An epoxide hydrolase inhibitor, 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA), reduces ischemic cerebral infarct size in stroke-prone spontaneously hypertensive rats.
Soluble epoxide hydrolase (sEH) inhibitors have been demonstrated to have cardiovascular protective actions. This hydrolase enzyme converts fatty acid epoxides to their corresponding diols, and this conversion can alter the biologic activity of these metabolites. We hypothesized that 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA), a sEH inhibitor, would protect stroke-prone spontaneously hypertensive rats from cerebral ischemia. AUDA was administered to 6-week-old male rats for 6 weeks, during which blood pressure was measured by telemetry. Cerebral ischemia was induced by middle cerebral artery occlusion, the size of the cerebral infarct was assessed after 6 hours of ischemia, and the results were expressed as a percentage of the hemisphere infarcted (%HI). Vascular structure and function were assessed using a pressurized arteriograph. Plasma levels of AUDA at the end of the treatment period averaged 5.0 +/- 0.4 ng/mL, and the urinary excretion rate was 99 +/- 21 ng/d. AUDA-treated rats had significantly smaller cerebral infarcts than control rats (36 +/- 4% vs 53 +/- 4% HI, treated versus control, P < 0.05, n = 6). This difference occurred independently of changes in blood pressure. AUDA treatment increased the passive compliance of the cerebral vessels but had no effect on vascular structure. The results of this study provide novel evidence suggesting that the sEH inhibitor AUDA is a possible therapeutic agent for ischemic stroke.
Dorrance
Anne M
AM
Department of Physiology, Medical College of Georgia, Augusta, Georgia 30912, USA. adorrance@mail.mcg.edu
Rupp
Nicole
N
Pollock
David M
DM
Newman
John W
JW
Hammock
Bruce D
BD
Imig
John D
JD
D000218:Adamantane / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy*; D002544:Cerebral Infarction / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D004852:Epoxy Compounds / Q000097:blood; D006973:Hypertension / Q000150:complications*; D007850:Lauric Acids / Q000378:metabolism / Q000627:therapeutic use*; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR
C504897:12-(3-adamantan-1-ylureido)dodecanoic acid; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D007850:Lauric Acids; D018696:Neuroprotective Agents; D004851:Epoxide Hydrolases; D000218:Adamantane