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Migraine Neuroscience: From Experimental Models to Target Therapy

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (20 February 2024) | Viewed by 36610

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Special Issue Editors

Prof. Dr. László Vécsei

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Guest Editor

1. Faculty of Medicine, Department of Neurology, Albert Szent-Györgyi Clinical Center, University of Szeged, Szeged, Hungary
2. MTA-SZTE Neuroscience Research Group, University of Szeged, Szeged, Hungary
Interests: neurology; headache; multiple sclerosis; Parkinson's disease; kynurenines; neurotransmission
Special Issues, Collections and Topics in MDPI journals

Dr. Bernadett Tuka

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Dr. Masaru Tanaka

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Neuroscience Research Group, Hungarian Academy of Sciences, University of Szeged (MTA-SZTE), 6720 Szeged, Hungary
Interests: neurohormones; neuropeptides; tryptophan; kynurenine; psychiatry; neurology; depression; anxiety; dementia; cognition; antidepressant; translational research
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The Brain Prize (awarded annually by the Lundbeck Foundation) is the most prestigious tribute in neuroscience. The winners in 2021 were migraine researchers: Lars Edvinsson, Peter Goadsby, Michael Moskowitz, and Jes Olesen. Migraine is a highly prevalent primary headache with a complicated pathomechanism. The aim of this Special Issue is to focus on experimental models to target therapy in migraine. It is accepted that the pathomechanism of migraine involves activation and sensitization of the trigeminovascular system, which leads to the release of several pro-inflammatory neuropeptides and neurotransmitters and causes a cascade of inflammatory tissue responses, including vasodilation, extravasation secondary capillary leakage, edema, and mast cell degranulation. Many molecules have a role to play in the development of migraine and other headaches, including nitric oxide (NO), calcitonin gene-related peptide (CGRP), substance P (SP), pituitary adenylate cyclase-activating polypeptide (PACAP), neurokinin A (NKA), interleukin (IL), kynurenines (KYNs), etc. The successful treatment of a large number of migraine patients with CGRP monoclonal antibodies is a milestone in therapy. Translational animal studies are currently moving the field of migraine research forward and may serve as a savior of migraineurs in the future.

Prof. Dr. László Vécsei
Dr. Bernadett Tuka
Dr. Masaru Tanaka
Guest Editors

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Keywords

migraine
experimental models
migraine therapy

Published Papers (11 papers)

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Research

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15 pages, 2936 KiB

Open AccessArticle

Glycerol Trinitrate Acts Downstream of Calcitonin Gene-Related Peptide in Trigeminal Nociception—Evidence from Rodent Experiments with Anti-CGRP Antibody Fremanezumab

by Nicola Benedicter, Birgit Vogler, Annette Kuhn, Jana Schramm, Kimberly D. Mackenzie, Jennifer Stratton, Mária Dux and Karl Messlinger

