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P450 arachidonic acid epoxides are endogenous neuroprotectants in experimental cerebral ischemia


, : P450 arachidonic acid epoxides are endogenous neuroprotectants in experimental cerebral ischemia. Society for Neuroscience Abstracts 27(1): 549

We have shown that cerebral ischemic preconditioning (IPC) induces expression of P450 AA epoxygenase, associated with tissue protection from stroke. We tested the hypothesis that epoxyeicosatrienoic acids (EETs), the P450 metabolites of AA, are neuroprotective. Thus, suppressing their formation by inhibiting brain P450 epoxygenase exacerbates stroke injury while augmenting their level by inhibiting EETs hydrolysis mimics the protection acquired by IPC. Adult male Wistar rats were either implanted with microdialysis probes for HPLC analysis of EETs in CSF or received one of two treatments 30 min prior to 2-hour middle cerebral artery occlusion (MCAO): 1) intracisternal injection of N-methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide (MS-PPOH, 100mul of 20 mumol/L) to inhibit brain P450 epoxygenase or 2) intraperitoneal injection of 4-phenylchalcone oxide (4-PCO, 5 mg/kg) to inhibit epoxide hydrolase. Endogenous EETs formation was detected by HPLC in micro-dialysate from animals undergoing ischemia (n=8). Infarct size at 22 hours of reperfusion was reduced by 4-PCO (n=7 vs n=7 vehicle) from 39+-9 to 14+-7% in cerebral cortex and from 69+-4 to 43+-11% in striatum. Cortical and striatal infarcts were increased by MS-PPOH (n=8 vs n=9 vehicle) by 70 and 30%, respectively. These findings suggest a role for P450 epoxygenase and EETs in endogenous protection against cerebral ischemia.

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