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United States Department of Agriculture

Agricultural Research Service

Title: An Epoxide Hydrolase Inhibitor, 12-(3-Adamantan-1-Yl-Ureido) Dodecanoic Acid (Auda), Reduces Ischemic Cerebral Infarct Size in Stroke-Prone Spontaneously Hypertensive Rats.

Authors
item Dorrance, A - MEDICAL COLLEGE GEORGIA
item Rupp, N - MEDICAL COLLEGE GEORGIA
item Pollock, D - MEDICAL COLLEGE GEORGIA
item Newman, John
item Hammock, J - UCD DEPT. OF ENTOMOLOGY
item Imig, J - MEDICAL COLLEGE GEORGIA

Submitted to: Popular Publication
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: August 24, 2005
Publication Date: December 1, 2005
Repository URL: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1444897/pdf/nihms-9480.pdf
Citation: Dorrance, A.M., Rupp, N., Pollock, D.M., Newman, J.W., Hammock, J.D., Imig, J.D. An epoxide hydrolase inhibitor, 12-(3-adamantan-1-yl-ureido) dodecanoic acid (auda), reduces ischemic cerebral infarct size in stroke-prone spontaneously hypertensive rats. Journal Cardiovasc Pharmacol. 2005; 46(6):842-848.

Interpretive Summary: Soluble epoxide hydrolase inhibitors protect cardiovascular tissues by preventing the conversion of fatty acid epoxides to diols. We hypothesized that treatment with these agents would protect stroke-prone rats from cerebral ischemic injury. Six-week old male rats were administered 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA) for 6-weeks, and cerebral ischemia was induced by blocking the middle cerebral artery. The AUDA treated animals had ~15% reduction in the size of the cerebral infarct (i.e. the tissue damaged my oxygen starvation). AUDA treatment increased the passive compliance of the cerebral vessels but did not alter the vascular structure. The results of this study provide novel evidence suggesting that the sEH inhibitor AUDA is a possible therapeutic agent for ischemic stroke.

Technical Abstract: 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.

Last Modified: 7/28/2014
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