Calcitonin gene-related peptide (CGRP) is a key molecule released in acute migraine attacks-Successful translation of...

Migraine is a highly prevalent neurovascular disorder afflicting more than 15% of the global population. Nearly three times more females are afflicted by migraine in the 18-50 years age group, compared to males. Migraine attacks are most often sporadic, but a subgroup of individuals experience a gradual increase in frequency over time; among these, up to 1%-2% of the global population develop chronic migraine. Although migraine symptoms have been known for centuries, the underlying mechanisms remain largely unknown. Two theories have dominated the current thinking-a neurovascular theory and a central neuronal theory with the origin of the attacks in the hypothalamus. During the last decades, the understanding of migraine has markedly advanced. This is supported by the early seminal demonstration of the trigeminovascular reflex 35 years ago and the insight that calcitonin gene-related peptide (CGRP) is a key molecule released in acute migraine attacks. The more recent findings that gepants, small molecule CGRP receptor blockers, and monoclonal antibodies generated against CGRP, or its canonical receptor are useful for the treatment of migraine, are other important issues. CGRP has been established as a key molecule in the neurobiology of migraine. Moreover, monoclonal antibodies to CGRP or the CGRP receptor represent a breakthrough in the understanding of migraine pathophysiology and have emerged as an efficacious prophylactic treatment for patients with severe migraine with excellent tolerability. This review describes the progression of research to reach the clinical usefulness of a large group of molecules that have in common the interaction with CGRP mechanisms in the trigeminal system to alleviate the burden for individuals afflicted by migraine.