PACAP

PACAP (Pituitary Adenylate Cyclase-Activating Polypeptide) is a highly conserved neuropeptide belonging to the VIP/secretin/glucagon superfamily. It exists in two bioactive forms: PACAP-38 (38 AA, predominant) and PACAP-27 (27 AA, N-terminal fragment). First isolated from ovine hypothalamus in 1989 by Miyata et al., PACAP is one of the most potent known neuroprotective agents. It is expressed broadly in the nervous system, gut, testes, and adrenal glands.

PACAP acts through three GPCRs: PAC1 (PACAP-selective, high affinity), VPAC1, and VPAC2 (shared with VIP). PAC1 activation stimulates adenylate cyclase, raising cAMP, and also activates PLC through Gq coupling. This triggers PKA/PKC signaling cascades that promote neuronal survival, inhibit apoptosis, reduce neuroinflammation, and stimulate neurotrophic factor synthesis. PACAP regulates diverse functions including neurodevelopment, circadian rhythms, pain modulation, immune function, and energy metabolism.

IV infusion of PACAP-38 triggers delayed migraine attacks in 55–58% of subjects, implicating it in trigeminovascular activation and validating PAC1 antagonism as a migraine target. Neuroprotective effects are demonstrated in ischemia, TBI, Parkinson's, and Alzheimer's models. PTSD-associated PACAP elevation (particularly in women) and PAC1R hypermethylation are emerging biomarkers. Short plasma half-life and metabolic instability have limited clinical translation; stable analogs are in development.