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Molecular and Cellular Neurobiology of Migraine: 2nd Edition
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Molecular and Cellular Neurobiology of Migraine: 2nd Edition

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: 20 January 2025 | Viewed by 18344

Special Issue Editors

Prof. Dr. Mamoru Shibata

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Guest Editor
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)
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Yasuo Terayama

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Guest Editor
Department of Neurology, Shonan Keiiku Hospital, 4360 Endo, Fujisawa, Kanagawa 252-0816, Japan
Interests: migraine; stroke
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Eiichiro Nagata

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Guest Editor
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
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

This Special Issue is a continuation of our previous Special Issue “Molecular and Cellular Neurobiology of Migraine”.

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 seem 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

Manuscript Submission Information

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Keywords

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

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Related Special Issue

Published Papers (7 papers)

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Editorial

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3 pages, 173 KiB  
Editorial
In Search of More Leaps to Realize the Precision Medicine of Migraine
by Mamoru Shibata
Int. J. Mol. Sci. 2023, 24(24), 17375; https://doi.org/10.3390/ijms242417375 - 12 Dec 2023
Viewed by 928
Abstract
Migraine, clinically characterized by recurrent headache attacks of moderate-to-severe intensity, is the second most disabling disease in terms of years lived with disability [...] Full article
(This article belongs to the Special Issue Molecular and Cellular Neurobiology of Migraine: 2nd Edition)

