title: 7-Nitroindazole, a nitric oxide synthase inhibitor, enhances the anticonvulsive action of ethosuximide and clonazepam against pentylenetetrazol-induced convulsions.
abstract: The interaction of 7-nitroindazole (7-NI), a nitric oxide synthase (NOS) inhibitor, with the protective activity of conventional antiepileptics against pentylenetetrazol (PTZ)-induced seizures was tested in mice. Alone, 7-nitroindazole (up to 50mg/kg) was ineffective in this model of experimental epilepsy. However, it potentiated the anticonvulsive activity of ethosuximide and clonazepam, significantly reducing their ED50S against PTZ-induced convulsions (from 144 to 76 mg/kg, and from 0.05 to 0.016 mg/kg, respectively). Conversely, the protective actions of valproate and phenobarbital were not affected by the NOS inhibitor. Since the nitric oxide precursor, L-arginine, did not reverse the action of 7-NI on ethosuximide or clonazepam, an involvement of central NO does not seem probable. Neither ethosuximide nor clonazepam, administered at their ED50S (144 and 0.05 mg/kg, respectively), produced significant adverse effects as regards motor coordination (chimney test) and long-term memory (passive avoidance task). Also 7-NI (50 mg/kg) and its combinations with ethosuximide and clonazepam (providing a 50% protection against PTZ-evoked seizures) did not disturb motor and mnemonic performance in mice. The interaction at the pharmacokinetic level does not seem probable, at least in the case of ethosuximide, because the NOS inhibitor did not interfere with its plasma or brain concentrations.
authors: Department of Pharmacology and Toxicology, Medical University, Poland.
authors: K K
authors: KK
authors: Borowicz
authors: J
authors: J
authors: Luszczki
authors: Z
authors: Z
authors: Kleinrok
authors: S J
authors: SJ
authors: Czuczwar
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D002998:Clonazepam / Q000494:pharmacology; D004195:Disease Models, Animal; D004347:Drug Interactions / Q000502:physiology*; D004831:Epilepsies, Myoclonic / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D005013:Ethosuximide / Q000493:pharmacokinetics; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009048:Motor Skills / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000187:drug effects* / Q000378:metabolism; D010433:Pentylenetetrazole / Q000494:pharmacology; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D000927:Anticonvulsants; D007191:Indazoles; D018696:Neuroprotective Agents; D009569:Nitric Oxide; D002998:Clonazepam; D005013:Ethosuximide; D019001:Nitric Oxide Synthase; C080122:7-nitroindazole; D010433:Pentylenetetrazole