The Role of Endothelin in the Pathophysiology of Migraine—a Systematic Review

Abstract

We identified 23 articles. Nine studies reported on endothelin-1 plasma concentrations in patients with migraine, eight studies investigated relevant genetic associations, five studies investigated endothelin-1 and spreading depression in animals, and one randomized controlled clinical trial tested the efficacy of an endothelin antagonist in the acute treatment of migraine in patients both with and without aura. Elevated endothelin-1 plasma levels have been reported in the early phase of migraine attacks. Genetic abnormalities related to the endothelin type A receptor have been reported in migraineurs. Endothelin-1 potently induces spreading depression in animals, which may explain the connection between endothelial irritation and migraine aura. Endothelin-1 could be a primary factor in the attack-triggering cascade of migraine attacks with and without aura. Additional studies in humans and animal models are needed to further elucidate the role of endothelin-1 in migraine.

Intravenous Endothelin‐1 Infusion Does Not Induce Aura or Headache in Migraine Patients With Aura

“…A role for ET‐1 in the pathophysiology of migraine has been suggested, primarily based on observations of increased plasma ET‐1 levels in the early phase of migraine attacks with and without aura, studies reporting abnormalities of the ET‐1 and ETA receptor genes in migraine patients, and studies of CSD‐induction in animals using ET‐1 . While the biochemical and genetics studies suggest an involvement of ET‐1 in migraine in general, they do not clearly support involvement of ET‐1 specifically in migraine with aura .…”

“…Migraine aura is a well‐known complication of sclerotherapy for varicose veins and plasma ET‐1 levels are increased in patients following this procedure . A recent, large genome‐wide association study found that migraine is associated with a gene variant that causes the higher expression of the ET‐1 gene and increased binding of ET‐1 to ETA receptors on vascular smooth muscle cells . Collectively, these observations suggest that ET‐1 may trigger CSD, and thus migraine aura symptoms, in patients suffering from migraine with aura.…”

Abstracts and Citations

“…7,8 ET-I antagonists have been studied unsuccessfully in migraine. 9 While it has been suggested that ET-I could be a primary factor in the attack-triggering cascade of migraine with and without aura 6 based on the findings of the present study, the authors state "it seems clear that even very high acute increases in systemic ET-1 levels (exceeding those seen in, eg, acute myocardial infarction) do not affect CBF or oxygen metabolism." Very elevated ET-I levels also do not affect migraine with aura, nor produce more headache than placebo.…”

“…3,4 ET-I potently induces spreading depression in animals, 5 possibly explaining the connection between endothelial irritation and migraine aura. 6 Some migraine persons are reported to harbor ET receptor A gene variants which modulate migraine risk. 7,8 ET-I antagonists have been studied unsuccessfully in migraine.…”

“…2,3 Proposed mechanisms of headache generation include intracranial pressure fluctuations, vascular steal phenomenon, and cortical spreading depression initiation from the cortex location of these lesions. Several case series have demonstrated treatment of the AVM either through embolization, radiosurgery, or microsurgical ablation results in improved headache outcome, [4][5][6] however these lacked placebo controls and are fraught with recall bias.…”