Alternative signaling pathways to CGRP in the generation of migraine attacks

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Migraine is a frequent and debilitating neurological disease with a complex pathophysiology. The neuropeptide calcitonin gene-related peptide (CGRP) plays a crucial role in the generation of migraine attacks. During a migraine attack, CGRP is released from trigeminal afferents and triggers an inflammatory response. In recent years, monoclonal antibodies against the CGRP signaling pathway have proven effective in migraine prevention. However, not all patients respond to CGRP-targeted treatment. Approximately 20% of patients treated with CGRP(-receptor) antibodies show no change in their migraine frequency and even good responders still report frequent migraine attacks. Migraine provocation studies have shown that only two-thirds of patients develop a migraine attack after intravenous administration of CGRP. This suggests that other molecular signaling pathways besides CGRP are involved in the development of migraine attacks. A current pathophysiological model proposes the opening of adenosine triphosphate-sensitive potassium (KATP) channels as the final step in the intracellular signaling cascade of migraine. Indeed, the KATP channel opener levcromakalim triggered migraine attacks in all examined patients. Various inflammatory neuropeptides can lead to the opening of KATP channels by binding to G-protein-coupled receptors. These include, besides CGRP, pituitary adenylate cyclase-activating polypeptide (PACAP-38) and other members of the calcitonin family such as adrenomedullin and amylin.The aim of this project is to investigate these other nociceptive signaling pathways in the development of migraine attacks. To prevent the activation of the CGRP pathway, the CGRP receptor will be blocked by the monoclonal antibody erenumab. The project consists of two subprojects. The first subproject is a placebo-controlled provocation study with levcromakalim in patients receiving erenumab therapy. According to the presented pathophysiogical model, migraine attacks triggered by levcromakalim should bypass a blockade of the CGRP receptor. The activation of KATP channels by other neuropeptides could explain why patients still develop frequent migraine attacks under erenumab treatment. The second subproject investigates changes in PACAP-38, adrenomedullin and amylin concentrations under erenumab therapy. The blockade of the CGRP receptor could lead to compensatory upregulation of these nociceptive signaling pathways. On the other hand, if these pathways are truly independent, no relevant changes are expected. The investigation of alternative inflammatory signaling pathways is crucial to explain the interindividual differences in the therapeutic response to CGRP-targeted therapies. Dissecting these molecular mechanisms will help identify new therapeutic approaches for the preventive treatment of migraine.