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Genetic and Molecular Mechanisms in Primary Headache and Treatment

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

Deadline for manuscript submissions: closed (17 November 2023) | Viewed by 8087

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Special Issue Editors

Dr. Caroline Ran

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Guest Editor

Department of Neuroscience, Karolinska Institutet, Biomedicum D7, Stockholm, Sweden
Interests: genetics; migraine; cluster headache; gene expression; pharmacogenetics; neuroscience
Special Issues, Collections and Topics in MDPI journals

Dr. Andrea Carmine Belin

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Guest Editor

Department of Neuroscience, Karolinska Institutet, Biomedicum D7, Stockholm, Sweden
Interests: genetics; headache; neuroscience; pain; circadian rhythm; neurology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Primary headache disorders are recognized as recurrent, medium to severe headaches that have no known underlying cause. These disorders have repeatedly been estimated to be one of the primary causes of years lived with disability by the WHO (world health organization). Fifty percent of the global population is approximated to suffer from primary headache disorders, most commonly tension-type headaches, migraine and trigeminal autonomic cephalalgias (TACs). Nevertheless, headache disorders are still underdiagnosed and undertreated. Genetic research on primary headache disorders has greatly advanced the research field in the last couple of years. In particular by performing genome-wide association studies (GWAS) on migraine and cluster headache (the most common TAC subtype). Numerous genetic loci have been associated with specific headache subtypes, as well as broadly defined headaches, and have also been linked to drug targets specific for headache treatments such as CGRP and triptans.

Genetic and molecular studies are key to discovering and deciphering the pathophysiological mechanisms underlying a disorder, finding biomarkers, refining diagnosis, developing new and more efficient treatments, and ultimately improving medical care. Further genetic and molecular studies will be crucial to develop and build on the current state of knowledge of headache pathophysiology. Accordingly, this Special Issue of the International Journal of Molecular Sciences welcomes submissions with a focus on genetic and molecular mechanisms that may be involved in headache pathophysiology and treatment mechanisms.

Dr. Caroline Ran
Dr. Andrea Carmine Belin
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

primary headache disorder
cluster headache
triptans
CGPR
nitric oxide

Published Papers (4 papers)

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Research

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12 pages, 952 KiB

Open AccessArticle

Associations between Cerebrovascular Function and the Expression of Genes Related to Endothelial Function in Hormonal Migraine

by Jemima S. A. Dzator, Robert A. Smith, Kirsten G. Coupland, Peter R. C. Howe and Lyn R. Griffiths

Int. J. Mol. Sci. 2024, 25(3), 1694; https://doi.org/10.3390/ijms25031694 - 30 Jan 2024

Viewed by 524

Abstract

There is evidence to suggest that hormonal migraine is associated with altered cerebrovascular function. We aimed to investigate whether the expression of genes related to endothelial function in venous blood (1) might influence cerebrovascular function, (2) differs between hormonal migraineur and non-migraineur women, and (3) changes following resveratrol supplementation. This study utilised data obtained from 87 women (59 hormonal migraineurs and 28 controls) where RNA from venous blood was used to quantify gene expression and transcranial Doppler ultrasound was used to evaluate cerebrovascular function. Spearman’s correlation analyses were performed between gene expression, cerebrovascular function, and migraine-related disability. We compared the expression of genes associated with endothelial function between migraineurs and non-migraineurs, and between resveratrol and placebo. The expression of several genes related to endothelial function was associated with alterations in cerebrovascular function. Notably, the expression of CALCA was associated with increased neurovascular coupling capacity (p = 0.013), and both CALCA (p = 0.035) and VEGF (p = 0.014) expression were associated with increased cerebral blood flow velocity in the overall study population. Additionally, VCAM1 expression correlated with decreased pulsatility index (a measure of cerebral arterial stiffness) (p = 0.009) and headache impact test-6 scores (p = 0.007) in the migraineurs. No significant differences in gene expression were observed between migraineurs and controls, or between placebo and resveratrol treatments in migraineurs. Thus, altering the expression of genes related to endothelial function may improve cerebrovascular function and decrease migraine-related disability. Full article

(This article belongs to the Special Issue Genetic and Molecular Mechanisms in Primary Headache and Treatment)

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9 pages, 1573 KiB

Open AccessCommunication

Investigating Vitamin D Receptor Genetic Markers in a Cluster Headache Meta-Analysis

by Felicia Jennysdotter Olofsgård, Caroline Ran, Yuyan Qin, Carmen Fourier, Christina Sjöstrand, Elisabet Waldenlind, Anna Steinberg and Andrea Carmine Belin

Int. J. Mol. Sci. 2023, 24(6), 5950; https://doi.org/10.3390/ijms24065950 - 21 Mar 2023