Cells 2024, 13(7), 572; https://doi.org/10.3390/cells13070572 - 25 Mar 2024

Viewed by 621

Abstract

Calcitonin gene-related peptide (CGRP) and nitric oxide (NO) have been recognized as important mediators in migraine but their mechanisms of action and interaction have not been fully elucidated. Monoclonal anti-CGRP antibodies like fremanezumab are successful preventives of frequent migraine and can be used to study CGRP actions in preclinical experiments. Fremanezumab (30 mg/kg) or an isotype control monoclonal antibody was subcutaneously injected to Wistar rats of both sexes. One to several days later, glyceroltrinitrate (GTN, 5 mg/kg) mimicking nitric oxide (NO) was intraperitoneally injected, either once or for three consecutive days. The trigeminal ganglia were removed to determine the concentration of CGRP using an enzyme-linked immunosorbent assay (ELISA). In one series of experiments, the animals were trained to reach an attractive sugar solution, the access to which could be limited by mechanical or thermal barriers. Using a semi-automated registration system, the frequency of approaches to the source, the residence time at the source, and the consumed solution were registered. The results were compared with previous data of rats not treated with GTN. The CGRP concentration in the trigeminal ganglia was generally higher in male rats and tended to be increased in animals treated once with GTN, whereas the CGRP concentration decreased after repetitive GTN treatment. No significant difference in CGRP concentration was observed between animals having received fremanezumab or the control antibody. Animals treated with GTN generally spent less time at the source and consumed less sugar solution. Without barriers, there was no significant difference between animals having received fremanezumab or the control antibody. Under mechanical barrier conditions, all behavioral parameters tended to be reduced but animals that had received fremanezumab tended to be more active, partly compensating for the depressive effect of GTN. In conclusion, GTN treatment seems to increase the production of CGRP in the trigeminal ganglion independently of the antibodies applied, but repetitive GTN administration may deplete CGRP stores. GTN treatment generally tends to suppress the animals’ activity and increase facial sensitivity, which is partly compensated by fremanezumab through reduced CGRP signaling. If CGRP and NO signaling share the same pathway in sensitizing trigeminal afferents, GTN and NO may act downstream of CGRP to increase facial sensitivity. Full article

(This article belongs to the Special Issue Migraine Neuroscience: From Experimental Models to Target Therapy)

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21 pages, 3597 KiB

Open AccessArticle

Src Family Kinases Facilitate the Crosstalk between CGRP and Cytokines in Sensitizing Trigeminal Ganglion via Transmitting CGRP Receptor/PKA Pathway

by Lingdi Nie, Kai Sun, Ziyang Gong, Haoyang Li, John P. Quinn and Minyan Wang

Cells 2022, 11(21), 3498; https://doi.org/10.3390/cells11213498 - 04 Nov 2022

Cited by 7 | Viewed by 2814

Abstract

The communication between calcitonin gene-related peptide (CGRP) and cytokines plays a prominent role in maintaining trigeminal ganglion (TG) and trigeminovascular sensitization. However, the underlying regulatory mechanism is elusive. In this study, we explored the hypothesis that Src family kinases (SFKs) activity facilitates the crosstalk between CGRP and cytokines in sensitizing TG. Mouse TG tissue culture was performed to study CGRP release by enzyme-linked immunosorbent assay, cytokine release by multiplex assay, cytokine gene expression by quantitative polymerase chain reaction, and phosphorylated SFKs level by western blot. The results demonstrated that a SFKs activator, pYEEI (YGRKKRRQRRREPQY(PO3H2)EEIPIYL) alone, did not alter CGRP release or the inflammatory cytokine interleukin-1β (IL-1β) gene expression in the mouse TG. In contrast, a SFKs inhibitor, saracatinib, restored CGRP release, the inflammatory cytokines IL-1β, C-X-C motif ligand 1, C-C motif ligand 2 (CCL2) release, and IL-1β, CCL2 gene expression when the mouse TG was pre-sensitized with hydrogen peroxide and CGRP respectively. Consistently with this, the phosphorylated SFKs level was increased by both hydrogen peroxide and CGRP in the mouse TG, which was reduced by a CGRP receptor inhibitor BIBN4096 and a protein kinase A (PKA) inhibitor PKI (14–22) Amide. The present study demonstrates that SFKs activity plays a pivotal role in facilitating the crosstalk between CGRP and cytokines by transmitting CGRP receptor/PKA signaling to potentiate TG sensitization and ultimately trigeminovascular sensitization. Full article

(This article belongs to the Special Issue Migraine Neuroscience: From Experimental Models to Target Therapy)

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18 pages, 2327 KiB

Open AccessArticle

Antagonism of CGRP Receptor: Central and Peripheral Mechanisms and Mediators in an Animal Model of Chronic Migraine

by Rosaria Greco, Chiara Demartini, Miriam Francavilla, Anna Maria Zanaboni and Cristina Tassorelli

