Inducible Nitric Oxide Synthase And Cyclooxygenase-2 Gene Expression In Neonatal Rats Contribute To Hypoxic-Ischemic Brain Damage

Objective Hypoxic-ischemic brain damage is followed by an inflammatory reaction that plays a role in the evolution of the tissue damage. Inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) are induced during inflammation and participate in inflammation-mediated cytotoxicity. We studied whether COX-2 and iNOS are induced in neonatal rats after hypoxic-ischemic brain damage and if so, whether such expression contribute to ischemic brain damage in neonatal rats. Methods Seven-day-old Wistar rat pups (n=6 to 8 per group) were subjected to left carotid artery occlusion followed by 2 h of hypoxic exposure (8% oxygen).The ischemic cortex was sampled for analysis 6h, 24h, 48h, and 5d after the onset of hypoxia-ischemia. iNOS and COX-2 mRNA was determined by the reverse-transcription PCR. Microscopical changes were observed. Results iNOS mRNA was not observed in control group. The iNOS mRNA appeared in ischemic brain at 6h, peaked between 24~48h significantly (P<0.01vs.6h), and subside at 5d. COX-2 mRNA was upregulated in the ischemic cortex, beginning 6 h after hypoxia-ischemia, reached its greatest expression at 24 h significantly(P<0.01 vs. control), and returned to normal level at 5d. There was anassociation between upregulation of iNOS and COX-2 mRNA and the extent of ischemic neuronal damage.Conclusions Hypoxic-ischemic brain damage is associated with expression of both inducible nitric oxide synthase and cyclooxygenase-2. The data implicate iNOS and COX-2 in the mechanisms of delayed neuronal death and provide the rational for neiiroprotective strategies employing iNOS and COX-2 inhibitors.