Cited by 2 | Viewed by 2121

Abstract

Patients diagnosed with the primary headache disorder known as cluster headache (CH) commonly report that their headache attacks occur in patterns of both circadian and seasonal rhythmicity. Vitamin D is essential for a variety of bodily functions and vitamin D levels are largely regulated by daylight exposure in connection with seasonal variation. For this Sweden-based study, the association between CH and three single-nucleotide polymorphisms in the vitamin D receptor gene, rs2228570, rs1544410, and rs731236, were investigated, as well as CH bouts and trigger factors in relation to seasonal and weather changes. Over 600 study participants with CH and 600 controls were genotyped for rs2228570, and genotyping results for rs1544410 and rs731236 were obtained from a previous genome-wide association study. The genotyping results were combined in a meta-analysis, with data from a Greek study. No significant association was found between rs2228570 and CH or the CH subtype in Sweden, nor did the meta-analysis show significant results for any of the three markers. The most common period of the year to experience CH bouts in Sweden was autumn, and conditions linked to weather or weather changes were also identified as potential triggers for CH bouts for a quarter of the responders who reported bout triggers. Though we cannot rule out vitamin D involvement in CH, this study does not indicate any connection between CH and the three vitamin D receptor gene markers. Full article

(This article belongs to the Special Issue Genetic and Molecular Mechanisms in Primary Headache and Treatment)

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Review

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17 pages, 564 KiB

Open AccessReview

Genetic Mechanisms of Migraine: Insights from Monogenic Migraine Mutations

by Helin Gosalia, Nazia Karsan and Peter J. Goadsby

Int. J. Mol. Sci. 2023, 24(16), 12697; https://doi.org/10.3390/ijms241612697 - 11 Aug 2023

Cited by 2 | Viewed by 1729

Abstract

Migraine is a disabling neurological disorder burdening patients globally. Through the increasing development of preclinical and clinical experimental migraine models, advancing appreciation of the extended clinical phenotype, and functional neuroimaging studies, we can further our understanding of the neurobiological basis of this highly disabling condition. Despite increasing understanding of the molecular and chemical architecture of migraine mechanisms, many areas require further investigation. Research over the last three decades has suggested that migraine has a strong genetic basis, based on the positive family history in most patients, and this has steered exploration into possibly implicated genes. In recent times, human genome-wide association studies and rodent genetic migraine models have facilitated our understanding, but most migraine seems polygenic, with the monogenic migraine mutations being considerably rarer, so further large-scale studies are required to elucidate fully the genetic underpinnings of migraine and the translation of these to clinical practice. The monogenic migraine mutations cause severe aura phenotypes, amongst other symptoms, and offer valuable insights into the biology of aura and the relationship between migraine and other conditions, such as vascular disease and sleep disorders. This review will provide an outlook of what is known about some monogenic migraine mutations, including familial hemiplegic migraine, familial advanced sleep-phase syndrome, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Full article

(This article belongs to the Special Issue Genetic and Molecular Mechanisms in Primary Headache and Treatment)

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25 pages, 1868 KiB

Open AccessReview

Molecular Mechanisms of Migraine: Nitric Oxide Synthase and Neuropeptides

by Nazia Karsan, Helin Gosalia and Peter J. Goadsby

Int. J. Mol. Sci. 2023, 24(15), 11993; https://doi.org/10.3390/ijms241511993 - 26 Jul 2023

Cited by 9 | Viewed by 2810

Abstract

Migraine is a common condition with disabling attacks that burdens people in the prime of their working lives. Despite years of research into migraine pathophysiology and therapeutics, much remains to be learned about the mechanisms at play in this complex neurovascular condition. Additionally, there remains a relative paucity of specific and targeted therapies available. Many sufferers remain underserved by currently available broad action preventive strategies, which are also complicated by poor tolerance and adverse effects. The development of preclinical migraine models in the laboratory, and the advances in human experimental migraine provocation, have led to the identification of key molecules likely involved in the molecular circuity of migraine, and have provided novel therapeutic targets. Importantly, the identification that vasoconstriction is neither necessary nor required for headache abortion has changed the landscape of migraine treatment and has broadened the therapy targets for patients with vascular risk factors or vascular disease. These targets include nitric oxide synthase (NOS) and several neuropeptides that are involved in migraine. The ability of NO donors and infusion of some of these peptides into humans to trigger typical migraine-like attacks has supported the development of targeted therapies against these molecules. Some of these, such as those targeting calcitonin gene-related peptide (CGRP), have already reached clinical practice and are displaying a positive outcome in migraineurs for the better by offering targeted efficacy without significant adverse effects. Others, such as those targeting pituitary adenylate cyclase activating polypeptide (PACAP), are showing promise and are likely to enter phase 3 clinical trials in the near future. Understanding these nitrergic and peptidergic mechanisms in migraine and their interactions is likely to lead to further therapeutic strategies for migraine in the future. Full article

(This article belongs to the Special Issue Genetic and Molecular Mechanisms in Primary Headache and Treatment)

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