex, amygdala, HIPP, thalamus, and hypothalamus [134,135]. Moreover, PACAP is
directly involved in the regulation of monoamine synthesis and metabolism, brain-derived
neurotrophic factor (BDNF) expression, and hypothalamic–pituitary–adrenal (HPA) axis
activation [136], which, taken together with its distribution in anatomical areas that play
a part in stress response and depression, allows the confirmation that this neuropeptide
is closely related to the behavioral and endocrine responses to stress, as well as synaptic
plasticity and neuroprotection [137].
Experimentally, the administration of PACAP in the paraventricular nucleus of the
hypothalamus (PVN), the central nucleus of the amygdala (CeA), and the bed nucleus of
the stria terminalis (BNST) has been shown to produce a stress-like response, and activate
the HPA axis and the extrahypothalamic corticotropin-releasing factor (CRF) systems in
rodents [138,139]. For example, PACAP-treated rats showed a dose-dependent increase in
intracranial self-stimulation (ICSS), which is correlated with depressive-like behavior [138];
yet, this effect disappeared after administering a PACAP antagonist [140]. None of these
depressive-like symptoms have been observed after the neuropeptide administration in
PACAP knockout mice [141].
When it comes to patients with depressive disorders, little is known regarding the in-
fluence of PACAP on the onset, development, or clinical course of depression. Quantitative
immunohistochemical staining of PACAP revealed elevated levels in the central BNST in
postmortem samples of patients with MDD and bipolar disorder. However, this finding
has only been observed in male subjects [142]. A significant positive correlation has also
been reported between the Cornell depression score and PVN-PACAP-immunoreactivity
in patients with Alzheimer’s disease and depressive or bipolar disorder [143].
Altogether, these data suggest that PACAP is involved in migraine and depression
(Figure 2), indicating another molecular target that could be assessed to develop new
pharmacological tools to enlarge the therapeutic armamentarium available to address both
clinical entities.

3.2.3. Neuropeptide Y
The craniocervical blood vessels, of great relevance in the etiopathology of migraine,
are innervated by sympathetic fibers from the cervical and stellate ganglions [144,145]
that store and release neuropeptide Y (NPY) [146–149]. This neuropeptide is crucial in
controlling brain circulation due to its long-lasting vasoconstrictor properties [150,151].
Studies focusing on evaluating the NPY levels in plasma found an increase during
attacks in migraine patients with aura and, to a lesser extent, in those without it [152]. In
contrast, other authors found no variation during migraine attacks in this regard [153].
Similarly, in the CSF, some studies showed that NPY levels were higher in migraineurs [154],
while other investigations found no alterations [155].
Recently, NPY signaling was shown to be involved in migraine via NPY receptor type
1 (Y1R). The microinjection of NPY into the medial habenula (MHb) exhibited analgesic
and anxiolytic-like effects in the mouse model of glyceryl trinitrate (GTN)-induced mi-
graine [156]. These effects are associated with the activation of Y1R, which, in turn, reduces
the trigeminal activity evoked by the dura mater.
NPY also plays an essential role in mechanisms related to emotional reactivity and
behavioral responses to stress [157], and its effects are influenced by the gut–brain axis [158].
In animal models of depression, decreased expression of NPY in the HIPP and hypothala-
mus [159] and reduced levels of NPY in the HIPP [160] have been observed. Furthermore, it
was concluded that low NPY concentrations lead to depression, and certain antidepressants
seem to increase NPY levels [161].
As has been demonstrated in migraine, the Y1R, NPY receptor 2 (Y2R), and NPY
receptor 5 (Y5R) are potential therapeutic targets for neuroprotective and antidepressant
drugs [162,163]. In animal models, the local injection of NPY into the medial prefrontal
cortex induced antidepressant properties via Y2R treated with lipopolysaccharides [164].
Biomolecules 2024, 14, 163 9 of 37

In addition, Y1R agonists increase neuroblast growth, promoting BDNF release in the
HIPP [165]. Intranasal administration of YR1 agonists also induces antidepressant-like
effects by increasing BDNF [165].
In summary, these data point out the role of NPY in migraine and depression. Future
studies with YR agonists will provide more information about their potential therapeu-
tic usefulness.

3.2.4. Substance P
Substance P (SP) is widely expressed in trigeminal sensory nerve fibers [166], primar-
ily in the nucleus raphe magnus (NRM), locus coeruleus (LC), and periaqueductal grey
(PAG) [167]. It plays a vital role in pain transmission [168,169] and vasodilation of the
cerebral dura mater [170].
Several studies have focused on determining the alterations of SP in migraineurs. In
spontaneous migraine attacks, no increase in cranial venous SP flow has been observed [153,171].
In contrast, there is an increase in salivary SP during spontaneous migraine attacks without
aura [172]. Another study found higher levels of SP in platelets of migraine patients [173].
Interestingly, increased plasma SP concentrations during periods without headache have
been detected in patients affected by episodic and chronic migraine [174,175].
Additionally, the evidence found to date indicates the involvement of the preferential
receptor of SP, the NK1 receptor, in migraine. Antagonists of the NK1 receptor showed a
robust effect in blocking plasma protein extravasation and decreasing the firing of second-
order neurons in the trigeminal nucleus caudalis (TNC) [176]. Nevertheless, clinical studies
with NK1 antagonists did not show a greater effect than the placebo in the acute manage-
ment or as a prophylactic treatment of migraine [176–179]. Further studies are needed to
investigate the role of NK1 receptors as potential new therapeutic targets for the treatment
of migraine.
In the case of depressive disorders, the role of SP and NK1 receptors in the patho-
physiology of depression is suggestive but not conclusive [180–182]. Opposite results
were found when plasma and serum concentrations of SP were analyzed in patients with
MDD. On one hand, it has been observed that plasma concentrations of SP are significantly
reduced in patients with MDD [183]. However, additional studies found no differences in
plasma SP levels between patients with MDD and healthy controls. No correlation has been
found between plasma levels of SP and psychiatric symptoms or cognitive function [184].
In contrast, higher serum SP levels were identified in another study carried out in MDD
patients [185].
In addition, SP is involved in the activation of the sympathetic system and the HPA
axis in response to stressors [186]. In animal models, stress increases the release of SP in the
AMY accompanied by anxious behavior [187]. Moreover, the central administration of SP
elicited depressive and anxious behaviors in animals, whereas NK-1R antagonists induced
anxiolytic and antidepressant-like effects [188–190].
Taken together, there is some evidence suggesting the involvement of SP in migraine,
with more studies needed, especially regarding migraine–depression comorbidity.

3.2.5. Orexins
There are two types of orexins (OX), orexin A (OXA) and orexin B (OXB) [191,192].
OXA binds to the OX1 (OX1R) and OX2 (OX2R) receptors, while OXB binds exclusively to
OX2R [192–194]. OXA and OXB are synthesized in the lateral, posterior, and paraventricular
nuclei of the hypothalamus [195–198], and their neurons project to nociceptive areas of the
brain such as the LC, PAG and NRM, closely related to migraine [193,199–201]. OX1R is
selectively expressed in the LC, while OX2R is expressed in the NRM [197,202].
There is evidence of the involvement of orexins in migraine. In migraine-related
structures, neurons containing orexin showed increased activation during wakefulness and
are inhibited during sleep [197]. Additionally, there is evidence that patients with chronic
migraine have higher CSF levels of orexins [203]. Notably, the orexin system modulates
Biomolecules 2024, 14, 163 10 of 37

the trigeminovascular system, inhibiting it through OX1R—which attenuates neurogenic

dural vasodilation [204]—or activating it via OX2R. This has led to pharmacological studies
evaluating the effects of drugs acting on these receptors.
Cady et al. demonstrated that dual OX1R and OX2R antagonists inhibited trigeminal
sensory neuronal activation in rats [205]. On the other hand, the inactivation of OX1R
in the basolateral amygdala (BLA) of rats increased photophobia, anxiety-like behavior,
and social interaction deficits in the NTG-induced migraine model. Additionally, OX1R
antagonism increased spontaneous migraine-like headache behaviors in NTG-treated rats.
Interestingly, the blockade of OX1R failed to reduce hyperalgesia in this model, suggesting
that OX1R play a more critical role in the modulation of emotional alterations rather than
sensory processing in migraine [206].
However, in humans, the only clinical trial conducted to date, a double-masked,
placebo-controlled study with an orexin receptor antagonist (filorexant), did not show its
efficacy as a prophylactic treatment for migraine [207]. Further studies are needed to assess
the therapeutic role of orexins in migraine. Based on the results obtained in animals, it
might be interesting to investigate the role of pharmacological modulation of OXR1 in
reducing anxiety and depression traits in migraine patients.
In the case of MDD, there is evidence supporting the involvement of orexins [208]; how-
ever, there is controversy as to whether orexin neurons are hyper- or hypoactive [209,210].
On the one hand, increased levels of orexins were detected in the hypothalamus of rats ex-
posed to a model of depression induced via the neonatal administration of clomipramine [208].
On the other hand, previous studies showed that the size of soma cells and the number
of orexin neurons are reduced in rodent models of depression [211–213]. In humans, clear
changes in plasma orexin concentrations have been found, with MDD patients having
lower levels than BP patients. Interestingly, depressed patients with suicidal ideation have
higher levels, being proposed as a biomarker for preventing suicide [214].
Additional experiments sowed that orexins increased the firing frequency of dopamin-
ergic neurons in the VTA [215], the brain area involved in depression [216,217]. In mice
exposed to a chronic mild stress model, a paradigm of depression, the activity of orexin
neurons projecting to the VTA was reduced. Furthermore, increasing orexin release in the
VTA using optogenetics and chemogenetics significantly reversed depressive-like behav-
iors [218].
Concerning orexin receptors, the investigations carried out to date have indicated
that OX1R and OX2R play distinct roles in anxiety and depression [213,219,220]. Firstly,
studies on the orexigenic system in affective disorders have focused on the description of
the anxiogenic and prodepressant actions of OrxA [221–224] through OX1R [220,225–227].
Subsequently, it was shown that OX2R activation, upon intracerebroventricular adminis-
tration of an OX2R agonist, exhibited anxiolytic and antidepressant activity [228]. In a rat
model of chronic mild stress, OX1R antagonism reduced depressive behaviors [229]. In
the case of ORX2 antagonism, animal studies have provided conflicting results [230,231].
Interestingly, dual orexin receptor antagonists have shown antidepressant effects [224,232].
In humans, dual orexin receptor antagonists, suvorexant and lemborexant, have been
approved for the treatment of insomnia disorder in the United States, characterized by
difficulties with sleep onset and/or sleep maintenance in adults based on the results of
pivotal phase 3 studies. In the case of MDD, a clinical trial found that suvorexant, a potent
and highly selective antagonist of OX2R, significantly reduced depressive symptoms and
alleviated insomnia in MDD patients with sleep disturbances [233].
In short, orexine receptors appear to be promising targets for treating anxiety and
depression in migraine patients, deserving further exploration.

