Arachidonic acid P450 metabolites epoxyeicosatrienoates (EETs) exhibit a wide array of biological actions in multiple tissues and organ systems, all of which are potentially beneficial in stroke. This includes vasodilation, cytoprotection, and suppression of platelet aggregation and post-ischemic inflammation. The biological activity of EETs is terminated via their metabolism into dihydroxyeicosatrienoates (DHETs) by the enzyme soluble epoxide hydrolase (sEH, Figure). Therefore, sEH inhibition increases EETs levels in brain and protects against ischemic brain injury. As such, inhibition of sEH represents a novel multi-mechanism approach for the treatment of stroke, offering the ability to harness EETs’ broad protective actions by pharmacologically targeting a single enzyme. GSK2256294 is an FDA-approved sEH inhibitor that has been used in clinical trials for multiple indications, including subarachnoid hemorrhage.

Schematic representation of the mechanism of action of soluble epoxide hydrolase inhibitor (sEH) GSK2256294

Clinical Trials Using Soluble Epoxide Hydrolase Inhibitor GSK2256294