What causes migraine and how can it be prevented?

Calcitonin gene-related peptide (CGRP) plays a causative role in migraine, said Antoinette Maassen van den Brink, Rotterdam, The Netherlands. In a symposium presentation for EAN 2020, she provided a clear summary of migraine pathophysiology, the role of CGRP, and why reducing CGRP activity reduces the frequency migraine.

What causes migraine?

Migraine is associated with trigeminal nerve activation and the release of CGRP

Genes, hormones, and possibly stress are risk factors for migraine, said Dr Maassen van den Brink, and attacks probably start in the brainstem.1,2

The subsequent pathophysiological processes lead to trigeminal vascular system activation with the release of a variety of molecules, including CGRP.1,2

CGRP then binds to CGRP receptors, which are abundant in the trigeminal system in smooth muscle and arteries and induces vasodilation. But Dr Maassen van den Brink noted that it is not clear whether vasodilation causes the headache or is a related phenomenon.2.

Does vasodilation cause the headache or is it a related phenomenon?

The involvement of higher brain centers leads to headache and migraine-associated symptoms such as photophobia, phonophobia, nausea, and vomiting.1

 

What is CGRP and what is the link between CGRP and migraine?

CGRP is a small 37-amino acid peptide, explained Dr Maassen van den Brink, and is not only a potent vasodilator, but also a messenger in nerve cells. It has two isoforms encoded by different genes:

  • αCGRP is located mainly in the nervous system and the main player in migraine
  • βCGRP is located mainly in the enteric system, but could also be involved in migraine3

Blood CGRP levels are increased during migraine

Blood CGRP levels during a migraine attack were first investigated 30 years ago and found to be increased compared with levels during the interictal period. CGRP levels then normalised after the attack.4

An intravenous injection of CGRP was subsequently found to cause an immediate headache in healthy volunteers, and migraine in people with migraine.5

 

Preventing CGRP activity can prevent migraine

Two different classes of drugs have been developed to block CGRP activity:

  • small molecule CGRP receptor antagonists (gepants)
  • monoclonal antibodies targeting either CGRP or the CGRP receptor6,7

CGRP-related therapies are designed to act target the trigeminal pain system,8 and seem to have few or no adverse effects.9 However, CGRP and its receptors are abundant in the vasculature and peripheral and central nervous system.6

CGRP may act as a vasodilatory safeguard during cerebral and cardiac ischemia, said Dr Maassen van den Brink, so CGRP blockade could transform mild ischemic events into infarcts.2 The long-term effects of blocking CGRP in special populations therefore need further investigation.6,9

 

This session was from a satellite symposium sponsored by Teva.

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

References
  1. Edvinsson L, et al. Pharmacol Ther 2012;136:319–33.
  2. MaassenVanDenBrink A, et al. Trends Pharmacol Sci 2016;37:779–88.
  3. Durham PL, Vause, C. CNS Drugs 2010;24:539–48.
  4. Goadsby PJ, et al. Ann Neurol 1990;28:183–7.
  5. Lassen LH, et al. Cephalalgia 2002;22:54–61.
  6. Deen M, et al. J Headache Pain 2017;18;96.
  7. Edvinsson L, et al. Nat Rev Neurol 2018;14:338–50.
  8. Rubio-Beltrán E, Maassen van den Brink A. Handb Exp Pharmacol 2019;255:131–50.
  9. De Vries T, et al. Pharmacol Ther 2020;107528. doi: 10.1016/j.pharmthera.2020.107528.
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