3.3. Sexual Hormones

3.3.1. Estrogens
As previously mentioned, migraine presents differences in prevalence based on sex,
with the number of cases being three times higher in women [1]. One factor that may
Biomolecules 2024, 14, 163 11 of 37

explain the sex disparity is the levels of ovarian steroid hormones and how these vary
according to the menstrual cycle. It is worth noting that there is an increase in the prevalence
of migraine at puberty, with a greater incidence in women of childbearing age, affecting
24% of women between 30 and 39 years of age [234,235]. Among all cases of women
with migraine, approximately 22% of the total were menstrual migraines in women of
childbearing age. Migraines without aura were more frequent than migraines with aura,
with menstrual-related migraine (MRM) being more common than pure menstrual migraine
(PMM) [236]. Moreover, attacks caused by menstrual migraine are more severe, painful,
disabling, last longer, and usually course with nausea and allodynia [237–239].
In the case of menstrual migraines, the hypothesis of estrogen withdrawal has been pro-
posed as the etiological mechanism. Accordingly, the precipitation of migraine headaches
is related to a drop in estrogen levels below 40–50 pg/mL [240]. Aspects such as the “mag-
nitude of the decline” and the “residual threshold” have been proposed as precipitating
factors. The first one assumes that a minimal reduction in estrogen is needed to trigger
a migraine attack. The second one assumes that a minimal concentration of estrogen in
the blood must be maintained to prevent migraine [241]. Another aspect is the rate of
estrogen decrease. In the Study of Women’s Health Across the Nation (SWAN) Daily
Hormone, women with migraine had a more rapid premenstrual decline in estrogen levels
than controls [242].
Several mechanisms have been proposed to underlie the association between de-
creased estrogen levels and migraine. Estrogen receptors are highly expressed in brain
regions involved in pain processing, such as the thalamus, PAG, AMY, and trigeminovascu-
lar system [243]. Estrogen depletion increases the susceptibility of vessels to prostaglandins,
activating the endothelial cell nitric oxide synthetase, and, consequently, the production
of the vasodilator NO [244]. Additionally, estrogen depletion reduces endogenous opioid
activity, as well as having effects through the serotonergic and dopaminergic systems [245].
Estrogens increase the expression of the rate-limiting enzyme tryptophan hydroxylase and
reduce the serotonin reuptake [245–247]. Thus, estrogen depletion impacts neuronal excita-
tion and pain perception, increases allodynia, induces central nervous system sensitization,
and promotes cortical-spreading depression [248–250].
As in the case of migraine, sex is also a risk factor for depression. MDD is more com-
mon in women than men, a difference that persists into old age [251,252]. Symptoms are
generally more severe in women; feelings of loneliness and low self-perception of health are
common among depressed women, experiencing prolonged or recurrent depression more
than depressed men, with a younger onset and lower quality of life [253–256]. Notably,
there are pieces of evidence supporting the impact of fluctuations in the ovarian estrogen
hormone levels on women’s well-being [257,258]. There is a relationship between the
menopausal period and the onset of depressive disorders. Moreover, the hormonal fluctua-
tions before menstruation and during pregnancy, the puerperium, or the perimenopausal
period are closely linked with mood disorders [257]. Additionally, sex also impacts antide-
pressant efficacy [259]. For instance, postmenopausal women have a diminished response
to antidepressants compared with younger women.
As in migraine, there is a relationship between low sex hormone levels and increased
prevalence of depression [260]. Furthermore, the administration of exogenous estrogens has
antidepressant effects in depressed women, with the effect more significant if administered
during perimenopause, in the form of a transdermal patch, or the postpartum period [261–263].
However, there is controversy, as other studies have shown that estrogens did not improve
mood in postmenopausal women or even increase the risk of cognitive impairment and
stroke [264–266].
Estrogens also play an important role in the efficacy of antidepressants by regulating
the CNS [267]. As mentioned before, estrogens are linked with the serotoninergic system.
Estrogens participate in the synthesis and degradation of 5-HT, in the density of serotonergic
receptors, and in the expression of 5-HT-related genes [268]. Notably, estrogens are thought
to promote serotonergic signaling to exert antidepressant effects [269–271].
 did not improve mood in postmenopausal women or even increase the risk of cognitive
impairment and stroke [264–266].
Estrogens also play an important role in the efficacy of antidepressants by regulating
the CNS [267]. As mentioned before, estrogens are linked with the serotoninergic system.
Biomolecules 2024, 14, 163 Estrogens participate in the synthesis and degradation of 5-HT, in the density of sero-
12 of 37
tonergic receptors, and in the expression of 5-HT-related genes [268]. Notably, estrogens
are thought to promote serotonergic signaling to exert antidepressant effects [269–271].
Additionally, estrogens activate transcription factor pathways, changing the gene ex-
Additionally, estrogens activate transcription factor pathways, changing the gene
pression of trophic factors such as BDNF [272], which is involved in neuronal survival
expression of trophic factors such as BDNF [272], which is involved in neuronal survival
and differentiation, synaptic transmission, learning, and memory [273–276]. BDNF has
and differentiation, synaptic transmission, learning, and memory [273–276]. BDNF has
been extensively
been extensively studied
studied andandlinked
linkedtotodepression
depression[277–281].
[277–281].Studies
Studieshave
have shown
shownthatthat
es-
tradiol and BDNF activate similar signaling pathways. Moreover,
estradiol and BDNF activate similar signaling pathways. Moreover, estradiol increases estradiol increases
BDNF expression
BDNF expression and
and proteins,
proteins, which
which fluctuates
fluctuates following
following thethe same
same dynamics
dynamics of of change
change
as estradiol
as estradiol during
during menstruation
menstruation [282–284].
[282–284].InInaddition,
addition,thetheexogenous
exogenous administration
administration of
estradiol to ovariectomized animals has been shown to reverse BDNF
of estradiol to ovariectomized animals has been shown to reverse BDNF depletion and depletion and pre-
vent thethe
prevent development
development of depressive
of depressive behavior
behavior [285–287].
[285–287].
In summary, although further studies
In summary, although further studies are needed,are needed, all
all this
this cumulative
cumulative evidence
evidence sup-
sup-
ports the involvement of estrogens in migraine. Fluctuations in estrogens
ports the involvement of estrogens in migraine. Fluctuations in estrogens are essential in are essential in
the pathophysiology
the pathophysiology of of migraine.
migraine. Moreover,
Moreover, changes
changes inin estrogens
estrogens also
also influence
influence mood
mood
state and
state anddirectly
directlyinfluence
influencethethebrain
braincircuits
circuitsinvolved
involvedinin emotional
emotional regulation.
regulation. TheThe clini-
clinical
cal implications of these findings suggest that estrogen status may be important
implications of these findings suggest that estrogen status may be important for migraine for mi-
graine and depression comorbidity and that estrogen treatment
and depression comorbidity and that estrogen treatment or replacement may deserveor replacement may de-
serve further exploration as a pharmacological option for
further exploration as a pharmacological option for women (Figure 3). women (Figure 3).

