Sequential changes of nitric oxide levels in the temporal lobes of kainic acid-treated mice following application of nitric oxide synthase inhibitors and phenobarbital.
Although studies have indicated a close relationship between nitric oxide (NO) and kainic acid (KA)-induced seizures, the role of NO in seizures is not fully understood. Here, we quantified NO levels in the brain of KA-treated mice using EPR spectrometry to elucidate the role of NO in KA-induced seizures. KA was administered to mice with or without pretreatment with one of the following: N(G)-nitro-l-arginine methyl ester (l-NAME), an NO synthase (NOS) inhibitor that acts on both endothelial NOS (eNOS) and neuronal NOS (nNOS); 7-nitroindazole (7-NI), which acts more selectively on nNOS in vivo; or the anti-epileptic drug, phenobarbital. To accurately assess NO production during seizure activity, we directly measured KA-induced NO levels in the temporal lobe using an electron paramagnetic resonance NO trapping technique. Our results revealed that the both dose- and time-dependent changes of NO levels in the temporal lobe of KA-treated mice were closely related to the development of seizure activity. l-NAME mediated suppression of the KA-induced NO generation led to enhanced severity of KA-induced seizures. In contrast, 7-NI induced only about 50% suppression and had little effect on seizure severity; while phenobarbital markedly reduced both NO production and seizure severity. These results show that KA-induced neuroexcitation leads to profound increases in NO release to the temporal lobe of KA-treated mice and that NO generation from eNOS exerts an anti-convulsant effect.
Institute for Life Support Technology, Yamagata Promotional Organization of Industrial Technology, 2-2-1 Matsuei, Yamagata 990-2473, Japan.
Naoki
N
Kato
Shinya
S
Sato
Hidekatsu
H
Yokoyama
Takamasa
T
Kayama
Tetsuhiko
T
Yoshimura
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007608:Kainic Acid / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology*; D013050:Spectrometry, Fluorescence / Q000379:methods; D013702:Temporal Lobe / Q000187:drug effects* / Q000201:enzymology
D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D007608:Kainic Acid; D010634:Phenobarbital