Soluble epoxide hydrolase: a novel therapeutic target in stroke.
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.
Zhang
Wenri
W
Department of Anesthesiology & Peri-Operative Medicine, Oregon Health & Science University, Portland, Oregon 97239, USA.
Koerner
Ines P
IP
Noppens
Ruediger
R
Grafe
Marjorie
M
Tsai
Hsing-Ju
HJ
Morisseau
Christophe
C
Luria
Ayala
A
Hammock
Bruce D
BD
Falck
John R
JR
Alkayed
Nabil J
NJ
D000218:Adamantane / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives; D001345:Autoradiography; D001812:Blood-Brain Barrier; D015153:Blotting, Western; D002196:Capillaries / Q000473:pathology; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020768:Middle Cerebral Artery / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000302:isolation & purification; D020521:Stroke / Q000188:drug therapy* / Q000201:enzymology*; D014508:Urea / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
C503559:12-(3-adamantan-1-ylureido)dodecanoic acid butyl ester; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D014508:Urea; D004851:Epoxide Hydrolases; D000218:Adamantane; D000983:Antipyrine; C008135:iodoantipyrine