Fig. 4

Proposed Mechanisms and Sites of Action of Cilostazol-Induced Migraine-Like Headache in Persons with PPTH. The illustration delineates a hypothesized mechanism and site of action whereby diverse pharmacological triggers contribute to the genesis of migraine-like headache in people with persistent post-traumatic headache (PPTH). In this proposed model, the neuropeptides calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP-38) engage with their respective G protein-coupled receptors situated on vascular smooth muscle cells within the walls of meningeal arteries. Both peptides instigate adenylate cyclase (AC) activation via their transmembrane receptors, leading to an augmented intracellular cyclic adenosine monophosphate (cAMP) production. Cilostazol, a selective inhibitor of phosphodiesterase type 3 (PDE-3), impedes cAMP breakdown, resulting in its accumulation. The cAMP signaling pathway is postulated to activate and open ATP-sensitive potassium channels (KATP) and large conductance calcium-activated potassium channels (BKCa) channels. These subsequent events lead to potassium efflux, accompanied by the vasodilation of meningeal arteries. Modified from Al-Khazali et al., 2023.[19, 23]