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Updated: Jul 4, 2025

Investigating Migraine-Like Behavior Using Light Aversion in Mice
Published on: August 11, 2021
Targeting the PACAP-38 pathway is an emerging therapeutic strategy for migraine prevention
Lanfranco Pellesi1, Messoud Ashina2, Paolo Martelletti3
1Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark.
Introduction:
The pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) has emerged as a key mediator of migraine pathogenesis. PACAP-38 and its receptors are predominantly distributed in arteries, sensory and parasympathetic neurons of the trigeminovascular system. Phase 2 trials have tested human monoclonal antibodies designed to bind and inhibit PACAP-38 and the pituitary adenylate cyclase-activating polypeptide type I (PAC1) receptor for migraine prevention.
Areas Covered:
This review focuses on the significance of the PACAP-38 pathway as a target in migraine prevention. English peer-reviewed articles were searched in PubMed, Scopus and ClinicalTrials.gov electronic databases.
Expert Opinion:
A PAC1 receptor monoclonal antibody was not effective for preventing migraine in a proof-of-concept trial, paving the way for alternative strategies to be considered. Lu AG09222 is a humanized monoclonal antibody targeting PACAP-38 that was effective in preventing physiological responses of PACAP38 and reducing monthly migraine days in individuals with migraine. Further studies are necessary to elucidate the clinical utility, long-term safety and cost-effectiveness of therapies targeting the PACAP pathway.
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