title: The threshold of pentylenetetrazole-induced convulsive seizures, but not that of nonconvulsive seizures, is controlled by the nitric oxide levels in murine brains.
abstract: Alterations in the NO pathway play an important role in the development of convulsive seizures via the glutamatergic and GABAergic systems in acute pentylenetetrazole (PTZ) seizure animals. We previously reported that the background NO levels under physiological conditions negatively regulate convulsive seizures, while excess NO levels under pathologic conditions positively regulate PTZ-induced convulsive seizures. In this study, the NO content in various brain regions after a single dose injection of PTZ was quantitatively and directly measured using the ex vivo X-band electron paramagnetic resonance method with an NO-trapping agent. Experimental data demonstrated the effects of NO on the convulsive seizure threshold: a 1.5-fold increase in the NO level in all brain regions compared to that observed in the control state showed proconvulsive properties without any involvement with nonconvulsive seizures. The distribution of the background NO content in the normal animals was higher in the temporal region of the cerebral cortex, including the amygdala, than in the hippocampus, cerebellum and other regions of the cerebral cortex. However, the levels of NO after the occurrence of acute PTZ-induced convulsive seizures significantly increased by more than 50% in all brain regions, thus suggesting that the NO levels in all brain regions contribute to PTZ-induced convulsions as a seizure threshold. In a pharmacological study, the inhibitor of neuronal NO synthase and antagonists of ionotropic glutamate receptors prevented PTZ-induced convulsions and excessive NO generation. In addition, therapeutic drugs, such as valproate and ethosuximide used to treat generalized seizures not only inhibited the increase in NO generation induced by PTZ, but also prevented both convulsive and nonconvulsive seizures caused by PTZ. We herein provide novel insight into the involvement of NO in PTZ-seizure susceptibility at the whole-animal level.
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Sanuki, Kagawa 769-2193, Japan. mwatanabe@kph.bunri-u.ac.jp
authors.forename: Masatomo
authors.initials: M
authors.lastname: Watanabe
authors.forename: Asuka
authors.initials: A
authors.lastname: Miyai
authors.forename: Sonoko
authors.initials: S
authors.lastname: Danjo
authors.forename: Yu
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Kouichi
authors.initials: K
authors.lastname: Itoh
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003292:Convulsants / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004578:Electron Spin Resonance Spectroscopy; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D010433:Pentylenetetrazole / Q000633:toxicity*; D012640:Seizures / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology*
chemical_list: D003292:Convulsants; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D019335:Nitroarginine; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D010433:Pentylenetetrazole
keywords: (5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine maleate; (E)-(±)-2-amino-4-methyl-5-phospho no-3-pentenoic acid ethyl ester; 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7 -sulfonamide; 3-(2-Chlorophenyl)-2-[2-[6-[(diethylamino) methyl]-2-pyridinyl]ethenyl]-6-fluoro-4(3H)-quinazolinone hydrochloride; 3-bromo-7-nitroindazole; 3Br7NI; AEDs; AMPA; AMPA receptor; AMPAR; Antiepileptic drugs; CBZ; CGP39551; CP465022; DETC; DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; DMSO; EPR; ESM; Electron paramagnetic resonance; GABA(A)R; Generalized seizure; L-NNA; LTG; MK-801; N,N-diethyldithiocarbamate Na; N-methyl-d-aspartate; NBQX; NMDA; NMDA receptor; NMDAR; NO; Neuronal nitric oxide synthase; Nitric oxide; Nω-nitro-l-arginine; PHT; PTZ; Pentylenetetrazole; S-methyl L-thiocitrulline; SMTC; VPA; antiepileptic drugs; carbamazepine; dimethyl sulfoxide; electron paramagnetic resonance; ethosuximide; gamma-aminobutyric acid (A) receptor; lamotrigine; nNOS; neuronal nitric oxide synthase; nitric oxide; pentylenetetrazole; phenytoin; sodium valproate