Future targets for migraine treatment beyond CGRP

The Journal of Headache and Pain

Review

Faisal Mohammad Amin¹  Fatemeh Farham²  Linda Al-Hassany³  Deirdre M. Boucherie³  Ruben W. A. van Drie⁴  Cédric Gollion⁵  Marta Waliszewska-Prosół⁶  Karol Marschollek⁶  Wietse Wiels⁷  Silvia Favaretto⁸  Hannah Lyons⁹  Lou Grangeon^1,10  Umberto Pensato^1,11  Dilara Onan^1,12  Emily Stanyer^1,13  Hui Zhou Chen^1,13  Hannah Creeney^1,13 

[1] Danish Headache Center, Department of Neurology, Faculty of Health and Medical Sciences, Rigshospitalet Glostrup, University of Copenhagen, Copenhagen, Denmark;Department of Neurorehabilitation/Traumatic Brain Injury, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark;Department of Headache, Iranian Centre of Neurological Researchers, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran;Department of Internal Medicine, Division of Vascular Medicine and Pharmacology, Erasmus MC University Medical Center, Rotterdam, The Netherlands;Department of Internal Medicine, Division of Vascular Medicine and Pharmacology, Erasmus MC University Medical Center, Rotterdam, The Netherlands;Department of Cardiology, Division of Experimental Cardiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands;Department of Neurology, University Hospital of Toulouse, Toulouse, France;Department of Neurology, Wroclaw Medical University, Wrocław, Poland;Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium;Headache Center, Neurology Clinic, University Hospital of Padua, Padua, Italy;Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK;Neurology Department, Rouen University Hospital, Rouen, France;Neurology and Stroke Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy;Humanitas University, Pieve Emanuele, Milan, Italy;Spine Health Unit, Faculty of Physical Therapy and Rehabilitation, Hacettepe University, Ankara, Turkey;Department of Clinical and Molecular Medicine, Sapienza University, Rome, Italy;Wolfson Centre for Age-Related Diseases, King’s College London, London, UK;

关键词: Migraine;    Non-CGRP targets;    Pituitary adenylate cyclase-activating polypeptide;    Vasoactive intestinal polypeptide;    Amylin;    Adrenomedullin;    Nitric oxide;    Phosphodiesterases;    Ion channels;   

DOI  :  10.1186/s10194-023-01567-4

 received in 2022-12-31, accepted in 2023-03-14,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundMigraine is a disabling and chronic neurovascular headache disorder. Trigeminal vascular activation and release of calcitonin gene-related peptide (CGRP) play a pivotal role in the pathogenesis of migraine. This knowledge has led to the development of CGRP(-receptor) therapies. Yet, a substantial proportion of patients do not respond to these treatments. Therefore, alternative targets for future therapies are warranted. The current narrative review provides a comprehensive overview of the pathophysiological role of these possible non-CGRP targets in migraine.FindingsWe covered targets of the metabotropic receptors (pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), amylin, and adrenomedullin), intracellular targets (nitric oxide (NO), phosphodiesterase-3 (PDE3) and -5 (PDE5)), and ion channels (potassium, calcium, transient receptor potential (TRP), and acid-sensing ion channels (ASIC)). The majority of non-CGRP targets were able to induce migraine-like attacks, except for (i) calcium channels, as it is not yet possible to directly target channels to elucidate their precise involvement in migraine; (ii) TRP channels, activation of which can induce non-migraine headache; and (iii) ASICs, as their potential in inducing migraine attacks has not been investigated thus far.Drugs that target its receptors exist for PACAP, NO, and the potassium, TRP, and ASIC channels. No selective drugs exist for the other targets, however, some existing (migraine) treatments appear to indirectly antagonize responses to amylin, adrenomedullin, and calcium channels. Drugs against PACAP, NO, potassium channels, TRP channels, and only a PAC1 antibody have been tested for migraine treatment, albeit with ambiguous results.ConclusionWhile current research on these non-CGRP drug targets has not yet led to the development of efficacious therapies, human provocation studies using these targets have provided valuable insight into underlying mechanisms of migraine headaches and auras. Further studies are needed on these alternative therapies in non-responders of CGRP(-receptor) targeted therapies with the ultimate aim to pave the way towards a headache-free future for all migraine patients.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

Fig. 7