Unraveling Migraine: Inflammation, Genetics, and Emerging Therapeutic Targets

Abstract

Migraine is a profoundly disabling neurological disorder, long misunderstood and trivialized as a simple headache.
Its true nature, however, is that of a complex brain state, rooted in genetic susceptibility and manifested through
a cascade of inflammatory and neurovascular events. This review article seeks to unravel the intricate threads of
migraine pathophysiology, charting the scientific journey that has transformed our understanding. We begin by
deconstructing the historical “vascular theory,” replacing it with the modern neurovascular model, which places
the brain at the center of the disorder. We then provide a deep dive into the inflammatory cascade of an attack,
detailing the pivotal role of the trigeminovascular system and the neuropeptide Calcitonin Gene-Related Peptide
(CGRP) – a target whose inhibition has revolutionized treatment. The article then explores the genetic architecture
of migraine, from the rare, illuminating channelopathies of Familial Hemiplegic Migraine that provided the first
molecular clues, to the large-scale genomic studies that have painted a picture of a polygenic, hyperexcitable
“migraine brain.” Finally, building on this foundation of knowledge, we survey the exciting horizon of emerging
therapeutic targets that lie beyond CGRP, including the PACAP pathway, novel ion channel modulators, and next
generation serotonin agonists. By weaving together the strands of inflammation and genetics, we present a holistic
view of migraine and look toward a future of increasingly precise and personalized medicine.