Migraine is a common neurological disorder characterized by recurrent headaches of moderate to severe intensity, which can last from a few hours to several days. Current treatments focus on relieving symptoms and preventing additional attacks. The available medicines comprise over-the-counter painkillers and prescription medicines such as triptans and calcitonin gene-related peptide (CGRP) antagonists. According to Evaluate Pharma the annual world-wide sales of prescription medicines are expected to increase from $5.6 billion in 2022 to $13.0 billion in 2028 of which the CGRP antagonists account for the lion’s share followed by botulinum toxin and triptans. Migraine affects about 12% of the population of which 3% suffers from chronic migraine. Migraine has huge socioeconomic and personal costs. It is the second most disabling of all diseases according to WHO and it has been estimated that socioeconomic costs in the European Union alone are 40-100 billion euro per year. There is for these reasons a significant medical need for new effective and safe treatment options. Professor Jes Olesen’s pioneering migraine research, which is based on both clinical and preclinical findings and most recently recognized via his receipt of the Lundbeck Foundation’s "The Brain Prize” in 2021, has led to the identification of a new and untapped target for the treatment of migraine.
Although the cause and mechanisms underlying migraine are multifactorial and not yet fully understood, artery dilation in the dural vasculature is a key component. The middle meningeal artery (MMA) is dilated during migraine attacks, and drugs shown to induce dilation of the MMA can provoke migraine attacks in migraineurs and headache in healthy volunteers.
Professor Jes Olesen’s group has shown that activation of the blood vessels’ KATP channels seems to be the most effective way to induce migraine attacks in patients, and potentially a unifying mechanism for most other chemical migraine inducers.
In two different migraine models in animals, Prof. Jes Olesen’s group has demonstrated that inhibition of KATP channels effectively suppresses pain in the head region. The KATP channel subtype Kir6.1/SUR2B is the dominant isoform in the large blood vessels of the brain, and since mice with a smooth muscle conditional loss-of-function mutation in Kir6.1 show reduced pain sensitivity to migraine-inducing substances, inhibition of Kir6.1/SUR2B seems to offer a new and highly relevant mechanism for the treatment of migraine.
KATP channels are large heteromeric protein complexes composed of four pore-forming inward rectifier potassium channel subunits (Kir6.1 or Kir6.2) and four regulatory sulfonylurea receptor subunits (SUR1, SUR2A or SUR2B).
The channels are activated by magnesium-bound nucleotides and ADP, which act on the SUR subunit, and they are inhibited upon binding of intracellular ATP to the Kir6 subunit.
The ability to couple cellular metabolic state (ATP/ADP ratio) to electrical activity of the cell membrane is critical in numerous physiological processes and is a key feature of KATP channels. Heterologous expression of Kir6 and SUR subunits in differing combinations reconstitutes different types of KATP channels with distinct functional properties as well as pharmacological sensitivities. KATP channels are distributed in migraine related structures and more specifically Kir6.1 and SUR2B subunits are expressed in cerebral and meningeal arteries and in the trigeminal system, making these channel subunits a relevant migraine target. Drugs that selectively inhibit Kir6.1/SUR2B could therefore represent a novel migraine treatment principle.
