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Molecular and Cellular Neurobiology of Migraine

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (15 May 2023) | Viewed by 34007

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Prof. Dr. Mamoru Shibata

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1. Department of Neurology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
2. Department of Neurology, Tokyo Dental College Ichikawa General Hospital, Chiba 272-8513, Japan
Interests: migraine; TRP channels; calcitonin gene-related peptide (CGRP); spreading depolarization/depression; trigeminal system; pituitary adenylate cyclase-activating polypeptide (PACAP); nitric oxide (NO)
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Prof. Dr. Yasuo Terayama

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Department of Neurology, Shonan Keiiku Hospital, 4360 Endo, Fujisawa, Kanagawa 252-0816, Japan
Interests: migraine; stroke
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Prof. Dr. Eiichiro Nagata

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Department of Neurology, Tokai University School of Medicine, 154 Shimo-Kasuya, Isehara, Kanagawa 259-1193, Japan
Interests: neuroscience; migraine; headache; neuroimmunology; neurodegenerative disorders; inositol polyphosphates; stroke
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Special Issue Information

Dear Colleagues,

Migraine is a common and debilitating neurological disorder characterized by recurrent headache attacks of moderate-to-severe intensity. Calcitonin gene-related peptide (CGRP)-mediated sensitization of the trigeminovascular system is known to be a crucial mechanism underlying such headache attacks, as evidenced by the excellent efficacy of CGRP-related monoclonal antibodies and CGRP receptor antagonists against migraine attacks. Emerging evidence also shows that other neuropeptides, such as pituitary adenylate cyclase-activating polypeptide and amylin, are involved in the activating process of the trigeminovascular system. A family of cation channels termed TRP channels seems to be implicated in the regulation of neuropeptide secretion. Moreover, migraine prodromes and aura are induced by hypothalamic and cortical abnormalities, respectively. These phenomena are likely to be induced by perturbations of ion channel and neurotransmitter functions. Lastly, migraine attacks often have triggers such as menstruation, emotional stress, and climate changes, which are not relevant to one another. Elucidation of the molecular and cellular mechanisms whereby such triggers induce migraine attacks should lead to the development of novel therapy of migraine.

Prof. Dr. Mamoru Shibata
Prof. Dr. Yasuo Terayama
Prof. Dr. Eiichiro Nagata
Guest Editors

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Keywords

migraine
calcitonin gene-related peptide (CGRP)
spreading depolarization/depression
TRP channels pituitary adenylate cyclase-activating polypeptide
TRP channels
PACAP

Related Special Issue

Molecular and Cellular Neurobiology of Migraine 2.0 in International Journal of Molecular Sciences (7 articles)

Published Papers (11 papers)

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Research

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7 pages, 270 KiB

Open AccessArticle

Lack of Association between Common LAG3/CD4 Variants and Risk of Migraine

by Elena García-Martín, Santiago Navarro-Muñoz, Pedro Ayuso, Christopher Rodríguez, Mercedes Serrador, Hortensia Alonso-Navarro, Marisol Calleja, Francisco Navacerrada, Laura Turpín-Fenoll, Marta Recio-Bermejo, Rafael García-Ruiz, Jorge Millán-Pascual, José Francisco Plaza-Nieto, Esteban García-Albea, José A. G. Agúndez and Félix Javier Jiménez-Jiménez

Int. J. Mol. Sci. 2023, 24(2), 1292; https://doi.org/10.3390/ijms24021292 - 9 Jan 2023

Cited by 2 | Viewed by 1261

Abstract

Several papers have been published suggesting a probable role of inflammatory factors in the etiopathogenesis of migraine. In this study, we investigated the possible association between common variants in the LAG3/CD4 genes (both genes, which are closely related, encode proteins involved in inflammatory and autoimmune responses) in the risk of migraine in a cohort of Caucasian Spanish participants. For this purpose, the frequencies of CD4 rs1922452, CD4 rs951818, and LAG3 rs870849 genotypes and allelic variants, using a specific TaqMan-based qPCR assay, were assessed in 290 patients diagnosed with migraine and in 300 healthy controls. The relationship of these variables with several clinical features of migraine was also analyzed. The frequencies of the analyzed LAG3/CD4 genotypes did not differ significantly between the two study groups and were not related to the sex, age at onset of migraine, family history of migraine, presence or absence of aura, or the triggering effect of ethanol on migraine episodes. These results suggest a lack of association between common variants in the LAG3/CD4 genes and the risk of developing migraine in the Caucasian Spanish population. Full article

