Sequential changes of nitric oxide levels in the temporal lobes of kainic acid-treated mice following application of nitric oxide synthase inhibitors and phenobarbital

Epilepsy Res. 2005 Jun;65(1-2):81-91. doi: 10.1016/j.eplepsyres.2005.05.001.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Enzyme Inhibitors / pharmacology*
  • Excitatory Amino Acid Agonists / pharmacology*
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Kainic Acid / pharmacology*
  • Male
  • Mice
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase / metabolism
  • Phenobarbital / pharmacology*
  • Spectrometry, Fluorescence / methods
  • Temporal Lobe / drug effects*
  • Temporal Lobe / enzymology

Substances

  • Enzyme Inhibitors
  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Kainic Acid
  • Phenobarbital