Activities of 7-nitroindazole and 1-(2-(trifluoromethylphenyl)-imidazole independent of neuronal nitric-oxide synthase inhibition

J Pharmacol Exp Ther. 2008 May;325(2):357-62. doi: 10.1124/jpet.107.135160. Epub 2008 Feb 12.

Abstract

7-Nitroindazole (NI) is a widely used inhibitor of neuronal nitricoxide synthase (nNOS) used to study the role of the neuronal NO pathway in the nervous system. 7-NI prevents convulsions, including 2-amino-4-methylphosphinobutyric acid (glufosinate)-induced convulsions, in experimental models. Herein, we examined nNOS involvement in glufosinate-induced convulsions and the specificity of 7-NI for nNOS. Another nNOS inhibitor, 1-[2-(trifluoromethyl)phenyl]imidazole (TRIM), inhibited NOS activity in vivo, and it prevented glufosinate-induced convulsions. In contrast, an endothelial NOS inhibitor, N(5)-(1-iminoethyl)-l-ornithine, inhibited NOS activity in vivo, but it did not prevent the convulsions. These results suggest the involvement of nNOS in glufosinate-induced convulsions. However, a nonspecific NOS inhibitor, N(omega)-nitro-l-arginine methyl ester, inhibited NOS activity in vivo, but it failed to prevent glufosinate-induced convulsions. 6-NI and indazole, which did not inhibit NOS activity in vivo, suppressed glufosinate-induced convulsions. Moreover, glufosinate elicited convulsions in nNOS-deficient mice. These results suggest the anticonvulsant effects of 7-NI and TRIM on glufosinate-induced convulsions do not involve nNOS inhibition, instead possibly being related to an undefined property of nitrogen-containing chemical structures.

MeSH terms

  • Aminobutyrates
  • Animals
  • Anticonvulsants / therapeutic use*
  • Brain / enzymology
  • Herbicides
  • Imidazoles / therapeutic use*
  • Indazoles / therapeutic use*
  • Male
  • Mice
  • Mice, Inbred Strains
  • Mice, Mutant Strains
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nitric Oxide Synthase Type I / antagonists & inhibitors
  • Nitric Oxide Synthase Type I / genetics
  • Nitric Oxide Synthase Type I / metabolism
  • Seizures / chemically induced
  • Seizures / drug therapy*
  • Seizures / metabolism

Substances

  • Aminobutyrates
  • Anticonvulsants
  • Herbicides
  • Imidazoles
  • Indazoles
  • 1-(2-trifluoromethylphenyl)imidazole
  • phosphinothricin
  • 6-nitroindazole
  • Nitric Oxide Synthase Type I
  • 7-nitroindazole
  • NG-Nitroarginine Methyl Ester