(This article belongs to the Special Issue Molecular and Cellular Neurobiology of Migraine)

24 pages, 4665 KiB

Open AccessArticle

Characterization of Antibodies against Receptor Activity-Modifying Protein 1 (RAMP1): A Cautionary Tale

by Erica R. Hendrikse, Tayla A. Rees, Zoe Tasma, Michael L. Garelja, Andrew Siow, Paul W. R. Harris, John B. Pawlak, Kathleen M. Caron, Elizabeth S. Blakeney, Andrew F. Russo, Levi P. Sowers, Thomas A. Lutz, Christelle Le Foll, Christopher S. Walker and Debbie L. Hay

Int. J. Mol. Sci. 2022, 23(24), 16035; https://doi.org/10.3390/ijms232416035 - 16 Dec 2022

Cited by 3 | Viewed by 2195

Abstract

Calcitonin gene-related peptide (CGRP) is a key component of migraine pathophysiology, yielding effective migraine therapeutics. CGRP receptors contain a core accessory protein subunit: receptor activity-modifying protein 1 (RAMP1). Understanding of RAMP1 expression is incomplete, partly due to the challenges in identifying specific and validated antibody tools. We profiled antibodies for immunodetection of RAMP1 using Western blotting, immunocytochemistry and immunohistochemistry, including using RAMP1 knockout mouse tissue. Most antibodies could detect RAMP1 in Western blotting and immunocytochemistry using transfected cells. Two antibodies (844, ab256575) could detect a RAMP1-like band in Western blots of rodent brain but not RAMP1 knockout mice. However, cross-reactivity with other proteins was evident for all antibodies. This cross-reactivity prevented clear conclusions about RAMP1 anatomical localization, as each antibody detected a distinct pattern of immunoreactivity in rodent brain. We cannot confidently attribute immunoreactivity produced by RAMP1 antibodies (including 844) to the presence of RAMP1 protein in immunohistochemical applications in brain tissue. RAMP1 expression in brain and other tissues therefore needs to be revisited using RAMP1 antibodies that have been comprehensively validated using multiple strategies to establish multiple lines of convincing evidence. As RAMP1 is important for other GPCR/ligand pairings, our results have broader significance beyond the CGRP field. Full article

(This article belongs to the Special Issue Molecular and Cellular Neurobiology of Migraine)

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12 pages, 2218 KiB

Open AccessArticle

Sustained Effects of CGRP Blockade on Cortical Spreading Depolarization-Induced Alterations in Facial Heat Pain Threshold, Light Aversiveness, and Locomotive Activity in the Light Environment

by Satoshi Kitagawa, Chunhua Tang, Miyuki Unekawa, Yohei Kayama, Jin Nakahara and Mamoru Shibata

Int. J. Mol. Sci. 2022, 23(22), 13807; https://doi.org/10.3390/ijms232213807 - 9 Nov 2022

Cited by 2 | Viewed by 1669

Abstract

A migraine is clinically characterized by repeated headache attacks that entail considerable disability. Many patients with migraines experience postdrome, the symptoms of which include tiredness and photophobia. Calcitonin gene-related peptide (GGRP) is critically implicated in migraine pathogenesis. Cortical spreading depolarization (CSD), the biological correlate of migraine aura, sensitizes the trigeminovascular system. In our previous study, CSD caused hypomotility in the light zone and tendency for photophobia at 72 h, at which time trigeminal sensitization had disappeared. We proposed that this CSD-induced disease state would be useful for exploring therapeutic strategies for migraine postdrome. In the present study, we observed that the CGRP receptor antagonist, olcegepant, prevented the hypomotility in the light zone and ameliorated light tolerability at 72 h after CSD induction. Moreover, olcegepant treatment significantly elevated the threshold for facial heat pain at 72 h after CSD. Our results raise the possibility that CGRP blockade may be efficacious in improving hypoactivity in the light environment by enhancing light tolerability during migraine postdrome. Moreover, our data suggest that the CGRP pathway may lower the facial heat pain threshold even in the absence of overt trigeminal sensitization, which provides an important clue to the potential mechanism whereby CGRP blockade confers migraine prophylaxis. Full article

