The selective cyclooxygenase‐2 inhibitor rofecoxib reduces kainate‐induced cell death in the rat hippocampus

Abstract

Treatment of male Sprague–Dawley rats with kainic acid (10 mg/kg, i.p.) triggered limbic seizures in 60% of the animals starting within 30 min and lasting for about 6 h. Cyclooxygenase‐2 (COX‐2) mRNA was strongly induced in the pyramidal cells of the hippocampus, in the amygdala and the piriform cortex after 8 h, as shown by in situ hybridization, and returned to control levels after 72 h. At this time marked cell loss occurred in the CA1–CA3 areas of the hippocampus. We hypothesize that rofecoxib, a selective COX‐2 inhibitor, might abbreviate the late neurotoxicity, possibly associated with COX‐2 induction. Animals which developed seizures were treated for 3 days with rofecoxib (10 mg/kg, i.p., n = 12) starting 6 or 8 h after kainic acid injection. Histological staining of viable cells confirmed that rofecoxib treatment selectively diminished cell loss in the hippocampus. The TdT‐mediated dUTP nick end labelling (TUNEL) technique was used to estimate delayed cell death. Abundant TUNEL‐positive cells were detected in seizure rats 72 h after kainic acid injection in pyramidal cells of the hippocampus (CA1–CA3), in cells of the thalamus, the amygdala and the piriform cortex. Treatment with rofecoxib selectively and significantly (P < 0.05) attenuated the number of TUNEL‐positive cells in the hippocampus, whereas the cells of the thalamus, amygdala and piriform cortex were not protected. Therefore we conclude that COX‐2 might contribute to cell death of pyramidal cells of the hippocampus as a consequence of limbic seizures.