Figure 3. The role of sexual hormones in migraine and depression. TH: tyrosine hydroxylase; 5-HT:
Figure 3.
serotonin; CNS:
serotonin; CNS: central
central nervous
nervous system;
system; TG:
TG: trigeminal
trigeminal ganglion;
ganglion; CGRP:
CGRP: calcitonin-gene-related
calcitonin-gene-related
peptide; PACAP: pituitary adenylate cyclase-activating polypeptide; HPA: hypothalamic–pitui-
peptide; PACAP: pituitary adenylate cyclase-activating polypeptide; HPA: hypothalamic–pituitary–
tary–adrenal axis; ↑ increase; ↓ decrease. Figure adapted from
adrenal axis; ↑ increase; ↓ decrease. Figure adapted from [288]. [288].

3.3.2. Progesterone
Progesterone is a neurosteroid hormone produced by the ovaries and placenta in
women and by the adrenal glands and brain in both sexes. In the CNS, progesterone is
synthesized by glial cells and neurons [289,290]. Its action on the progesterone receptor
mediates the physiological effects of progesterone. Beyond its effects on controlling repro-
duction, progesterone has been found to play a role in developing and maintaining the
neurons in the brain [291–293]. In the case of migraine, progesterone receptors are involved
in regulating pain sensitivity and migraine susceptibility in women [294].
Cumulative evidence highlights the potential for progesterone to modulate sensory
neurotransmission and vascular responses in a complex manner, indicating that proges-
terone primarily serves as a modulator rather than as an elicitor. Progesterone down-
Biomolecules 2024, 14, 163 13 of 37

regulates estrogen receptors, which in turn reduces the activation of trigeminovascular

pain pathways [295]. Additional progesterone actions observed include the control of
vasodilatation by decreasing histamine secretion from mast cells and prostaglandin pro-
duction [246,296,297].
Progesterone also plays a major role in depression, possibly mediated by its neuros-
teroid derivative tetrahydroprogesterone [298]. Peripheral progesterone has a protective
effect on mood and has therefore been tested for the treatment of postpartum depres-
sion [299,300]. In ovariectomized mice exposed to a model of depression, progesterone
administration was shown to reduce anxiety and depression via changes in the gut mi-
crobiota [301]. These findings suggest that progesterone may be useful in improving
depressive symptoms in menopausal women [302,303].
Thus, the broad role of progesterone in migraine and the efficacy of progesterone
modulating depressive symptoms make it mandatory to further explore its potential
therapeutic role in migraine–depression comorbidity (Figure 3).

3.3.3. Prolactin
Prolactin (PRL) is another crucial hormone involved in migraine. PRL receptors are
expressed in the neurons of the trigeminal ganglia as well as in dural afferent neuronal fibers,
which are structures involved in the nociception and pathogenesis of migraine [304,305].
Clinical and preclinical studies have supported the involvement of PRL and its recep-
tors in migraine, with important sex differences. The dural administration of prolactin-
induced long-lasting migraine-like behaviors only in women [306]. Moreover, higher
expression of PRLP receptors has been observed in women compared to men in trigemi-
nal ganglion sensory neurons and in the neuronal fibers that innervate the dura
mater [306–309]. Importantly, PRL is also associated with CGRP, the serotonin system, and
PACAP-38 [130,306,308]. Evidence has indicated that PRL is involved in the modulation of
neuronal excitability and pain mainly via its action on TRPV receptors [310–312].
Alterations in PRL have been observed in migraine patients, being associated with the
progression of migraine. Thus, increased PRL levels are considered as a worsening factor
for migraine [313,314]. Preventive drugs and triptans also modified PRL levels [315,316].
There is evidence of the reduction in PRL levels after the administration of triptans, such as
sumatriptan [316].
Prolactin has also been studied in depressive disorder. The hypothalamic–prolactin
axis is dysregulated in depressive patients with suicidal behavior, especially if the suicide
attempt has been severe [317]. It was suggested that prolactin can reduce stress by attenuat-
ing the responsiveness of the HPA axis [318]. However, other studies showed that prolactin
secretion is increased in stressful situations [319]. Notably, it was observed that plasma
prolactin levels were higher in individuals with MDD than in controls, suggesting that
prolactin dysregulation may be a feature of MDD [320].
Altogether, all these data indicate PRL and their receptors as new candidates to be
further explored in the migraine–depression comorbidity (Figure 3).

