Paradoxical facilitation of pentylenetetrazole-induced convulsion susceptibility in mice lacking neuronal nitric oxide synthase

• Published in: Neuroscience Vol. 159; no. 2; pp. 735 - 743
• Main Authors: Itoh, K, Watanabe, M
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 17.03.2009; Elsevier
• Subjects: Animals; Biological and medical sciences; Convulsants; Disease Models, Animal; Dizocilpine Maleate - pharmacology; Dose-Response Relationship, Drug; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; generalized epilepsy model; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Imidazoles; Indazoles; ionotropic glutamate receptor knockout mice; kindling; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; N-Methylaspartate - therapeutic use; Nervous system (semeiology, syndromes); Neurology; Neuroprotective Agents - therapeutic use; Nitric Oxide - metabolism; Nitric Oxide Synthase Type I - antagonists & inhibitors; Nitric Oxide Synthase Type I - deficiency; nNOS inhibitors; Pentylenetetrazole; Quinoxalines - therapeutic use; Seizures - chemically induced; Seizures - drug therapy; Seizures - genetics; Vertebrates: nervous system and sense organs; eNOS; AMPA; DMSO; TRIM; aminoguanidine; DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; endothelial nitric oxide synthase; iNOS; postsynaptic density 95; nitric oxide synthase; GABA AR; PBN; nitric oxide; AG; gamma-aminobutyric acid A receptor; l-NNA; N-tert-butyl-α-phenylnitrone; 1-[2-(trifluoromethyl)phenyl] imidazole; 3Br7NI; NOS; nNOS; NMDAR; GAPDH; (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine maleate; NO; MK-801 (dizocilpine); CGP39551; cGMP; inducible nitric oxide synthase; 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide; dimethyl sulfoxide; PTZ; pentylenetetrazole; NMDA; N-methyl-D-aspartate; glyceraldehyde-3-phosphate dehydrogenase; nNOS inhibitors; generalized epilepsy model; (E)-(±)-2-amino-4-methyl-5-phospho no-3-pentenoic acid ethyl ester; neuronal nitric oxide synthase; AMPAR; cyclic guanosine 3′,5′-monophosphate; AMPA receptor; PSD95; ionotropic glutamate receptor knockout mice; NMDA receptor; Nω-nitro- l -arginine; 3-bromo-7-nitroindazole; kindling; NBQX; Ionotropic receptor; Nervous system diseases; Enzyme; Kindling; Epilepsy; Rodentia; Glutamate receptor; Nitric-oxide synthase; Cerebral disorder; Vertebrata; Sensitivity; Mammalia; Mouse; Animal; Central nervous system disease; Models; Oxidoreductases; Mutation
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2008.12.040

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 α 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.