1. Academic Validation
  2. No central action of CGRP antagonising drugs in the GTN mouse model of migraine

No central action of CGRP antagonising drugs in the GTN mouse model of migraine

  • Cephalalgia. 2020 Aug;40(9):924-934. doi: 10.1177/0333102420914913.
Sarah L Christensen 1 Charlotte Ernstsen 1 Jes Olesen 1 David M Kristensen 1 2
Affiliations

Affiliations

  • 1 Danish Headache Center, Glostrup Research Institute, Rigshospitalet Glostrup, Glostrup, Denmark.
  • 2 University of Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail) - UMR_S 1085, Rennes, France.
Abstract

Introduction: Clinically, Calcitonin gene-related peptide antagonising drugs are recognized as effective in migraine treatment, but their site of action is debated. Only a small fraction of these compounds pass the blood-brain barrier and accesses the central nervous system. Regardless, it has been argued that the central nervous system is the site of action. Here, we test this hypothesis by bypassing the blood-brain barrier through intracerebroventricular injection of Calcitonin gene-related peptide antagonising drugs.

Methods: We used the glyceryl trinitrate (GTN) mouse model, which is well validated by its response to specific migraine drugs. The Calcitonin gene-related peptide receptor antagonist olcegepant and the Calcitonin gene-related peptide monoclonal antibody ALD405 were administered either intraperitoneally or intracerebroventricularly. The outcome measure was cutaneous mechanical allodynia.

Results: Mice given olcegepant intraperitoneally + GTN on day 1 had a mean 50% withdrawal threshold of 1.2 g in contrast to mice receiving placebo + GTN, which had a threshold of 0.3 g (p < 0.001). Similarly, in the ALD405 + GTN group, mice had thresholds of 1.2 g versus 0.2 g in the placebo + GTN group (p < 0.001). However, both drugs were ineffective when delivered intracerebroventricularly, as control and active groups had identical mechanical sensitivity thresholds, 0.2 g versus 0.1 g and 0.1 g versus 0.1 g for olcegepant and ALD405, respectively (p > 0.99 in both cases).

Discussion: The site of action of olcegepant and of the monoclonal antibody ALD405 is outside the blood-brain barrier in this mouse model of migraine. It is likely that these results can be generalised to all gepants and all Antibodies and that the results are relevant for human migraine.

Keywords

ALD405; CGRP; GTN mouse model; blood-brain barrier; intracerebroventricular; olcegepant.

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