Research

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22 pages, 11814 KiB  
Article
Dopaminergic Projections from the Hypothalamic A11 Nucleus to the Spinal Trigeminal Nucleus Are Involved in Bidirectional Migraine Modulation
by Chenhao Li, Yang Li, Wenwen Zhang, Zhenjie Ma, Shaobo Xiao, Wei Xie, Shuai Miao, Bozhi Li, Guangshuang Lu, Yingyuan Liu, Wenhao Bai and Shengyuan Yu
Int. J. Mol. Sci. 2023, 24(23), 16876; https://doi.org/10.3390/ijms242316876 - 28 Nov 2023
Cited by 1 | Viewed by 1752
Abstract
Clinical imaging studies have revealed that the hypothalamus is activated in migraine patients prior to the onset of and during headache and have also shown that the hypothalamus has increased functional connectivity with the spinal trigeminal nucleus. The dopaminergic system of the hypothalamus [...] Read more.
Clinical imaging studies have revealed that the hypothalamus is activated in migraine patients prior to the onset of and during headache and have also shown that the hypothalamus has increased functional connectivity with the spinal trigeminal nucleus. The dopaminergic system of the hypothalamus plays an important role, and the dopamine-rich A11 nucleus may play an important role in migraine pathogenesis. We used intraperitoneal injections of glyceryl trinitrate to establish a model of acute migraine attack and chronicity in mice, which was verified by photophobia experiments and von Frey experiments. We explored the A11 nucleus and its downstream pathway using immunohistochemical staining and neuronal tracing techniques. During acute migraine attack and chronification, c-fos expression in GABAergic neurons in the A11 nucleus was significantly increased, and inhibition of DA neurons was achieved by binding to GABA A-type receptors on the surface of dopaminergic neurons in the A11 nucleus. However, the expression of tyrosine hydroxylase and glutamic acid decarboxylase proteins in the A11 nucleus of the hypothalamus did not change significantly. Specific destruction of dopaminergic neurons in the A11 nucleus of mice resulted in severe nociceptive sensitization and photophobic behavior. The expression levels of the D1 dopamine receptor and D2 dopamine receptor in the caudal part of the spinal trigeminal nucleus candalis of the chronic migraine model were increased. Skin nociceptive sensitization of mice was slowed by activation of the D2 dopamine receptor in SP5C, and activation of the D1 dopamine receptor reversed this behavioral change. GABAergic neurons in the A11 nucleus were activated and exerted postsynaptic inhibitory effects, which led to a decrease in the amount of DA secreted by the A11 nucleus in the spinal trigeminal nucleus candalis. The reduced DA bound preferentially to the D2 dopamine receptor, thus exerting a defensive effect against headache. Full article
(This article belongs to the Special Issue Molecular and Cellular Neurobiology of Migraine: 2nd Edition)
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15 pages, 3300 KiB  
Article
The Anti-Calcitonin Gene-Related Peptide (Anti-CGRP) Antibody Fremanezumab Reduces Trigeminal Neurons Immunoreactive to CGRP and CGRP Receptor Components in Rats
by Birgit Vogler, Annette Kuhn, Kimberly D. Mackenzie, Jennifer Stratton, Mária Dux and Karl Messlinger
Int. J. Mol. Sci. 2023, 24(17), 13471; https://doi.org/10.3390/ijms241713471 - 30 Aug 2023
Cited by 2 | Viewed by 1861
Abstract
Treatment with the anti-CGRP antibody fremanezumab is successful in the prevention of chronic and frequent episodic migraine. In preclinical rat experiments, fremanezumab has been shown to reduce calcitonin gene-related peptide (CGRP) release from trigeminal tissues and aversive behaviour to noxious facial stimuli, which [...] Read more.
Treatment with the anti-CGRP antibody fremanezumab is successful in the prevention of chronic and frequent episodic migraine. In preclinical rat experiments, fremanezumab has been shown to reduce calcitonin gene-related peptide (CGRP) release from trigeminal tissues and aversive behaviour to noxious facial stimuli, which are characteristic pathophysiological changes accompanying severe primary headaches. To further decipher the effects of fremanezumab that underlie these antinociceptive effects in rats, immunohistochemistry and ELISA techniques were used to analyse the content and concentration of CGRP in the trigeminal ganglion, as well as the ratio of trigeminal ganglion neurons which are immunoreactive to CGRP and CGRP receptor components, 1–10 days after subcutaneous injection of fremanezumab (30 mg/kg) compared to an isotype control antibody. After fremanezumab treatment, the fraction of trigeminal ganglion neurons which were immunoreactive to CGRP and the CGRP receptor components calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) was significantly lowered compared to the control. The content and concentration of CGRP in trigeminal ganglia were not significantly changed. A long-lasting reduction in CGRP receptors expressed in trigeminal afferents may contribute to the attenuation of CGRP signalling and antinociceptive effects of monoclonal anti-CGRP antibodies in rats. Full article
(This article belongs to the Special Issue Molecular and Cellular Neurobiology of Migraine: 2nd Edition)
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11 pages, 2741 KiB  
Article
Calcitonin Gene-Related Peptide mRNA Synthesis in Trigeminal Ganglion Neurons after Cortical Spreading Depolarization
by Mamoru Shibata, Satoshi Kitagawa, Miyuki Unekawa, Tsubasa Takizawa and Jin Nakahara
Int. J. Mol. Sci. 2023, 24(14), 11578; https://doi.org/10.3390/ijms241411578 - 18 Jul 2023
Cited by 4 | Viewed by 1425
Abstract
Migraine is a debilitating neurovascular disorder characterized by recurrent headache attacks of moderate to severe intensity. Calcitonin gene-related peptide (GGRP), which is abundantly expressed in trigeminal ganglion (TG) neurons, plays a crucial role in migraine pathogenesis. Cortical spreading depolarization (CSD), the biological correlate [...] Read more.
Migraine is a debilitating neurovascular disorder characterized by recurrent headache attacks of moderate to severe intensity. Calcitonin gene-related peptide (GGRP), which is abundantly expressed in trigeminal ganglion (TG) neurons, plays a crucial role in migraine pathogenesis. Cortical spreading depolarization (CSD), the biological correlate of migraine aura, activates the trigeminovascular system. In the present study, we investigated CGRP mRNA expression in TG neurons in a CSD-based mouse migraine model. Our in situ hybridization analysis showed that CGRP mRNA expression was observed in smaller-sized neuronal populations. CSD did not significantly change the density of CGRP mRNA-synthesizing neurons in the ipsilateral TG. However, the cell sizes of CGRP mRNA-synthesizing TG neurons were significantly larger in the 48 h and 72 h post-CSD groups than in the control group. The proportions of CGRP mRNA-synthesizing TG neurons bearing cell diameters less than 14 μm became significantly less at several time points after CSD. In contrast, we found significantly greater proportions of CGRP mRNA-synthesizing TG neurons bearing cell diameters of 14–18 μm at 24 h, 48, and 72 h post-CSD. We deduce that the CSD-induced upward cell size shift in CGRP mRNA-synthesizing TG neurons might be causative of greater disease activity and/or less responsiveness to CGRP-based therapy. Full article
(This article belongs to the Special Issue Molecular and Cellular Neurobiology of Migraine: 2nd Edition)
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Review

