Systemic administration of N omega-nitro-L-arginine methyl ester and indomethacin reduces the elevation of brain PGE2 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) synthase (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) enzyme protein in the dorsal hippocampus and elevate brain PGE2 content during the preconvulsive period. The latter effect, but not enhanced COX-2 expression, is inhibited by previous (30 min before tacrine) administration 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 mechanism of stimulation of COX activity leading to elevation of brain PGE2 content. Indomethacin (10 mg/kg given i.p. 30 min before tacrine), an inhibitor of COX activity, prevented brain PGE2 elevation and abolished the expression of seizures and hippocampal damage thus supporting a role for this metabolite of the arachidonic acid cascade in the mechanisms of LiCl and tacrine-evoked neurotoxicity in rat.
Paoletti
A M
AM
Experimental Neurobiology Center Mondino-Tor Vergata, Rome, Italy.
Piccirilli
S
S
Costa
N
N
Rotiroti
D
D
Bagetta
G
G
Nisticò
G
G
D000818:Animals; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007213:Indomethacin / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D018021:Lithium Chloride / Q000633:toxicity*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D013619:Tacrine / Q000633:toxicity*
D002800:Cholinesterase Inhibitors; D007527:Isoenzymes; D013619:Tacrine; D019001:Nitric Oxide Synthase; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D018021:Lithium Chloride; D015232:Dinoprostone; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin