Investigations of the involvement of different isoforms of KATP channels in headache and migraine pathophysiology

Migraine is a prevalent neurovascular condition affecting 1 billion people worldwide. Even though disease-specific treatments have recently been developed, the precise pathophysiological mechanisms underlying migraine have yet to be revealed. The involvement of adenosine 5'-triphosphate-sensitive K+ (KATP) channels in headache and migraine pathogenesis has been established over the past years. KATP channels are expressed throughout the trigeminovascular system, which is believed to be the pathophysiological substrate of migraine pain. Various studies using the human experimental model of migraine have established that activation of KATP channels is directly linked to headache and migraine initiation. Moreover, preclinical studies have indicated that the KATP channel might be a downstream molecule in the migraine-triggering intracellular pathways of compounds known for their crucial role in migraine, like the pituitary adenylate cyclase-activating polypeptide-38 (PACAP38).
In the present thesis, we conducted three crossover, double-blind, placebo-controlled studies. In healthy participants, we investigated the effect of the non-specific KATP channel blocker glibenclamide on the headache induced by KATP channel opener levcromakalim (study I) and on the headache and vascular changes induced by PACAP38 (study II). In both studies, glibenclamide did
not attenuate the headache and vasodilation. Afterwards, we investigated the effect of NN414, a specific Kir6.2/SUR1 KATP channel opener in individuals with migraine without aura (study III). NN414 did not trigger migraine attacks, indicating that the Kir6.2/SUR1 subunit is unlikely to be involved in migraine initiation. The thesis concludes that non-specific KATP channel blockers, such as glibenclamide, are not an effective treatment strategy for headache and migraine. We instead suggest that the Kir6.1/SUR2B subtype expressed in cerebral vasculature is potentially involved in the signaling pathways leading to migraine attacks and is a possible novel therapeutic target.