Abstract
Inhibition of soluble epoxide hydrolase (sEH) has been shown to reduce infarct volume after transient middle cerebral artery occlusion (MCAO), but to the best of our knowledge, has not been tested in a model of permanent MCAO. Here, we produced permanent MCAO in male C57Bl6 mice by coagulation of the distal MCA and administered vehicle or the sEH inhibitor TPPU [1‐trifluoromethoxyphenyl‐3‐(1‐propionylpiperidin‐4‐yl)urea] at 90 min after MCAO and daily over the subsequent 6 days. Protein expression of sEH was measured at 1, 3, 7, 14, and 28 days after MCAO and was found to nearly double at 3 and 7 days after MCAO before decreasing at 14 days and returning to the surgical sham control levels at 28 days. Tissue activity of sEH tripled 3 days after MCAO and was attenuated by 2.7, 64.5, and 62.6% with ip administration of 0.3, 1, and 3 mg/kg/day TPPU. Subsequent experiments used a dose of 1 mg/kg/day. Infarct volume was significantly decreased from 23.9±8.2% (±SD) in the vehicle group to 16.6±4.1% in the TPPU group (P<0.01, n=13). Likewise, sensorimotor function, as assessed by the time to recognize adhesive tape on the affected paw, was significantly improved at 1, 3, 7, and 14 days after MCAO in the TPPU‐treated group. Tissue cytokine mRNA was measured at 1, 3, and 7 days after MCAO. Relative to vehicle treatment, TPPU attenuated the increase in IL‐1β and TNFα mRNA at 3 days after MCAO and augmented the increase in IL‐10 mRNA at 7 days after MCAO. These results indicate that ischemic neuroprotection by administration of a sEH inhibitor does not require reperfusion and that TPPU limits expression of pro‐inflammatory cytokine expression and augments the delayed increase in reparative IL‐10 expression after permanent focal cerebral ischemia.Support or Funding InformationSupported by NIH NS060703This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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