Abstract W P363: Mechanism of Protection by Soluble Epoxide Hydrolase Inhibition in Type 2 Diabetic Stroke

Abstract

Hyperglycemia worsens stroke, yet rigorous glycemic control does not improve neurologic outcome. An alternative is to target downstream molecular mediators triggered by hyperglycemia. Soluble epoxide hydrolase (sEH) is a potential mediator of ischemic injury via its metabolism of neuroprotective epoxyeicosatrienoic acids (EETs). We previously demonstrated that sEH mRNA is overexpressed in type 1 diabetic (T1D) mice, and specific sEH blockade protects the brain from the deleterious effect of T1D on stroke. We tested the hypothesis that type 2 diabetes (T2D) exacerbates injury following middle cerebral artery occlusion (MCAO) in part by up-regulating expression of EPHX2 (gene encoding for sEH) and decreasing brain concentrations of neuroprotective EETs. T2D was produced by combined high-fat diet, nicotinamide and streptozotocin in male C57BL/6J mice. T2D and control mice were treated with vehicle or the sEH inhibitor trans-4-[4-(3-Adamantan-1-yl-ureido) -cyclohexyloxy]-benzoic acid (t-AUCB; 1mg/kg, i.p., 7 days), then subjected to 60-min MCAO. Compared to normal chow-fed mice, high fat diet-fed mice exhibited a 1.7 fold upregulation of EPHX2 mRNA in brain (p<0.05, n=7). T2D mice had increased blood glucose levels compared to control mice before, during and after MCAO (p<0.001, n=4-5). Relative laser-Doppler perfusion of the MCA territory after reperfusion was decreased in T2D mice compared to controls (p<0.05, n= 4-5). Vehicle-treated T2D mice sustained larger cortical infarcts than vehicle-treated control mice (p<0.05, n=5-7). t-AUCB decreased fasting glucose levels at baseline and throughout ischemia (p<0.001, n=4-5) and improved cortical perfusion after MCAO (p<0.001, n=4-5) in T2D mice. In line with these improvements, t-AUCB significantly reduced infarct size in T2D mice (p<0.05 vs. T2D vehicle, n= 5-7). We conclude that increasing EETs bioavailability via sEH inhibition improves stroke outcome in T2D in part by improving glycemic status and improving post-ischemic reperfusion in the ischemic territory.