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Second messenger signalling bypasses CGRP receptor blockade to provoke migraine attacks in humans.

Authors :
Do, Thien Phu
Deligianni, Christina
Amirguliyev, Sarkhan
Snellman, Josefin
Lopez, Cristina Lopez
Al-Karagholi, Mohammad Al-Mahdi
Guo, Song
Ashina, Messoud
Source :
Brain: A Journal of Neurology. Dec2023, Vol. 146 Issue 12, p5224-5234. 11p.
Publication Year :
2023

Abstract

There are several endogenous molecules that can trigger migraine attacks when administered to humans. Notably, calcitonin gene-related peptide (CGRP) has been identified as a key player in a signalling cascade involved in migraine attacks, acting through the second messenger cyclic adenosine monophosphate (cAMP) in various cells, including intracranial vascular smooth muscle cells. However, it remains unclear whether intracellular cAMP signalling requires CGRP receptor activation during a migraine attack in humans. To address this question, we conducted a randomized, double-blind, placebo-controlled, parallel trial using a human provocation model involving the administration of CGRP and cilostazol in individuals with migraine pretreated with erenumab or placebo. Our study revealed that migraine attacks can be provoked in patients by cAMP-mediated mechanisms using cilostazol, even when the CGRP receptor is blocked by erenumab. Furthermore, the dilation of cranial arteries induced by cilostazol was not influenced by the CGRP receptor blockade. These findings provide clinical evidence that cAMP-evoked migraine attacks do not require CGRP receptor activation. This discovery opens up new possibilities for the development of mechanism-based drugs for the treatment of migraine. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00068950
Volume :
146
Issue :
12
Database :
Academic Search Index
Journal :
Brain: A Journal of Neurology
Publication Type :
Academic Journal
Accession number :
174108466
Full Text :
https://doi.org/10.1093/brain/awad261