dizocilpine-maleate and 1-(2-trifluoromethylphenyl)imidazole

The major aim of this study was to elucidate the relationship between nitric oxide (NO) and generalized epilepsy. Mice lacking the neuronal nitric oxide synthase (nNOS) gene (nNOS(-/-)) were used in this study to determine the relationship between nNOS alpha and NO in pentylentetrazole (PTZ)-induced convulsions. nNOS(-/-) mice exhibited severe convulsions following injection with a subconvulsive dose of PTZ (40 mg/kg i.p.) and convulsive doses were lethal in all of the mice (60 mg/kg i.p.) following tonic convulsions. The results were confirmed by using selective nNOS inhibitors in wild-type (nNOS(+/+)) mice. The higher doses of the nNOS inhibitors 1-[2-(trifluoromethyl)phenyl] imidazole (TRIM) and 3-bromo-7-nitroindazole (3Br7NI) inhibited clonic-tonic convulsions induced by a convulsive dose of PTZ (60 mg/kg) in nNOS(+/+) mice. In contrast, either TRIM or 3Br7NI at lower doses enhanced convulsions following injection with a subconvulsive dose of PTZ (40 mg/kg) in nNOS(+/+) mice similar to nNOS(-/-) mice treated with PTZ. Such a proconvulsant effect was observed in nNOS(+/+) mice pretreated with nNOS inhibitors but not other NOS inhibitors. These results indicate that NO may be regarded as an anticonvulsant or a proconvulsant substance in relation to convulsions induced by PTZ in mice. Pretreatment with N-methyl-d-aspartate (NMDA) receptor antagonists (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine maleate (MK-801), (E)-(+/-)-2-amino-4-methyl-5-phospho no-3-pentenoic acid ethyl ester, CGP39551) and DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist (2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide, NBQX) inhibited a subconvulsive dose of PTZ-induced convulsions in nNOS(-/-) mice, demonstrating that convulsions induced by PTZ are modulated by endogenous NO production and ionotropic glutamate receptor-mediated stimulation. These results suggest a negative or positive modulation of neuronal interactions by basal or enhanced NO production, respectively.

Topics: Animals; Convulsants; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Gene Expression Regulation; Imidazoles; Indazoles; Mice; Mice, Inbred C57BL; Mice, Knockout; N-Methylaspartate; Neuroprotective Agents; Nitric Oxide; Nitric Oxide Synthase Type I; Pentylenetetrazole; Quinoxalines; Seizures