Soluble Epoxide Hydrolase Blockade after Stroke Onset Protects Normal but Not Diabetic Mice

Figures

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  Figure 1. tAUCB administration at reperfusion reduces infarct volume. Mice were given 0.5, 1.0, 1.5 or 2.0 mg/kg tAUCB i.p. at the time of vessel reperfusion, hemispheric infarct was assessed 24 h later by TTC. (A) The highest dose tested, 2.0 mg/kg, reduced infarct (* p < 0.05, 2.0 mg/kg vs. vehicle); lower doses of tAUCB did not significantly affect infarct volume. n = 4–7/group. (B) Representative TTC images coronal brain sections from mice treated with 2.0 mg/kg tAUCB dose.

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  Figure 2. tAUCB administered during vessel occlusion reduces infarct volume in non-diabetic, but not in diabetic mice. tAUCB, 2 mg/kg, was administered i.p. 30 min into 1 h MCA occlusion, infarct was assessed by TTC 24 h later. (A) Representative TTC images of coronal sections from non-diabetic (left) and diabetic (right) mouse brains. Infarct volume in (B) cortex, (C) caudate putamen, and (D) hemisphere of non-diabetic (left) and diabetic (right) mice, n = 7–8, * p < 0.05.

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  Figure 3. tAUCB does not alter blood glucose concentration in diabetic mice. Mice on high-fat diet injected with NA and STZ develop a diabetic phenotype: (A) Mice were placed on a high-fat diet for 7 weeks, and injected with NA and STZ (indicated by first vertical red line) to induce type 2 diabetes, body weight increased following 1 week on high-fat diet, and persisted throughout (p < 0.0001 vs. week 0, n = 16). (B) After 6 weeks on high-fat diet (indicated by second vertical red line), and 2 weeks following NA and STZ injections, glucose tolerance testing revealed hyperglycemia at baseline (time 0), and impaired glucose clearance with blood glucose concentration remaining elevated 2 h after ingestion of 2 g/kg glucose (**** p < 0.0001 vs. time 0, n = 16). (C) Blood glucose concentration measured 24 h following tAUCB administration and MCAO show no difference between tAUCB and vehicle groups in DM2 mice (n/s, n = 8/group).

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  Figure 4. tAUCB selectively increases plasma 14,15-EET and 14,15-EET:DHET ratio in diabetic mice. Plasma concentrations of (a) EET, (b) DHET, (c) EET:DHET ratio and (d) HETE regioisomers assessed by LC-MS/MS 24 h following tAUCB administration and MCAO. Plasma 14,15-EET concentration and 14,15-EET:DHET ratio, are elevated in the tAUCB group compared to vehicle (** p < 0.01, * p < 0.05, n = 7–8/group).

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  Figure 5. CBF is unaltered by tAUCB. CBF, assessed by laser Doppler probe, during and immediately after MCA occlusion does not differ between vehicle or tAUCB treated mice in either (A) non-diabetic, or (B) diabetic mice (BL, baseline; RP5’, 5 min reperfusion; n= 7–8/group).