3.3.4. Oxytocin
Oxytocin (OT) is highly implicated in the process of migraine initiation and may,
in turn, be a potential therapeutic target [321]. OT is a pleiotropic hypothalamic neuro-
transmitter that exerts an antinociceptive effect via its OTR receptor to inhibit trigeminal
neuronal excitability. This is of relevance because of the involvement of the hypothalamus
in the different phases of migraine, increasing blood flow in this brain region during pre-
monitory symptoms and processing nociception [230,322]. Activation of the OTR results in
intracellular Ca2+ mobilization, inhibiting nociception through GABAergic signaling, inhi-
bition of transient potassium current, desensitization of TRPV1 channels, and disruption of
NMDA-coordinated neuronal network activity [323–325].
Additionally, spinal oxytocin reduced the neuronal firing of the trigeminocervical
complex caused by meningeal electrical stimulation in rats [325]. Additional studies showed
Biomolecules 2024, 14, 163 14 of 37

that OTR are expressed in the trigeminal vascular system in rats but not in the cranial
arteries [326,327]. OT receptors are present in the neuronal structures closely related to
migraine precipitation, such as the trigeminal ganglion and caudal trigeminal nucleus.
In an animal model of chronic migraine, the intranasal administration of OT abolished
central sensitization by regulating synaptic plasticity [328]. Moreover, in menstrual mi-
graine, alterations in OT levels and OTR expression appear to be involved in the activation
of meningeal trigeminal nociceptors and the subsequent risk of migraine attacks during
menstruation [329].
Oxytocin is also crucial in modulating emotional behaviors, with evidence of anx-
iolytic and antidepressant effects [330–334]. Among other aspects, oxytocin has been
associated with attachment, social bonding, feelings of trust, positive communication, altru-
ism, and empathy in different studies [335–340]. Oxytocin is an essential neuromodulator
in the amygdala, hypothalamus, and nucleus accumbens, brain regions closely related to
depression [341,342].
Exogenous oxytocin has been shown to significantly decrease anxious and depressive
behaviors in mice, with its effects influenced by sex, estrous cycle, and hormone levels [343].
The effect of exogenous oxytocin administration is attenuated in females, as shown in
different animal models, involving social defeat, social avoidance, and social preference
and avoidance induced by maternal defeat [344–346].
On the other hand, oxytocin may affect neuronal plasticity in response to environmen-
tal conditions, thereby modifying behavioral and psychological outcomes [347,348]. The
relationship between oxytocin and depression is not fully understood, as some studies did
not report consistent findings [349–351].
Concerning the therapeutic potential of the oxytocinergic system in depressive disor-
ders, one clinical trial showed an improvement in mood when oxytocin was administered
for two weeks together with escitalopram treatment [352]. Notably, after the use of different
antidepressant treatments in depressive patients, serum oxytocin levels were not affected,
despite reduced depressive scores [353]. However, this does not imply that oxytocin is
unrelated to the development of depression or that it is not useful as a prophylactic [354].
One promising finding is that oxytocin may be used as an adjunct drug to antidepressant
treatment or to treat specific aspects of depressive disorders [355].
Therefore, the oxytocinergic system is an ideal new potential therapeutic target de-
serving further exploration in the treatment of depression in migraine (Figure 3).

3.4. Glutamate and GABA

Glutamic acid/glutamate and γ-aminobutiric acid (GABA) are the main excitatory
and inhibitory neurotransmitters in the CNS, respectively. Glutamate is taken up from the
circulation or directly synthesized from glutamine, α-ketoglutarate, and 5-oxoproline and
catabolized in the neurons and glia [356]. GABA’s precursors are mainly glutamate, pyru-
vate, and other amino acids [357]. Dysregulations in both glutamatergic and GABAergic
neurotransmission systems have been continuously linked to different neuropsychiatric
disorders, including migraine and depression.
It is known that migraine pain-relay centers, including the trigeminal ganglion,
trigeminocervical complex (TCC), and sensory thalamus, contain glutamate-positive neu-
rons [358]. However, the brains of migraineurs differ pharmacologically from those of
nonmigraine sufferers, and it seems that glutamate may play a major role in such differ-
ences [359]. For example, magnetic resonance spectroscopy studies of the cortex and the
thalamus found higher interictal glutamate levels in the visual cortex and thalamus of
migraine patients but no group differences in GABA levels, supporting the hypothesis
of cortical and thalamic hyperexcitability in migraine driven by the excess availability of
glutamate [360,361]. Despite these results, a recent study also found increased GABA levels
in the visual cortex from interictal toward the preictal state for migraine patients compared
with healthy controls, thus supporting a potential role for GABA in migraine [362].
Biomolecules 2024, 14, 163 15 of 37