Cells 2022, 11(19), 3092; https://doi.org/10.3390/cells11193092 - 30 Sep 2022

Cited by 18 | Viewed by 2515

Abstract

Calcitonin-gene-related peptide (CGRP) plays a key role in migraine pathophysiology and more specifically in the mechanisms underlying peripheral and central sensitization. Here, we explored the interaction of CGRP with other pain mediators relevant for neuronal sensitization in an animal model of chronic migraine. Male Sprague-Dawley rats were exposed to nitroglycerin (NTG, 5 mg/kg, i.p.) or vehicle co-administered with the CGRP receptor antagonist olcegepant (2 mg/kg i.p.), or its vehicle, every other day over a 9-day period. Twenty-four hours after the last injection of NTG (or vehicle), behavioral test and ex vivo analysis were performed. Olcegepant attenuated NTG-induced trigeminal hyperalgesia in the second phase of the orofacial formalin test. Interestingly, it also reduced gene expression and protein levels of CGRP, pro-inflammatory cytokines, inflammatory-associated miRNAs (miR-155-5p, miR-382-5p, and miR-34a-5p), and transient receptor potential ankyrin channels in the medulla–pons area, cervical spinal cord, and trigeminal ganglia. Similarly, olcegepant reduced the NTG-induced increase in CGRP and inflammatory cytokines in serum. The findings show that the activation of the CGRP pathway in a migraine animal model was associated to the persistent activation of inflammatory pathways, which was paralleled by a condition of hyperalgesia. These molecular events are relevant for informing us about the mechanisms underlying chronic migraine. Full article

(This article belongs to the Special Issue Migraine Neuroscience: From Experimental Models to Target Therapy)

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21 pages, 2391 KiB

Open AccessArticle

Citalopram Neuroendocrine Challenge Shows Altered Tryptophan and Kynurenine Metabolism in Migraine

by Kinga Gecse, Andrea Edit Édes, Tamás Nagy, Adrienn Katalin Demeter, Dávid Virág, Márton Király, Borbála Dalmadi Kiss, Krisztina Ludányi, Zsuzsanna Környei, Adam Denes, Gyorgy Bagdy and Gabriella Juhasz

Cells 2022, 11(14), 2258; https://doi.org/10.3390/cells11142258 - 21 Jul 2022

Cited by 5 | Viewed by 2938

Abstract

Altered tryptophan (TRP) metabolism may have an important role in migraine susceptibility through its main metabolites, serotonin and kynurenine (KYN). Both affect pain processing and stress response by interfering with neural and brain hypersensitivity and by interacting with chemokines and cytokines that control vascular and inflammatory processes. The involvement of these pathways in migraine has been widely studied, but acute citalopram neuroendocrine challenge on TRP metabolism and cytokine profile has not been investigated yet. In our study, females with episodic migraine without aura and healthy controls were studied before and after acute citalopram or placebo in a double-blind setting. At baseline, increased TRP/large neutral amino acid (LNAA) ratio and decreased RANTES chemokine concentration were detected in migraine patients compared to controls. The challenge induced a significant increase in TRP, KYN, and TRP/LNAA in healthy controls, but not in migraine patients. Furthermore, migraine attack frequency negatively correlated with KYN/TRP ratio and positively correlated with the neuroendocrine-challenge-induced KYN concentration increase. Our results support a decreased breakdown of TRP via KYN pathway and a failure to modulate TRP–KYN pathway during citalopram-induced acute stress together with an increased vascular sensitivity in migraine. These mechanisms may provide useful drug targets for future drug development. Full article

(This article belongs to the Special Issue Migraine Neuroscience: From Experimental Models to Target Therapy)

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18 pages, 2056 KiB

Open AccessArticle

The Anti-CGRP Antibody Fremanezumab Lowers CGRP Release from Rat Dura Mater and Meningeal Blood Flow

by Mária Dux, Birgit Vogler, Annette Kuhn, Kimberly D. Mackenzie, Jennifer Stratton and Karl Messlinger

