The role of Kynurenine-Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) axis in migraine pathophysiology and therapy.

Abstract

Migraine is one of the most common types of primary headaches, and its pathomecha nism is not yet fully understood. Our know ledge of its pathophysiology has previously focused primarily on the serotonin system; however, in recent years, increa sing attention has been given to tryptophan metabolism, particularly the Kynurenine pathway (KP). The KP, which is involved in the regulation of glutamatergic neurotransmission, is responsible for the synthesis of several neuroprotective and neurotoxic metabolites. Kynurenic acid (KYNA) is endogenous glutamate NMDA receptor antagonist in the body. Experimental data indicate that KYNA plays an important role in the pathophysiology of migraine attacks. Preclinical studies support that KYNA and its synthetic analogs are able to inhibit the pathological processes occur ring during migraine. Our previous clinical studies have confirmed that in patients with migraine, the balance maintained by neuroprotective and neurotoxic KP metabolites is disrupted, affecting both the protective and the toxic side. It is important to note, however, that various molecules of KP metabolism can exert both positive and negative effects depending on their concentration at multiple sites of the body, and therefore there is no international consensus regarding the spectrum of protective and toxic molecules. Recently, "migraine associated" neuropeptides have emerged as another promising target for migraine therapy. Calcitonin gene related peptide (CGRP) and pituitary adenylate cyclase activating polypeptide (PACAP) are involved, among other process es, in nociception and neurogenic inflammation, and their expression is altered duringmigraine attacks. Monoclonal antibody therapies targeting these neuropeptides are currently considered the most promising treatment for migraine. Our experimental data have demonstrated a close correla tion between the kynurenine pathway (KP), PACAP, and CGRP signaling, which suggests that investigation of these systems together may offer a new approach to understanding the pathological processes underlying migraine.