SYSTEMIC ADMINISTRATION OF N(OMEGA)NITRO-L-ARGININE METHYL-ESTER AND INDOMETHACIN REDUCES THE ELEVATION OF BRAIN PGE(2) CONTENT AND PREVENTS SEIZURES AND HIPPOCAMPAL DAMAGE EVOKED BY LICL AND TACRINE IN RAT

Administration of tacrine (5 mg/kg i.p.), an anticholinesterase agent, in rats pretreated (24 h beforehand) with lithium chloride (LiCl; 12 mEq/kg i.p.) enhances the expression of neuronal nitric oxide (NO) syn thase (NOS), increases NO, and causes seizures and hippocampal damage. Here we report immunohistochemistry evidence showing that in rat LiCl and tacrine enhance the expression of cyclooxygenase type 2 (COX-2) e nzyme protein in the dorsal hippocampus and elevate brain PGE(2) conte nt during the preconvulsive period. The latter effect, but not enhance d COX-2 expression, is inhibited by previous (30 min before tacrine) a dministration of N-omega-nitro-L-arginine-methyl ester (L-NAME; 10 mg/ kg i.p.), an inhibitor of NO synthesis, thus implicating NO in the mec hanism of stimulation of COX activity leading to elevation of brain PG E(2) content. Indomethacin (10 mg/kg given i.p. 30 min before tacrine) , an inhibitor of COX activity, prevented brain PGE(2) elevation and a bolished the expression of seizures and hippocampal damage thus suppor ting a role for this metabolite of the arachidonic acid cascade in the mechanisms of LiCl and tacrine-evoked neurotoxicity in rat. (C) 1998 Academic Press.