Inhibition of soluble
epoxide hydrolase (SEH), the
enzyme responsible for degradation of vasoactive
epoxides, protects against
cerebral ischemia in rats. However, the molecular and
biological mechanisms that confer protection in normotension and
hypertension remain unclear. Here we show that 6 weeks of SEH inhibition via 2 mg/day of 12-(3-adamantan-1-yl-ureido)
dodecanoic acid (AUDA) in spontaneously hypertensive
stroke-prone (SHRSP) rats protects against
cerebral ischemia induced by
middle cerebral artery occlusion, reducing percent hemispheric
infarct and neurodeficit score without decreasing blood pressure. This level of cerebral protection was similar to that of the
angiotensin-converting enzyme inhibitor,
enalapril, which significantly lowered blood pressure. SEH inhibition is also protective in normotensive Wistar-Kyoto (WKY) rats, reducing both hemispheric
infarct and neurodeficit score. In SHRSP rats, SEH inhibition reduced wall-to-lumen ratio and
collagen deposition and increased cerebral microvessel density, although AUDA did not alter middle cerebral artery structure or microvessel density in WKY rats. An apoptosis
mRNA expression microarray of brain tissues from AUDA-treated rats revealed that AUDA modulates gene expression of mediators involved in the regulation of apoptosis in neural tissues of both WKY and SHRSP rats. Hence, we conclude that chronic SEH inhibition protects against
cerebral ischemia via vascular protection in SHRSP rats and neural protection in both the SHRSP and WKY rats, indicating that SEH inhibition has broad pharmacological potential for treating
ischemic stroke.