(This article belongs to the Special Issue Molecular and Cellular Neurobiology of Migraine)

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7 pages, 639 KiB

Open AccessCommunication

Effect of Goreisan, a Japanese Traditional Medicine, on Cortical Spreading Depolarization in Mice

by Chisato Iba, Miyuki Unekawa, Yoshikane Izawa, Jin Nakahara and Tsubasa Takizawa

Int. J. Mol. Sci. 2022, 23(22), 13803; https://doi.org/10.3390/ijms232213803 - 9 Nov 2022

Cited by 1 | Viewed by 2827

Abstract

Goreisan, a traditional Japanese Kampo medicine, is often used to treat headaches, including migraines; however, the underlying mechanisms remain unknown. Therefore, we investigated whether chronic treatment with Goreisan affects cortical spreading depolarization (CSD) in migraines. CSD susceptibility was assessed in male and female C57BL/6 mice by comparing CSD threshold, propagation velocity, and CSD frequency between animals treated with Goreisan for approximately 3 weeks and the corresponding controls with a potassium-induced CSD model. No significant differences were observed in CSD susceptibility between mice that were chronically treated with Goreisan and the control mice. Additionally, no significant differences were observed in other physiological parameters, including body weight, blood gases, and blood pressure. CSD susceptibility was not affected by chronic treatment with Goreisan, which suggests that the drug treats headaches via mechanisms that do not involve CSD modulation. Full article

(This article belongs to the Special Issue Molecular and Cellular Neurobiology of Migraine)

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23 pages, 15723 KiB

Open AccessArticle

PAC₁, VPAC₁, and VPAC₂ Receptor Expression in Rat and Human Trigeminal Ganglia: Characterization of PACAP-Responsive Receptor Antibodies

by Zoe Tasma, Andrew Siow, Paul W. R. Harris, Margaret A. Brimble, Simon J. O’Carroll, Debbie L. Hay and Christopher S. Walker

Int. J. Mol. Sci. 2022, 23(22), 13797; https://doi.org/10.3390/ijms232213797 - 9 Nov 2022

Cited by 4 | Viewed by 2081

Abstract

Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide expressed in the trigeminal ganglia (TG). The TG conducts nociceptive signals in the head and may play roles in migraine. PACAP infusion provokes headaches in healthy individuals and migraine-like attacks in patients; however, it is not clear whether targeting this system could be therapeutically efficacious. To effectively target the PACAP system, an understanding of PACAP receptor distribution is required. Therefore, this study aimed to characterize commercially available antibodies and use these to detect PACAP-responsive receptors in the TG. Antibodies were initially validated in receptor transfected cell models and then used to explore receptor expression in rat and human TG. Antibodies were identified that could detect PACAP-responsive receptors, including the first antibody to differentiate between the PAC_1n and PAC_1s receptor splice variants. PAC₁, VPAC₁, and VPAC₂ receptor-like immunoreactivity were observed in subpopulations of both neuronal and glial-like cells in the TG. In this study, PAC₁, VPAC₁, and VPAC₂ receptors were detected in the TG, suggesting they are all potential targets to treat migraine. These antibodies may be useful tools to help elucidate PACAP-responsive receptor expression in tissues. However, most antibodies exhibited limitations, requiring the use of multiple methodologies and the careful inclusion of controls. Full article

(This article belongs to the Special Issue Molecular and Cellular Neurobiology of Migraine)

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Review

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39 pages, 2145 KiB

Open AccessReview

Excitation-Inhibition Imbalance in Migraine: From Neurotransmitters to Brain Oscillations

by Louise O’Hare, Luca Tarasi, Jordi M. Asher, Paul B. Hibbard and Vincenzo Romei

Int. J. Mol. Sci. 2023, 24(12), 10093; https://doi.org/10.3390/ijms241210093 - 13 Jun 2023

