Effect of ibuprofen on regional eicosanoid production and neuronal injury after forebrain ischemia in rats.
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 B2 (TxB2), 6-keto-PGF1 alpha and PGF2 alpha 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 TxB2, 6-keto-PGF1 alpha and PGF2 alpha 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 TxB2 and PGF2 alpha increased in both CN and HPC. Levels of 6-keto-PGF1 alpha increased in the CN but not in the HPC. The administration of ibuprofen substantially reduced post-ischemic TxB2 and PGF2 alpha levels in both CN and HPC and decreased 6-keto-PGF1 alpha 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 PGF2 alpha levels were measured in this group. Increased levels of PGF2 alpha comparable to the original control group were detected after probe penetration. Nonetheless, after ibuprofen administration, the pre- and post-ischemic levels of PGF2 alpha 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.(ABSTRACT TRUNCATED AT 400 WORDS)
Patel
P M
PM
Department of Anesthesiology, University of California, San Diego.
Drummond
J C
JC
Sano
T
T
Cole
D J
DJ
Kalkman
C J
CJ
Yaksh
T L
TL
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000818:Animals; D001835:Body Weight / Q000502:physiology; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D002421:Caudate Nucleus / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D003956:Dialysis; D015237:Dinoprost / Q000096:biosynthesis; D015777:Eicosanoids / Q000096:biosynthesis*; D006624:Hippocampus / Q000473:pathology; D007052:Ibuprofen / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D016548:Prosencephalon / Q000473:pathology*; D051381:Rats; D011921:Rats, Inbred WKY; D013238:Stereotaxic Techniques
D015777:Eicosanoids; D015121:6-Ketoprostaglandin F1 alpha; D015237:Dinoprost; D007052:Ibuprofen