PACAP (Pituitary Adenylate Cyclase-Activating Peptide)
Neuroprotection / HormonalAlso known as: Pituitary Adenylate Cyclase-Activating Peptide, PACAP-38, PACAP-27, ADCYAP1
Mechanism
PACAP is a neuroprotective peptide found throughout the brain and nervous system. It stimulates cAMP production in the pituitary (hence its name) and has broad protective effects on neurons, including defense against oxidative stress and apoptosis. It exists in two forms (27 and 38 amino acids) and is involved in migraine pathology, stress responses, and circadian rhythm regulation.
Technical detail
PACAP exists as PACAP-38 (predominant) and PACAP-27, products of the ADCYAP1 gene. It binds PAC1R (PACAP-specific, Gs/Gq-coupled) and VPAC1R/VPAC2R (shared with VIP). PAC1R activation drives adenylyl cyclase-cAMP-PKA and PLC-PKC pathways, upregulating CREB-mediated neuroprotective gene expression including BDNF and Bcl-2. PACAP is a potent vasodilator implicated in migraine pathogenesis (similar to CGRP), and PAC1R antagonists are under investigation for migraine prevention. Also functions as a hypothalamic hypophysiotropic factor stimulating GH, prolactin, and ACTH release.
Evidence
- strong
PACAP38-induced migraine attacks are independent of CGRP signaling: a randomized controlled trial.
Al-Karagholi et al. (2025) — The Journal of Headache and Pain — PMID: 40229719
Among 38 adults with migraine without aura, PACAP38 induced migraine attacks despite prior eptinezumab or placebo, supporting PACAP signaling as a CGRP-independent migraine pathway.
- strong
A Monoclonal Antibody to PACAP for Migraine Prevention.
Ashina et al. (2024) — The New England Journal of Medicine — PMID: 39231342
In 237 participants with migraine, a single 750 mg infusion of the anti-PACAP antibody Lu AG09222 reduced monthly migraine days by 2.0 more days than placebo over weeks 1-4, supporting PACAP as a therapeutic target.
- strong
PACAP27 induces migraine-like attacks in migraine patients.
Ghanizada et al. (2020) — Cephalalgia — PMID: 31299857
In 20 patients with migraine without aura, PACAP27 infusion provoked migraine-like attacks in 55% versus 10% after placebo and significantly increased headache intensity and duration.