Cells 2022, 11(11), 1768; https://doi.org/10.3390/cells11111768 - 28 May 2022

Cited by 12 | Viewed by 2323

Abstract

Monoclonal antibodies directed against the neuropeptide calcitonin gene-related peptide (CGRP) belong to a new generation of therapeutics that are effective in the prevention of migraine. CGRP, a potent vasodilator, is strongly implicated in the pathophysiology of migraine, but its role remains to be fully elucidated. The hemisected rat head preparation and laser Doppler flowmetry were used to examine the effects on CGRP release from the dura mater and meningeal blood flow of the subcutaneously injected anti-CGRP monoclonal antibody fremanezumab at 30 mg/kg, when compared to an isotype control antibody. Some rats were administered glycerol trinitrate (GTN) intraperitoneally to produce a migraine-like sensitized state. When compared to the control antibody, the fremanezumab injection was followed by reduced basal and capsaicin-evoked CGRP release from day 3 up to 30 days. The difference was enhanced after 4 h of GTN application. The samples from the female rats showed a higher CGRP release compared to that of the males. The increases in meningeal blood flow induced by acrolein (100 µM) and capsaicin (100 nM) were reduced 13–20 days after the fremanezumab injection, and the direct vasoconstrictor effect of high capsaicin (10 µM) was intensified. In conclusion, fremanezumab lowers the CGRP release and lasts up to four weeks, thereby lowering the CGRP-dependent meningeal blood flow. The antibody may not only prevent the released CGRP from binding but may also influence the CGRP release stimulated by noxious agents relevant for the generation of migraine pain. Full article

(This article belongs to the Special Issue Migraine Neuroscience: From Experimental Models to Target Therapy)

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Review

Jump to: Research

21 pages, 1042 KiB

Open AccessReview

From CGRP to PACAP, VIP, and Beyond: Unraveling the Next Chapters in Migraine Treatment

by Masaru Tanaka, Ágnes Szabó, Tamás Körtési, Délia Szok, János Tajti and László Vécsei

Cells 2023, 12(22), 2649; https://doi.org/10.3390/cells12222649 - 17 Nov 2023

Cited by 7 | Viewed by 3274

Abstract

Migraine is a neurovascular disorder that can be debilitating for individuals and society. Current research focuses on finding effective analgesics and management strategies for migraines by targeting specific receptors and neuropeptides. Nonetheless, newly approved calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) have a 50% responder rate ranging from 27 to 71.0%, whereas CGRP receptor inhibitors have a 50% responder rate ranging from 56 to 71%. To address the need for novel therapeutic targets, researchers are exploring the potential of another secretin family peptide, pituitary adenylate cyclase-activating polypeptide (PACAP), as a ground-breaking treatment avenue for migraine. Preclinical models have revealed how PACAP affects the trigeminal system, which is implicated in headache disorders. Clinical studies have demonstrated the significance of PACAP in migraine pathophysiology; however, a few clinical trials remain inconclusive: the pituitary adenylate cyclase-activating peptide 1 receptor mAb, AMG 301 showed no benefit for migraine prevention, while the PACAP ligand mAb, Lu AG09222 significantly reduced the number of monthly migraine days over placebo in a phase 2 clinical trial. Meanwhile, another secretin family peptide vasoactive intestinal peptide (VIP) is gaining interest as a potential new target. In light of recent advances in PACAP research, we emphasize the potential of PACAP as a promising target for migraine treatment, highlighting the significance of exploring PACAP as a member of the antimigraine armamentarium, especially for patients who do not respond to or contraindicated to anti-CGRP therapies. By updating our knowledge of PACAP and its unique contribution to migraine pathophysiology, we can pave the way for reinforcing PACAP and other secretin peptides, including VIP, as a novel treatment option for migraines. Full article