Furthermore, CSF concentrations of glutamate have also been found to be higher in mi-
graineurs than in healthy volunteers, confirming the excess of neuroexcitatory transmission
in the CNS [358]. This glutamate release affects the spinal dorsal horn, causing glutamate
receptor activations and central sensitization, with allodynia and hypersensitivity being
the most common clinical consequences of this excitatory disbalance, suggesting a defec-
tive cellular reuptake mechanism for glutamate in migraine patients at the neuronal/glial
level [363]. More specifically, multiple pain models suggest that this central sensitization
includes multiple mechanisms of synaptic plasticity caused by changes in the density,
nature, and properties of ionotropic and metabotropic glutamate receptors [364,365]. Even
other characteristic features such as aura seem to be directly or indirectly caused by this
hyperexcitatory status, since the local release of glutamate by neurons is thought to initiate
the cortical-spreading depression that causes this visual symptom [366].
Additionally, glutamate is involved in the nociception of migraine through its kainate
receptors. This observation is based on studies that showed how preventive, approved
treatments such as topiramate inhibit third-order neurons responding to trigeminovascular
stimulation and to selectively block the excitation induced by kainate receptor agonists but
not by N-metil-D-aspartate (NMDA) or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (AMPA) receptor agonists [367]. Nevertheless, noncompetitive NMDA receptor chan-
nel blockers like memantine have demonstrated significant effects in reducing headache
frequency and mean disability scores when given as a preventive treatment of refractory
migraine [368–370]. Other anticonvulsants, such as lamotrigine, have also exerted potential
prophylactic properties that could be superior to topiramate. However, the outcomes in
this regard have been conflicting [371,372].
The glutamate signaling pathway is also indirectly modulated by other approved
treatments for migraine, such as triptans and CGRP monoclonal antibodies. Triptans have
been shown to interfere with the release of glutamate from the primary afferents in the TCC
by decreasing the amplitude of glutamatergic excitatory postsynaptic currents and reducing
the frequency of spontaneous excitatory postsynaptic currents. These actions are potentially
mediated by the presence of 5-HT1D and/or 5-HT1B receptors on the presynaptic terminal,
thus affecting presynaptic Ca2+ influx [373]. On the other hand, anti-GCRP monoclonal
antibodies are thought to prevent NMDA- and AMPA-evoked firing potentiation and the
nociceptive activation of second-order neurons [374].
Regarding depression, the glutamate hypothesis was proposed in the 1990s, when an-
tagonists of the NMDA receptor were found to possess antidepressant-like mechanism [375].
To date, many clinical and animal studies have reported impairment of the glutamatergic
system in various limbic and cortical areas of the brain of depressed subjects [376]. Several
authors have also reported the decreased expression of NMDA [377] and AMPA, alongside
the decreased availability of metabotropic receptor 5 (mGluR5) in the PFC, cingulate cortex,
thalamus, and hippocampus in depressed individuals [378,379].
The crosstalk between the glutamatergic and serotonergic systems is essential to
understand the antidepressant effect of drugs [380]. mGluR2 and -3 antagonism exert
antidepressant effects in rodent models similar to those of ketamine, with shared synaptic
response and neural mechanisms, implicating the serotonergic system [380]. This blockade
increases the extracellular5-HT levels in the rat medial prefrontal cortex (mPFC) through
activation of the AMPA receptor (which leads to an increase in the activity of 5-HT neurons
in the dorsal raphe nucleus (DRN), presumably via the mPFC-DRN projection), activating
downstream synaptogenic signaling pathways (e.g., BDNF, mTOR) [381]. The antidepres-
sant actions of ketamine are blocked under the pharmacological depletion of 5-HT in the
brain [382]. This observation shows how crucial serotonin–glutamate interaction is to
understand the pathophysiology of MDD and develop therapeutic tools that can modulate
this crosstalk.
The role of GABA in depression has also been extensively studied. GABAergic in-
terneurons are identified by their expression of specific receptors: somatostatin (SST),
parvalbumin (PV), and serotonin 3A (5-HT3A ). SST and PV interneurons make up 30 and
Biomolecules 2024, 14, 163 16 of 37

40%, respectively, of the total GABAergic neuronal pool [383]. Postmortem studies of de-
pressed patients identified reduced levels of SST and PV interneurons in PFC as well as in
other cortical areas [384]. Additionally, diminished levels of SST messenger RNA (mRNA)
have been found in several brain regions in depressive patients, including the dorsolateral
PFC [385] and amygdala [386], key regions involved in emotional processing. Furthermore,
reduced expression of MDD subjects [386,387]; treatment with various antidepressants,
electroconvulsive therapy (ECT), and cognitive-behavioral therapy tends to restore GABA
levels [388,389].
Taken together, the evidence presented above suggests that by targeting the gluta-
matergic system through the NMDA, AMPA or mGLU receptors, an impact could be made
on patients who suffer from migraine or MDD concomitantly. Also, the modulation of the
GABAergic pathway could ameliorate symptoms in patients who suffer from these two
entities; yet, this would require a deeper understanding of how inter-related migraine and
MDD are regarding GABA signaling.

3.5. Immune System

The accumulated evidence clearly suggests that the activation of the immune system
leading to peripheral and central inflammatory phenomena is a common element in the
pathomechanism of migraine and depression. In this sense, exposure to stressful stimuli
might be a shared environmental factor in both diseases. Stress has been recognized as
one of the most critical factors exacerbating migraine pain. It is responsible for meningeal
vasodilation and an increase in vascular permeability, favoring the influx of inflammatory
cells that would ultimately lead to the activation of microglia, resulting in a neuroinflam-
matory process. Similarly, in depression, exposure to chronic stress is commonly linked to
chronic inflammation, with a pronounced increase in proinflammatory cytokines crossing
the blood–brain barrier (BBB), which, in turn, activates the microglia and induces a neu-
roinflammatory state [390]. Hence, this section aims to recapitulate the main findings about
the inflammatory processes shared by migraine and depression.
The pathophysiological basis of migraine is based on the local terminal release of
trigeminovascular afferents products that are able to provoke not only the dilation of
meningeal vessels but also a very evident neuroinflammatory state [391,392]. It has been
proposed that cortical-spreading depression (CSD), an electrophysiological phenomena
underlying migraine aura [393], as well as stress and/or hormonal fluctuations could
underlie two independent cascades generating an inflammatory state in the intracranial
meninges mediated to a large extent by dural immune cells [394] and microglia [395],
which sensitize and activate trigeminal meningeal nociceptors, also referred as neurogenic
inflammation [396,397]. Additionally, a dysfunction of the glymphatic system has been re-
cently proposed as another mechanism involved in meningeal inflammation and trigeminal
nociception [398–400].
Overall, this neuroinflammatory state leads to vasodilation, plasma extravasation
secondary to capillary leakage, edema, and mast-cell degranulation. Mast cells have a
pivotal role in the neuroinflammatory state associated with migraine [401–403], which was
first introduced by Sicuteri et al. in the 1950s [404], due to their close proximity to both
vasculatures and nerve fibers [403]. Mast cells can selectively release proinflammatory
cytokines such as tumor necrosis factor-alpha (TNF-α), IL-1β, and IL-6, as well as lipid-
derived mediators (i.e., leukotrienes and prostanoids), without requiring the degranulation
phenomenon [405,406].
Alterations in several major proinflammatory cytokines, including TNF-α, IL-1β,
IL-6, and IL-8, have been found in different biological samples of migraineurs [80]. In
fact, TNF-α presence is commonly increased in the plasma, serum, and/or urine during
migraine attacks and attack-free intervals, suggesting the pathogenic role of TNF-α in the
inflammatory state of these patients [407–412]. Likewise, circulating IL-1β, IL-6, or IL-8
levels are often enhanced in migraineurs compared to healthy controls, especially during
the ictal stage of migraine [413–416], as recently shown by a meta-analysis [417].
Biomolecules 2024, 14, 163 17 of 37

