Soluble epoxide inhibition is protective against cerebral ischemia via vascular and neural protection

Alexis N. Simpkins, R. Daniel Rudic, Derek A. Schreihofer, Sid Roy, Marlina Manhiani, Hsing Ju Tsai, Bruce D. Hammock, John D. Imig

Research output: Contribution to journalArticle

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Abstract

Inhibition of soluble epoxide hydrolase (SEH), the enzyme responsible for degradation of vasoactive epoxides, protects against cerebral ischemia in rats. However, the molecular and biological mechanisms that confer protection in normotension and hypertension remain unclear. Here we show that 6 weeks of SEH inhibition via 2 mg/day of 12-(3-adamantan-1-ylureido) dodecanoic acid (AUDA) in spontaneously hypertensive stroke-prone (SHRSP) rats protects against cerebral ischemia induced by middle cerebral artery occlusion, reducing percent hemispheric infarct and neurodeficit score without decreasing blood pressure. This level of cerebral protection was similar to that of the angiotensin-converting enzyme inhibitor, enalapril, which significantly lowered blood pressure. SEH inhibition is also protective in normotensive Wistar-Kyoto (WKY) rats, reducing both hemispheric infarct and neurodeficit score. In SHRSP rats, SEH inhibition reduced wall-to-lumen ratio and collagen deposition and increased cerebral microvessel density, although AUDA did not alter middle cerebral artery structure or microvessel density in WKY rats. An apoptosis mRNA expression microarray of brain tissues from AUDA-treated rats revealed that AUDA modulates gene expression of mediators involved in the regulation of apoptosis in neural tissues of both WKY and SHRSP rats. Hence, we conclude that chronic SEH inhibition protects against cerebral ischemia via vascular protection in SHRSP rats and neural protection in both the SHRSP and WKY rats, indicating that SEH inhibition has broad pharmacological potential for treating ischemic stroke.

Original languageEnglish (US)
Pages (from-to)2086-2095
Number of pages10
JournalAmerican Journal of Pathology
Volume174
Issue number6
DOIs
StatePublished - Jun 2009

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Epoxide Hydrolases
lauric acid
Epoxy Compounds
Brain Ischemia
Blood Vessels
Stroke
Inbred WKY Rats
Microvessels
Apoptosis
Blood Pressure
Enalapril
Middle Cerebral Artery Infarction
Middle Cerebral Artery
Angiotensin-Converting Enzyme Inhibitors
Neuroprotection
Collagen
Pharmacology
Hypertension
Gene Expression
Messenger RNA

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Simpkins, A. N., Rudic, R. D., Schreihofer, D. A., Roy, S., Manhiani, M., Tsai, H. J., ... Imig, J. D. (2009). Soluble epoxide inhibition is protective against cerebral ischemia via vascular and neural protection. American Journal of Pathology, 174(6), 2086-2095. https://doi.org/10.2353/ajpath.2009.080544

Soluble epoxide inhibition is protective against cerebral ischemia via vascular and neural protection. / Simpkins, Alexis N.; Rudic, R. Daniel; Schreihofer, Derek A.; Roy, Sid; Manhiani, Marlina; Tsai, Hsing Ju; Hammock, Bruce D.; Imig, John D.

In: American Journal of Pathology, Vol. 174, No. 6, 06.2009, p. 2086-2095.

Research output: Contribution to journalArticle

Simpkins, AN, Rudic, RD, Schreihofer, DA, Roy, S, Manhiani, M, Tsai, HJ, Hammock, BD & Imig, JD 2009, 'Soluble epoxide inhibition is protective against cerebral ischemia via vascular and neural protection', American Journal of Pathology, vol. 174, no. 6, pp. 2086-2095. https://doi.org/10.2353/ajpath.2009.080544
Simpkins, Alexis N. ; Rudic, R. Daniel ; Schreihofer, Derek A. ; Roy, Sid ; Manhiani, Marlina ; Tsai, Hsing Ju ; Hammock, Bruce D. ; Imig, John D. / Soluble epoxide inhibition is protective against cerebral ischemia via vascular and neural protection. In: American Journal of Pathology. 2009 ; Vol. 174, No. 6. pp. 2086-2095.
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