(This article belongs to the Special Issue Migraine Neuroscience: From Experimental Models to Target Therapy)

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21 pages, 747 KiB

Open AccessReview

Monoclonal Antibodies against Calcitonin Gene-Related Peptide for Migraine Prophylaxis: A Systematic Review of Real-World Data

by Antun R. Pavelic, Christian Wöber, Franz Riederer and Karin Zebenholzer

Cells 2023, 12(1), 143; https://doi.org/10.3390/cells12010143 - 29 Dec 2022

Cited by 16 | Viewed by 3363

Abstract

Objective: To perform a systematic review of real-world outcomes for anti-CGRP-mAbs. Methods: Following the PRISMA guidelines, we searched PubMed for real-world data of erenumab, galcanezumab, fremanezumab, or eptinezumab in patients with migraines. Results: We identified 134 publications (89 retrospective), comprising 10 pharmaco-epidemiologic and 83 clinic-based studies, 38 case reports, and 3 other articles. None of the clinic-based studies provided follow-up data over more than one year in more than 200 patients. Findings suggest that there are reductions in health insurance claims and days with sick-leave as well as better treatment adherence with anti-CGRP-mAbs. Effectiveness, reported in 77 clinic-based studies, was comparable to randomized controlled trials. A treatment pause was associated with an increase in migraine frequency, and switching to another antibody resulted in a better response in some of the patients. Adverse events and safety issues were addressed in 86 papers, including 24 single case reports. Conclusion: Real-world data on anti-CGRP-mAbs are limited by retrospective data collection, small patient numbers, and short follow-up periods. The majority of papers seem to support good effectiveness and tolerability of anti-CGRP-mAbs in the real-world setting. There is an unmet need for large prospective real-world studies providing long-term follow-ups of patients treated with anti-CGRP-mAbs. Full article

(This article belongs to the Special Issue Migraine Neuroscience: From Experimental Models to Target Therapy)

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20 pages, 2626 KiB

Open AccessReview

Exploring the Tryptophan Metabolic Pathways in Migraine-Related Mechanisms

by Tamás Körtési, Eleonóra Spekker and László Vécsei

Cells 2022, 11(23), 3795; https://doi.org/10.3390/cells11233795 - 27 Nov 2022

Cited by 9 | Viewed by 4451

Abstract

Migraine is a complex neurovascular disorder, which causes intense socioeconomic problems worldwide. The pathophysiology of disease is enigmatic; accordingly, therapy is not sufficient. In recent years, migraine research focused on tryptophan, which is metabolized via two main pathways, the serotonin and kynurenine pathways, both of which produce neuroactive molecules that influence pain processing and stress response by disturbing neural and brain hypersensitivity and by interacting with molecules that control vascular and inflammatory actions. Serotonin has a role in trigeminal pain processing, and melatonin, which is another product of this pathway, also has a role in these processes. One of the end products of the kynurenine pathway is kynurenic acid (KYNA), which can decrease the overexpression of migraine-related neuropeptides in experimental conditions. However, the ability of KYNA to cross the blood–brain barrier is minimal, necessitating the development of synthetic analogs with potentially better pharmacokinetic properties to exploit its therapeutic potential. This review summarizes the main translational and clinical findings on tryptophan metabolism and certain neuropeptides, as well as therapeutic options that may be useful in the prevention and treatment of migraine. Full article

(This article belongs to the Special Issue Migraine Neuroscience: From Experimental Models to Target Therapy)