In addition to the role of cytokines in migraine, there is a growing interest in studying

changes in the immune system at the cellular level. These may reflect specific alterations
associated with the pathophysiology and severity of migraine. Among the most relevant
findings that can be highlighted are a reduction in CD4+ CD25+ regulatory T cells [418–420];
higher CD3, CD4, CD8, and CD19 in patients with chronic migraine compared with episodic
migraine [421]; or increased proportion of Treg CD45R0+ CD62L−, and CD45R0-CD62L−
cells [422]. Also, a study comparing episodic migraine patients with healthy controls
revealed higher values of several lymphocyte-related blood parameters in migraineurs.
Interestingly, a lower value of CD4+ TEM (effector memory helper T lymphocytes) appears
to represent a potential biomarker determining the severity of migraine [423]. In line
with these results, a recent report showed a significantly lower percentage of blood CD3+
CD4+ helper T cells and CD4+ CD25+ regulatory T cells in migraineurs, suggesting a
dysregulated peripheral immune cell homeostasis [424].
Another approach used to assess the pathophysiological role of the immune sys-
tem in migraine is to evaluate inflammatory response markers by obtaining the ratios
between different cellular subtypes. Serum neutrophil/lymphocyte ratio (NLR), mono-
cyte/lymphocyte ratio (MLR), and platelet/lymphocyte ratio (PLR) may represent biomark-
ers associated with different migraine clinical features such as the attack period, aura, or
family history [425].
Genome-wide gene expression studies have been performed to characterize further
immune function alterations associated with migraine. In this sense, whole-blood next-
generation RNA sequencing revealed differentially expressed genes related to immune and
inflammatory pathways, including those expressed in microglial cells [426]. Furthermore,
RNA sequencing in peripheral blood mononuclear cells (PBMCs) was carried out to analyze
the transcriptome of migraineurs during and between attacks. This study suggested the
importance of inflammatory pathways and the potential contribution of several cytokines
to migraine susceptibility, upregulated in both interictal and ictal samples from migraineurs
compared to healthy controls [427]. Moreover, small-RNA sequencing analyses in PBMCs
followed by mRNA transcriptomics unveiled that several micro-RNAs (miRNAs) related
to immune and inflammatory responses, neuroinflammation, and oxidative stress were
differentially expressed during and between headaches in migraineurs compared to healthy
volunteers [428]. A recent study identified 45 shared genes between migraine and MDD
via single-cell RNA sequencing. Among those related to inflammation, IL-1β was highly
expressed in microglia cells [429].
The latest evidence also points to the gut–brain–immune axis as a critical player in mi-
graine’s etiology, pathogenesis, frequency, and severity. However, more research is needed
to elucidate and understand the underlying mechanisms. For now, it is hypothesized that
alterations in the microbiome may impact the levels of certain neurotransmitters, mainly
serotonin, as well as on the peripheral inflammatory state and its reflection in the central
nervous system [430,431].
With regard to depression, the accumulated preclinical and clinical evidence clearly
indicates that there is systemic immune activation, which is reflected in significant changes
in the levels of inflammatory markers and in the type and number of immune cells [432–434].
In fact, increased levels of peripheral proinflammatory cytokines, mainly IL-1β, IL-6, and
TNFα, have been described in depressed patients [435,436]. Likewise, several recent studies
have shown that alterations occur in the cellular component of the immune system related
to depression, with an increase in circulating monocytes [437,438], Th17 cells, Th17:Treg
ratio [439], and Treg cells [440,441], as well as an association with NLR and PLR [442].
It is important to note that differential changes associated with an impaired peripheral
inflammatory state have been described according to symptomatology [443], including
suicidal risk [444,445], as well as the severity [446,447], clinical progress [448,449], or
treatment response [450–453] of the depressive disorder, among other relevant aspects [454].
Peripheral molecular and cellular immune dysfunction affects the CNS, inducing
a neuroinflammatory state that is becoming better understood in the context of depres-
Biomolecules 2024, 14, 163 18 of 37

sion [455]. Among the different neuropathological findings that have been described, the
activation of microglia seems to be one of the most relevant phenomena [456] and has
been proposed to be related to alterations occurring in the hypothalamus–pituitary–axis
(HPA) axis as a consequence of stress exposure [457], the latter being one of the shared
etiological events between depression and migraine, as discussed above. Interestingly, a
very recent study identified 45 shared genes between MDD and migraine via single-cell
RNA sequencing. Among those related to inflammation, IL-1β was highly expressed in
CNS microglia cells [429].
Finally, and briefly, the gut–brain–immune axis appears to play a very relevant role in
the pathogenesis of depression, as also discussed for migraine. There is growing evidence
linking alterations in the gut microbiota of depressed patients with their impact on the
immune system and the eventual reflex on the CNS, being related with disturbances in
monoamine neurotransmission and neuroinflammation [458–463].
In conclusion, functional changes, either molecular or cellular, in the peripheral and
central immune system appear to be a critical pathophysiological feature that may be
shared, at least in part, between migraine and depression. This clearly justifies the need
for further research to better understand the common mechanisms involved and how
they might help to improve the diagnosis, follow-up, or treatment of patients with this
comorbidity.