Cited by 4 | Viewed by 2746

Abstract

Migraine is among the most common and debilitating neurological disorders typically affecting people of working age. It is characterised by a unilateral, pulsating headache often associated with severe pain. Despite the intensive research, there is still little understanding of the pathophysiology of migraine. At the electrophysiological level, altered oscillatory parameters have been reported within the alpha and gamma bands. At the molecular level, altered glutamate and GABA concentrations have been reported. However, there has been little cross-talk between these lines of research. Thus, the relationship between oscillatory activity and neurotransmitter concentrations remains to be empirically traced. Importantly, how these indices link back to altered sensory processing has to be clearly established as yet. Accordingly, pharmacologic treatments have been mostly symptom-based, and yet sometimes proving ineffective in resolving pain or related issues. This review provides an integrative theoretical framework of excitation–inhibition imbalance for the understanding of current evidence and to address outstanding questions concerning the pathophysiology of migraine. We propose the use of computational modelling for the rigorous formulation of testable hypotheses on mechanisms of homeostatic imbalance and for the development of mechanism-based pharmacological treatments and neurostimulation interventions. Full article

(This article belongs to the Special Issue Molecular and Cellular Neurobiology of Migraine)

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15 pages, 1856 KiB

Open AccessReview

Molecular and Cellular Neurobiology of Circadian and Circannual Rhythms in Migraine: A Narrative Review

by Noboru Imai

Int. J. Mol. Sci. 2023, 24(12), 10092; https://doi.org/10.3390/ijms241210092 - 13 Jun 2023

Cited by 2 | Viewed by 1272

Abstract

Migraine—a primary headache—has circadian and circannual rhythms in the onset of attacks. The circadian and circannual rhythms involve the hypothalamus, which is strongly associated with pain processing in migraines. Moreover, the role of melatonin in circadian rhythms has been implied in the pathophysiology of migraines. However, the prophylactic effect of melatonin in migraines is controversial. Calcitonin gene-related peptide (CGRP) has recently attracted attention in the pathophysiology and treatment of migraines. Pituitary adenylate cyclase-activating peptide (PACAP)—a neuropeptide identical to CGRP—is a potential therapeutic target after CGRP. PACAP is involved in the regulation of circadian entrainment to light. This review provides an overview of circadian and circannual rhythms in the hypothalamus and describes the relationship between migraines and the molecular and cellular neurobiology of circadian and circannual rhythms. Furthermore, the potential clinical applications of PACAP are presented. Full article

(This article belongs to the Special Issue Molecular and Cellular Neurobiology of Migraine)

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16 pages, 588 KiB

Open AccessReview

Experimental and Clinical Investigation of Cytokines in Migraine: A Narrative Review

by Gaku Yamanaka, Kanako Hayashi, Natsumi Morishita, Mika Takeshita, Chiako Ishii, Shinji Suzuki, Rie Ishimine, Akiko Kasuga, Haruka Nakazawa, Tomoko Takamatsu, Yusuke Watanabe, Shinichiro Morichi, Yu Ishida, Takashi Yamazaki and Soken Go

Int. J. Mol. Sci. 2023, 24(9), 8343; https://doi.org/10.3390/ijms24098343 - 6 May 2023

Cited by 8 | Viewed by 2148

Abstract

The role of neuroinflammation in the pathophysiology of migraines is increasingly being recognized, and cytokines, which are important endogenous substances involved in immune and inflammatory responses, have also received attention. This review examines the current literature on neuroinflammation in the pathogenesis of migraine. Elevated TNF-α, IL-1β, and IL-6 levels have been identified in non-invasive mouse models with cortical spreading depolarization (CSD). Various mouse models to induce migraine attack-like symptoms also demonstrated elevated inflammatory cytokines and findings suggesting differences between episodic and chronic migraines and between males and females. While studies on human blood during migraine attacks have reported no change in TNF-α levels and often inconsistent results for IL-1β and IL-6 levels, serial analysis of cytokines in jugular venous blood during migraine attacks revealed consistently increased IL-1β, IL-6, and TNF-α. In a study on the interictal period, researchers reported higher levels of TNF-α and IL-6 compared to controls and no change regarding IL-1β levels. Saliva-based tests suggest that IL-1β might be useful in discriminating against migraine. Patients with migraine may benefit from a cytokine perspective on the pathogenesis of migraine, as there have been several encouraging reports suggesting new therapeutic avenues. Full article

(This article belongs to the Special Issue Molecular and Cellular Neurobiology of Migraine)

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29 pages, 487 KiB

Open AccessReview

Exploring Novel Therapeutic Targets in the Common Pathogenic Factors in Migraine and Neuropathic Pain

by János Tajti, Délia Szok, Anett Csáti, Ágnes Szabó, Masaru Tanaka and László Vécsei

Int. J. Mol. Sci. 2023, 24(4), 4114; https://doi.org/10.3390/ijms24044114 - 18 Feb 2023

