Abstract |
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.
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Authors | K Itoh, M Watanabe |
Journal | Neuroscience
(Neuroscience)
Vol. 159
Issue 2
Pg. 735-43
(Mar 17 2009)
ISSN: 0306-4522 [Print] United States |
PMID | 19162139
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 3-bromo-7-nitroindazole
- Convulsants
- Imidazoles
- Indazoles
- Neuroprotective Agents
- Quinoxalines
- 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline
- 1-(2-trifluoromethylphenyl)imidazole
- Nitric Oxide
- N-Methylaspartate
- Dizocilpine Maleate
- Nitric Oxide Synthase Type I
- Nos1 protein, mouse
- Pentylenetetrazole
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Topics |
- Animals
- Convulsants
- Disease Models, Animal
- Dizocilpine Maleate
(pharmacology)
- Dose-Response Relationship, Drug
- Gene Expression Regulation
(drug effects, genetics)
- Imidazoles
- Indazoles
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- N-Methylaspartate
(therapeutic use)
- Neuroprotective Agents
(therapeutic use)
- Nitric Oxide
(metabolism)
- Nitric Oxide Synthase Type I
(antagonists & inhibitors, deficiency)
- Pentylenetetrazole
- Quinoxalines
(therapeutic use)
- Seizures
(chemically induced, drug therapy, genetics)
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