The P450
eicosanoids epoxyeicosatrienoic
acids (EETs) are produced in brain and perform important
biological functions, including protection from ischemic injury. The beneficial effect of EETs, however, is limited by their metabolism via soluble
epoxide hydrolase (sEH). We tested the hypothesis that sEH inhibition is protective against ischemic brain damage in vivo by a mechanism linked to enhanced cerebral blood flow (CBF). We determined expression and distribution of sEH immunoreactivity (IR) in brain, and examined the effect of sEH inhibitor 12-(3-adamantan-1-yl-ureido)-dodecanoic
acid butyl
ester (
AUDA-BE) on CBF and
infarct size after experimental
stroke in mice. Mice were administered a single
intraperitoneal injection of
AUDA-BE (10 mg/kg) or vehicle at 30 mins before 2-h
middle cerebral artery occlusion (MCAO) or at reperfusion, in the presence and absence of P450 epoxygenase inhibitor N-methylsulfonyl-6-(2-propargyloxyphenyl)
hexanamide (
MS-PPOH). Immunoreactivity for sEH was detected in vascular and non-vascular brain compartments, with predominant expression in neuronal cell bodies and processes. 12-(3-Adamantan-1-yl-ureido)-dodecanoic
acid butyl
ester was detected in plasma and brain for up to 24 h after
intraperitoneal injection, which was associated with inhibition of sEH activity in brain tissue. Finally,
AUDA-BE significantly reduced
infarct size at 24 h after MCAO, which was prevented by
MS-PPOH. However, regional CBF rates measured by
iodoantipyrine (IAP) autoradiography at end
ischemia revealed no differences between
AUDA-BE- and vehicle-treated mice. The findings suggest that sEH inhibition is protective against ischemic injury by non-vascular mechanisms, and that sEH may serve as a therapeutic target in
stroke.