Cited by 32 | Viewed by 5751

Abstract

Migraine and neuropathic pain (NP) are both painful, disabling, chronic conditions which exhibit some symptom similarities and are thus considered to share a common etiology. The calcitonin gene-related peptide (CGRP) has gained credit as a target for migraine management; nevertheless, the efficacy and the applicability of CGRP modifiers warrant the search for more effective therapeutic targets for pain management. This scoping review focuses on human studies of common pathogenic factors in migraine and NP, with reference to available preclinical evidence to explore potential novel therapeutic targets. CGRP inhibitors and monoclonal antibodies alleviate inflammation in the meninges; targeting transient receptor potential (TRP) ion channels may help prevent the release of nociceptive substances, and modifying the endocannabinoid system may open a path toward discovery of novel analgesics. There may exist a potential target in the tryptophan-kynurenine (KYN) metabolic system, which is closely linked to glutamate-induced hyperexcitability; alleviating neuroinflammation may complement a pain-relieving armamentarium, and modifying microglial excitation, which is observed in both conditions, may be a possible approach. Those are several potential analgesic targets which deserve to be explored in search of novel analgesics; however, much evidence remains missing. This review highlights the need for more studies on CGRP modifiers for subtypes, the discovery of TRP and endocannabinoid modulators, knowledge of the status of KYN metabolites, the consensus on cytokines and sampling, and biomarkers for microglial function, in search of innovative pain management methods for migraine and NP. Full article

(This article belongs to the Special Issue Molecular and Cellular Neurobiology of Migraine)

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13 pages, 7916 KiB

Open AccessReview

Migraine Pathophysiology Revisited: Proposal of a New Molecular Theory of Migraine Pathophysiology and Headache Diagnostic Criteria

by Yasushi Shibata

Int. J. Mol. Sci. 2022, 23(21), 13002; https://doi.org/10.3390/ijms232113002 - 27 Oct 2022

Cited by 9 | Viewed by 7476

Abstract

Various explanations for the pathophysiology of migraines have been proposed; however, none of these provide a complete explanation. The author critically reviews previous theories and proposes a new molecular theory of migraine pathophysiology. The diagnosis of primary headaches is generally based on clinical histories and symptoms only because there is no reliable diagnostic examination. The author proposes a new classification system and set of diagnostic criteria for headaches based on molecular markers. Full article

(This article belongs to the Special Issue Molecular and Cellular Neurobiology of Migraine)

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Other

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18 pages, 4051 KiB

Open AccessOpinion

Human Brain Organoids in Migraine Research: Pathogenesis and Drug Development

by Parisa Gazerani

Int. J. Mol. Sci. 2023, 24(4), 3113; https://doi.org/10.3390/ijms24043113 - 4 Feb 2023

Cited by 1 | Viewed by 2785

Abstract

Human organoids are small, self-organized, three-dimensional (3D) tissue cultures that have started to revolutionize medical science in terms of understanding disease, testing pharmacologically active compounds, and offering novel ways to treat disease. Organoids of the liver, kidney, intestine, lung, and brain have been developed in recent years. Human brain organoids are used for understanding pathogenesis and investigating therapeutic options for neurodevelopmental, neuropsychiatric, neurodegenerative, and neurological disorders. Theoretically, several brain disorders can be modeled with the aid of human brain organoids, and hence the potential exists for understanding migraine pathogenesis and its treatment with the aid of brain organoids. Migraine is considered a brain disorder with neurological and non-neurological abnormalities and symptoms. Both genetic and environmental factors play essential roles in migraine pathogenesis and its clinical manifestations. Several types of migraines are classified, for example, migraines with and without aura, and human brain organoids can be developed from patients with these types of migraines to study genetic factors (e.g., channelopathy in calcium channels) and environmental stressors (e.g., chemical and mechanical). In these models, drug candidates for therapeutic purposes can also be tested. Here, the potential and limitations of human brain organoids for studying migraine pathogenesis and its treatment are communicated to generate motivation and stimulate curiosity for further research. This must, however, be considered alongside the complexity of the concept of brain organoids and the neuroethical aspects of the topic. Interested researchers are invited to join the network for protocol development and testing the hypothesis presented here. Full article

(This article belongs to the Special Issue Molecular and Cellular Neurobiology of Migraine)

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