Abstract
During the three decades of studying vasoactive substances in migraine pathophysiology, ample theoretical knowledge has been accumulated that has ushered in a groundbreaking era in migraine treatment. Pituitary adenylate cyclase activating polypeptide (PACAP) is one of these promising therapeutic targets and the subject of ongoing clinical trials.
In this review article, we focus on PACAP as an endogenous signaling molecule, describing its basic properties, binding to specific receptors (PAC1, VPAC1, VPAC2) and its biological activity. The latter relates to basic physiological processes of the organism (reproduction, nutrition, aging, etc.), neuroprotection in acute and chronic injury, and it is of particular importance in tissue and organ protection in ischemic stroke.
The vasomotor effect of PACAP consists of cAMP-mediated relaxation of the cranial artery smooth muscle. In migraine patients, experimental application of PACAP induces vasodilation of the arteria meningea media and correlates with lateralized headache with a migrainous phenotype.
Although this vasodilatation is preventable by sumatriptan, a monoclonal antibody directed against the PAC1 receptor (AMG301) completely failed in migraine prevention. Currently, the results of clinical trials (phase 1 and 2) of monoclonal antibodies directed against PACAP (ALD1910 or Lu-AG09222, LY3451838) are eagerly awaited.
If their prophylactic effect in migraine is demonstrated, this would open a new therapeutic option for patients with previously failed treatment. However, a prerequisite for potential medical use will be the demonstration of long-term safety, especially with regard to cardiovascular health.