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14 pages, 837 KiB  
Review
Calcitonin Gene-Related Peptide Systemic Effects: Embracing the Complexity of Its Biological Roles—A Narrative Review
by Adriano Bonura, Nicoletta Brunelli, Marilena Marcosano, Gianmarco Iaccarino, Luisa Fofi, Fabrizio Vernieri and Claudia Altamura
Int. J. Mol. Sci. 2023, 24(18), 13979; https://doi.org/10.3390/ijms241813979 - 12 Sep 2023
Cited by 4 | Viewed by 2857
Abstract
The calcitonin gene-related peptide (CGRP) is a neuropeptide widely distributed throughout the human body. While primarily recognized as a nociceptive mediator, CGRP antagonists are currently utilized for migraine treatment. However, its role extends far beyond this, acting as a regulator of numerous biological [...] Read more.
The calcitonin gene-related peptide (CGRP) is a neuropeptide widely distributed throughout the human body. While primarily recognized as a nociceptive mediator, CGRP antagonists are currently utilized for migraine treatment. However, its role extends far beyond this, acting as a regulator of numerous biological processes. Indeed, CGRP plays a crucial role in vasodilation, inflammation, intestinal motility, and apoptosis. In this review, we explore the non-nociceptive effects of CGRP in various body systems, revealing actions that can be contradictory at times. In the cardiovascular system, it functions as a potent vasodilator, yet its antagonists do not induce arterial hypertension, suggesting concurrent modulation by other molecules. As an immunomodulator, CGRP exhibits intriguing complexity, displaying both anti-inflammatory and pro-inflammatory effects. Furthermore, CGRP appears to be involved in obesity development while paradoxically reducing appetite. A thorough investigation of CGRP’s biological effects is crucial for anticipating potential side effects associated with its antagonists’ use and for developing novel therapies in other medical fields. In summary, CGRP represents a neuropeptide with a complex systemic impact, extending well beyond nociception, thus offering new perspectives in medical research and therapeutics Full article
(This article belongs to the Special Issue Molecular and Cellular Neurobiology of Migraine: 2nd Edition)
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16 pages, 1483 KiB  
Review
The Role of Glial Cells in Different Phases of Migraine: Lessons from Preclinical Studies
by Marta Vila-Pueyo, Otilia Gliga, Víctor José Gallardo and Patricia Pozo-Rosich
Int. J. Mol. Sci. 2023, 24(16), 12553; https://doi.org/10.3390/ijms241612553 - 8 Aug 2023
Cited by 6 | Viewed by 5049
Abstract
Migraine is a complex and debilitating neurological disease that affects 15% of the population worldwide. It is defined by the presence of recurrent severe attacks of disabling headache accompanied by other debilitating neurological symptoms. Important advancements have linked the trigeminovascular system and the [...] Read more.
Migraine is a complex and debilitating neurological disease that affects 15% of the population worldwide. It is defined by the presence of recurrent severe attacks of disabling headache accompanied by other debilitating neurological symptoms. Important advancements have linked the trigeminovascular system and the neuropeptide calcitonin gene-related peptide to migraine pathophysiology, but the mechanisms underlying its pathogenesis and chronification remain unknown. Glial cells are essential for the correct development and functioning of the nervous system and, due to its implication in neurological diseases, have been hypothesised to have a role in migraine. Here we provide a narrative review of the role of glia in different phases of migraine through the analysis of preclinical studies. Current evidence shows that astrocytes and microglia are involved in the initiation and propagation of cortical spreading depolarization, the neurophysiological correlate of migraine aura. Furthermore, satellite glial cells within the trigeminal ganglia are implicated in the initiation and maintenance of orofacial pain, suggesting a role in the headache phase of migraine. Moreover, microglia in the trigeminocervical complex are involved in central sensitization, suggesting a role in chronic migraine. Taken altogether, glial cells have emerged as key players in migraine pathogenesis and chronification and future therapeutic strategies could be focused on targeting them to reduce the burden of migraine. Full article
(This article belongs to the Special Issue Molecular and Cellular Neurobiology of Migraine: 2nd Edition)
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30 pages, 1589 KiB  
Review
Migraine Treatment: Towards New Pharmacological Targets
by Marcello Silvestro, Luigi Francesco Iannone, Ilaria Orologio, Alessandro Tessitore, Gioacchino Tedeschi, Pierangelo Geppetti and Antonio Russo
Int. J. Mol. Sci. 2023, 24(15), 12268; https://doi.org/10.3390/ijms241512268 - 31 Jul 2023
Cited by 8 | Viewed by 3934
Abstract
Migraine is a debilitating neurological condition affecting millions of people worldwide. Until a few years ago, preventive migraine treatments were based on molecules with pleiotropic targets, developed for other indications, and discovered by serendipity to be effective in migraine prevention, although often burdened [...] Read more.
Migraine is a debilitating neurological condition affecting millions of people worldwide. Until a few years ago, preventive migraine treatments were based on molecules with pleiotropic targets, developed for other indications, and discovered by serendipity to be effective in migraine prevention, although often burdened by tolerability issues leading to low adherence. However, the progresses in unravelling the migraine pathophysiology allowed identifying novel putative targets as calcitonin gene-related peptide (CGRP). Nevertheless, despite the revolution brought by CGRP monoclonal antibodies and gepants, a significant percentage of patients still remains burdened by an unsatisfactory response, suggesting that other pathways may play a critical role, with an extent of involvement varying among different migraine patients. Specifically, neuropeptides of the CGRP family, such as adrenomedullin and amylin; molecules of the secretin family, such as pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP); receptors, such as transient receptor potential (TRP) channels; intracellular downstream determinants, such as potassium channels, but also the opioid system and the purinergic pathway, have been suggested to be involved in migraine pathophysiology. The present review provides an overview of these pathways, highlighting, based on preclinical and clinical evidence, as well as provocative studies, their potential role as future targets for migraine preventive treatment. Full article
(This article belongs to the Special Issue Molecular and Cellular Neurobiology of Migraine: 2nd Edition)
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