Effect of ibuprofen on regional eicosanoid production and neuronal injury after forebrain ischemia in rats

Abstract

Post-ischemic metabolism of arachidonic acid by cyclooxygenase results in the elaboration of numerous eicosanoids and in the generation of free radicals. Accordingly, the effect of cyclooxygenase inhibition by ibuprofen on post-ischemic eicosanoid production and delayed neuronal death was evaluated in Wistar-Kyoto rats subjected to incomplete forebrain ischemia. In control (C) and ibuprofen-treated groups ( n = 5 each), pre- and post-ischemic eicosanoid production in the caudate nucleus (CN) and dorsal hippocampus (HPC) were evaluated by microdialysis. The ibuprofen-treated animals were given ibuprofen, 15 mg/kg i.v., prior to insertion of microdialysis probes. Forebrain ischemia was induced by bilateral carotid artery occlusion (BCAO) for 10 min with simultaneous hypotension to 35 Torr. The concentrations of thromboxane B 2 (TxB 2), 6-keto-PGF 1α and PGF 2α in the microdialysate were measured by radioimmunoassay. In two additional concurrent groups of rats ( >n = 10 each), neuronal injury in the HPC, CN and cortex (parietal, temporal and entorhinal regions) was evaluated histologically three days after 10 min of forebrain ischemia with and without pre-ischemic ibuprofen administration. In the control microdialysis group, levels of TxB 2, 6-keto-PGF 1α and PGF 2α increased in both CN and HPC after probe insertion. These probe related increases were substantially reduced in the ibuprofen group. After ischemia and reperfusion in the control group, the levels of TxB 2 and PGF 2α increased in both CN and HPC. Levels of 6-keto-PGF 1α increased in the CN but not in the HPC. The administration of ibuprofen substantially reduced post-ischemic TxB 2 and PGF 2α levels in both CN and HPC and decreased 6-keto-PGF 1α levels in the CN. The results of these initial microdialysis studies left the possibility that, in the ibuprofen group, the reduction in eicosanoid levels after probe penetration might have influenced the subsequent post-ischemic eicosanoid production. Therefore, in an additional group of animals ( n = 5), ibuprofen was administered after probe insertion. Only PGF 2α levels were measured in this group. Increased levels of PGF 2α comparable to the original control group were detected after probe penetration. Nonetheless, after ibuprofen administration, the pre- and post-ischemic levels of PGF 2α were again significantly reduced. In the histologic evaluation groups, overall neuronal injury was significantly less in the ibuprofen treated animals. This protective effect of ibuprofen was most clearly evident in the CA3 sector of the HPC. The data suggest that metabolism of arachidonic acid by cylooxygenase may contribute to post-ischemic neuronal injury, though the relative contributions of eicosanoids per se and of free radicals remains undefined.