1. ¹Department of Anesthesiology & Peri-Operative Medicine, Oregon Health & Science University, Portland, Oregon, USA
2. ²Department of Pathology, Oregon Health & Science University, Portland, Oregon, USA
3. ³Department of Entomology and UCD Cancer Center, University of California, Davis, California, USA
4. ⁴Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas, USA

Correspondence: Dr NJ Alkayed, Department of Anesthesiology & Peri-Operative Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, UHS-2, Portland, Oregon 97239-3098, USA. E-mail: alkayedn@ohsu.edu

Received 31 October 2006; Revised 8 March 2007; Accepted 13 March 2007; Published online 18 April 2007.

Abstract

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.