Article

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

Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226, USA.
American Journal Of Pathology (Impact Factor: 4.6). 06/2009; 174(6):2086-95. DOI: 10.2353/ajpath.2009.080544
Source: PubMed

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-yl-ureido) 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.

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Available from: John D Imig, Dec 21, 2013
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    • "EETs mediate this protection, as inhibition of CYP epoxygenase (the EET synthesis enzyme) prevents sEH benefits (Zhang et al., 2007, 2008). This protective mechanism increases astrocyte survival (Liu and Alkayed, 2005), elevates antiapoptotic factors (Simpkins et al., 2009) and increases neurovascular coupling (Zhang et al., 2007, 2008). Conversely, 20-HETE is elevated during ischemia (Tanaka et al., 2007), and inhibition of 20-HETE production is also neuroprotective in rodent models (Miyata et al., 2005; Poloyac et al., 2006; Tanaka et al., 2007; Dunn et al., 2008; Renic et al., 2009). "
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    • "Consistent with the previous reports, data in the current study demonstrated that rAAV-CYP2J2 treatment resulted in prolonged elevation of renal CYP2J2 expression and significantly lowered blood pressure in 5/6- nephrectomized rats. In addition, it should be mentioned that inhibition of soluble epoxide hydrolase (sEH) to increase the level of EETs also has an antihypertensive effect, although the effects are model dependent (Fornage et al., 2002; Simpkins et al., 2009). The pathogenesis of hypertension in chronic renal failure is tremendously complex (Klahr and Morrissey, 2003), and the precise molecular mechanisms of EETs on blood pressure control and renal function require further investigation. "
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    • "A possible reason could be a low in vivo potency of the AR9281 compound at the dosage used (AR9281 is 10 times less potent than t-AUCB). Nonetheless, animal studies suggested that pharmacologic sEH blockade or genetic deficiency of the enzyme exert cardiovascular protective effects on brain, heart and kidneys and sEH blockers may be useful for treating pulmonary hypertension and in the prevention of atherosclerosis (Imig & Hammock 2009, Simpkins et al. 2009, Wang et al. 2010). In conclusion, a pharmacologic activation of endothelial KCa channels as well as pharmacologic enhancement of the availability of endothelial relaxing factors such as EETs, at least under some circumstances, could be therapeutic options to treat cardiovascular disease (Fig. 7). Figure 7 Schematic illustration of the action of the KCa3.1/KCa2.3 "
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