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Graphical abstract

22 pages, 856 KiB

Open AccessReview

Pathophysiology and Therapy of Associated Features of Migraine

by Maria Dolores Villar-Martinez and Peter J. Goadsby

Cells 2022, 11(17), 2767; https://doi.org/10.3390/cells11172767 - 05 Sep 2022

Cited by 11 | Viewed by 5122

Abstract

Migraine is a complex and debilitating disorder that is broadly recognised by its characteristic headache. However, given the wide array of clinical presentations in migraineurs, the headache might not represent the main troublesome symptom and it can even go unnoticed. Understanding migraines exclusively as a pain process is simplistic and certainly hinders management. We describe the mechanisms behind some of the most disabling associated symptoms of migraine, including the relationship between the central and peripheral processes that take part in nausea, osmophobia, phonophobia, vertigo and allodynia. The rationale for the efficacy of the current therapeutic arsenal is also depicted in this article. The associated symptoms to migraine, apart from the painful component, are frequent, under-recognised and can be more deleterious than the headache itself. The clinical anamnesis of a headache patient should enquire about the associated symptoms, and treatment should be considered and individualised. Acknowledging the associated symptoms as a fundamental part of migraine has permitted a deeper and more coherent comprehension of the pathophysiology of migraine. Full article

(This article belongs to the Special Issue Migraine Neuroscience: From Experimental Models to Target Therapy)

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17 pages, 1231 KiB

Open AccessReview

Could Experimental Inflammation Provide Better Understanding of Migraines?

by Philip Victor Reducha, Lars Edvinsson and Kristian Agmund Haanes

Cells 2022, 11(15), 2444; https://doi.org/10.3390/cells11152444 - 06 Aug 2022

Cited by 9 | Viewed by 2927

Abstract

Migraines constitute a common neurological and headache disorder affecting around 15% of the world’s population. In addition to other mechanisms, neurogenic neuroinflammation has been proposed to play a part in migraine chronification, which includes peripheral and central sensitization. There is therefore considerable evidence suggesting that inflammation in the intracranial meninges could be a key element in addition to calcitonin gene-related peptide (CGRP), leading to sensitization of trigeminal meningeal nociceptors in migraines. There are several studies that have utilized this approach, with a strong focus on using inflammatory animal models. Data from these studies show that the inflammatory process involves sensitization of trigeminovascular afferent nerve terminals. Further, by applying a wide range of different pharmacological interventions, insight has been gained on the pathways involved. Importantly, we discuss how animal models should be used with care and that it is important to evaluate outcomes in the light of migraine pathology. Full article

(This article belongs to the Special Issue Migraine Neuroscience: From Experimental Models to Target Therapy)

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23 pages, 1303 KiB

Open AccessReview

ATP-Sensitive Potassium Channels in Migraine: Translational Findings and Therapeutic Potential

by Amalie Clement, Song Guo, Inger Jansen-Olesen and Sarah Louise Christensen

Cells 2022, 11(15), 2406; https://doi.org/10.3390/cells11152406 - 04 Aug 2022

Cited by 13 | Viewed by 4711

Abstract

Globally, migraine is a leading cause of disability with a huge impact on both the work and private life of affected persons. To overcome the societal migraine burden, better treatment options are needed. Increasing evidence suggests that ATP-sensitive potassium (K_ATP) channels are involved in migraine pathophysiology. These channels are essential both in blood glucose regulation and cardiovascular homeostasis. Experimental infusion of the K_ATP channel opener levcromakalim to healthy volunteers and migraine patients induced headache and migraine attacks in 82-100% of participants. Thus, this is the most potent trigger of headache and migraine identified to date. Levcromakalim likely induces migraine via dilation of cranial arteries. However, other neuronal mechanisms are also proposed. Here, basic K_ATP channel distribution, physiology, and pharmacology are reviewed followed by thorough review of clinical and preclinical research on K_ATP channel involvement in migraine. K_ATP channel opening and blocking have been studied in a range of preclinical migraine models and, within recent years, strong evidence on the importance of their opening in migraine has been provided from human studies. Despite major advances, translational difficulties exist regarding the possible anti-migraine efficacy of K_ATP channel blockage. These are due to significant species differences in the potency and specificity of pharmacological tools targeting the various K_ATP channel subtypes. Full article

(This article belongs to the Special Issue Migraine Neuroscience: From Experimental Models to Target Therapy)

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