4. Discussion
In summary, the present review provides relevant information about the common
pathways that are altered in migraine–depression comorbidity (Figure 4). The pathophysi-
ology of migraine is complex and is not yet fully understood. Mainly, neurotransmitters
and peptides closely related to the control of pain at the peripheral and central levels have
been proposed to play a relevant role in different pathophysiological aspects of migraine.
Serotonin is highly relevant in migraine since the levels of 5-HT are considered an indicator
of pain-modulating system dysfunction. Moreover, genetic studies revealed that two poly-
morphisms, VNTR STin2 and 5-HTTLPR, are associated with migraine. More importantly,
GWAS studies supported the finding that migraine is a polygenetic disorder. In the case
of depression, vast information supports the role of serotonin. However, studies focused
on examining the role of serotonin in the comorbidity of depression and migraine are
scarce. Despite this, the findings are promising, since a more pronounced reduction in brain
volume has been described in migraine patients with depression, as well as alterations in
the activity of different brain regions, such as the medial prefrontal cortex, dorsal raphe,
and thalamus.
CGRP is closely related to migraine, being involved in vasodilatation and central and
peripheral sensitization, contributing to pain exacerbation. The role of CGRP in migraine
is the rationale behind the use of anti-CGRP monoclonal antibodies in episodic/chronic
migraine that is unresponsive to other preventive therapies. Interestingly, some evidence
shows alterations in CGRP in patients with MDD; curiously, preliminary studies showed
promising results, with anti-CGRP monoclonal antibodies improving depression in indi-
viduals with migraine.
In addition, PACAP is closely related to migraine, controlling vasodilatation, mod-
ulation of the parasympathetic nervous system, mast-cell degranulation, and activation
of the trigeminovascular system. Evidence points to the potential utility of monoclonal
antibodies for PACP38 in migraine. Regarding PACAP in MDD, some published work
shows elevated levels in the central BNST in postmortem samples of male patients with
MDD; yet, there is no available evidence on how PACAP could impact patients with
migraine–MDD comorbidity.
Data also support the involvement of NPY in migraine and depression, showing
that the pharmacological modulation of NPY receptors, such as Y2R and Y5R, displays
antidepressant effects. In the case of SP and its preferential receptor NK1, which participates
in the control of pain transmission and vasodilatation of the cerebral dura mater, only
Biomolecules 2024, 14, 163 19 of 37

one clinical study was conducted to date to analyze the efficacy of NK1 antagonism in
migraine, reporting negative results. Interestingly, NK1 antagonism induced anxiolytic and
antidepressant-like effects in animal models. Likewise, the pharmacological modulation
of orexin receptors also represents a potential new avenue to explore in the treatment of
migraine and depression.
Sexual hormones, mainly estrogens, are of relevance for migraine and depression.
Fluctuations in sexual hormones impact women’s well-being. There is a close relation be-
tween estrogens and the efficacy of antidepressants since estrogens are thought to promote
serotoninergic signaling and are linked with neuroplasticity. Moreover, progesterone is
a key modulator of sensory neurotransmission and vascular responses that has emerged
as an important factor, especially in women with migraine and depression. Last, but not
least, prolactin is closely related to CGRP, serotonin, and PACAP. It is also a key player in
the differences between men and women in migraine. Finally, oxytocin has been strongly
implicated in the process of migraine initiation and emotional disturbances, and may, in
turn, be a therapeutic target for migraine-and-depression comorbidity.
Alterations in the excitatory/inhibitory balance have been described in depression.
Additionally, cumulative evidence also supports alterations in glutamate and, to a lesser
extent, GABA in migraine. The evidence suggests that targeting glutamate receptors, for
example, NMDA or AMPA receptors, may be of interest for those patients who suffer
migraine and MDD concomitantly.
Finally, neuroinflammation is also of relevance in psychiatric disorders such as depres-
sion; more recently, it has been explored as an etiopathological mechanism of migraine,
with promising results.
Although there is evidence for the role of neuropeptides, sex hormones, glutamate/GABA,
and the immune system for both clinical entities separately, there are no studies that
have investigated their role in depression–migraine comorbidity. Considering the clinical
Biomolecules 2024, 14, x FOR PEER REVIEW 20 of 39
relevance of this comorbidity, further studies are needed that will focus on examining the
role of these promising systems, hormones, or peptides in migraine patients with MDD.

Figure4.4.The
Figure Theetiopathogenic
etiopathogenicmechanisms
mechanisms involved
involved in
inmigraine
migraineand
anddepression.
depression. GLU:
GLU: glutamate,
glutamate,
GABA:
GABA:gamma-aminobutyric
gamma-aminobutyric acid,
acid, 5-HT:
5-HT: 5-ydroxytryptamine,
5-ydroxytryptamine, DRN:
DRN: dorsal
dorsal raphe
raphe nucleus,
nucleus, TNC:
TNC:
trigeminal
trigeminalnuclear
nuclearcomplex,
complex, NPY:
NPY:neuropeptide
neuropeptideY, Y,PACAP:
PACAP:pituitary
pituitaryadenylate
adenylatecyclase-activating
cyclase-activating
polypeptide,CGRP:
polypeptide, CGRP:calcitonin
calcitonin-gene-related
-gene-relatedpeptide,
peptide,SP:
SP:substance
substanceP.P.

Author Contributions: Conceptualization, A.V.-M. and M.S.G.-G.; methodology, A.B.T., A.V.-M.

and M.S.G.-G.; writing—original draft preparation, A.V.-M., A.B.T., F.N. and M.S.G.-G.; writing—
review and editing, A.V.-M. and M.S.G.-G. All authors have read and agreed to the published ver-
sion of the manuscript.
Funding: This research received no external funding.
Biomolecules 2024, 14, 163 20 of 37

Author Contributions: Conceptualization, A.V.-M. and M.S.G.-G.; methodology, A.B.T., A.V.-M. and
M.S.G.-G.; writing—original draft preparation, A.V.-M., A.B.T., F.N. and M.S.G.-G.; writing—review
and editing, A.V.-M. and M.S.G.-G. 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.
Acknowledgments: We thank BioRender.com for Figures 1–4.
Conflicts of Interest: The authors declare no conflicts of interest.

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