Alternative signaling pathways to CGRP in the generation of migraine attacks
Final Report Abstract
Calcitonin Gene-Related Peptide (CGRP) is one key neuropeptide in the initiation of migraine attacks. Medications targeting the CGRP pathway, such as the CGRP receptor antibody erenumab, have demonstrated efficacy in migraine prevention. Nevertheless, no medication has yielded an absolute therapeutic response, suggesting the involvement of mechanisms other than CGRP in the pathogenesis of migraine. Our current understanding of the intracellular signaling pathways of migraine highlights two key routes: the cyclic adenosine monophosphate (cAMP) and the cyclic guanosine monophosphate (cGMP) pathway. CGRP activates the cAMP pathway, while substances like glyceryl trinitrate (a nitric oxide donor) or phosphodiesterase-5 (PDE-5) inhibitors stimulate the cGMP pathway. Both pathways are supposed to converge into the opening of ATP-sensitive potassium channels (KATP channels), which represent the final step of the proposed intracellular signaling cascade. A key feature of migraine is that various trigger molecules can initiate an attack, providing a unique opportunity to explore disease mechanisms by experimentally inducing migraine attacks in humans. During my one-year research stay at the Danish Headache Center, I conducted two human provocation studies to elucidate signaling cascades involved in migraine attack initiation after blocking the CGRP receptor with erenumab: 1) Migraine Provocation via KATP Channel Opener Levcromakalim: In 16 patients pre-treated with erenumab, levcromakalim induced migraine attacks in 14 patients compared to 2 after receiving a placebo. Additionally, levcromakalim led to a decrease in mean arterial blood pressure, an increase in heart rate, and dilation of the superficial temporal artery compared to placebo. This shows that migraine provocation via KATP channels is independent of CGRP receptor activation, supporting the downstream position of KATP channels in the migraine signaling cascade. 2) Migraine Provocation via PDE-5 Inhibitor Sildenafil (cGMP Pathway Stimulation): In 16 patients pre-treated with erenumab, sildenafil induced migraine attacks in 10 patients, as opposed to 3 after receiving a placebo. Furthermore, sildenafil administration was associated with a decrease in mean blood pressure and an increase in heart rate compared to placebo. This underscores that migraine activation via the cGMP pathway is independent of CGRP receptor activation, supporting the existence of two separate signaling pathways (cAMP and cGMP) in migraine pathogenesis. In conclusion, these two studies underscore the significant involvement of KATP channels (Study 1) and the cGMP pathway (Study 2) in migraine pathogenesis, emphasizing their potential as targets for future treatment avenues.
Publications
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Activation of ATP-sensitive potassium channels triggers migraine attacks independent of calcitonin gene-related peptide receptors: a randomized placebo-controlled trial. Cephalalgia, 44(1).
Raffaelli, Bianca; Do, Thien Phu; Chaudhry, Basit Ali; Amin, Faisal Mohammad; Ashina, Håkan; Snellman, Josefin; Maio-Twofoot, Tina & Ashina, Messoud
