title: Anticonvulsant action of indazole.
abstract: Here we report that indazole is characterized as a potential anticonvulsant, inhibiting pentylenetetrazole-, electroshock- and strychnine-induced convulsions in mice (ED50's: 39.9, 43.2 and 82.4 mg/kg, respectively) but not bicuculline- and picrotoxin-induced convulsions. The median toxic dose (TD(50)) of indazole was 52.3 mg/kg by the minimal motor impairment test. Therefore, nontoxic doses produced anticonvulsant activity against pentylenetetrazole- and electroshock-induced seizures. Indazole (50 mg/kg) had no effect on spontaneous activity but induced hypothermia. It also inhibited the metabolism of dopamine and 5-hydroxytryptamine in the brain in vivo and the activities of monoamine oxidase A and B in vitro, with IC(50) values of 20.6 μM and 16.3 μM, respectively. However, these inhibitory effects do not account for the anticonvulsant activity because treatment with typical monoamine oxidase inhibitors such as pargyline or tranylcypromine did not completely reproduce the anticonvulsant activity of indazole. In the animal seizure models tested, the anticonvulsant profile of indazole most resembled that of gabapentin and somewhat resembled those of the AMPA/kainate antagonist NBQX and the sodium channel inhibitor phenytoin, but differed from that of benzodiazepine. The isobolographic analyses showed that the interactive mode of indazole with gabapentin, NBQX or phenytoin is additive. These results suggest that indazole has anticonvulsant activity and multiple mechanisms.
authors.affiliation: Department of Pharmacology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
authors.forename: Nobuko
authors.initials: N
authors.lastname: Matsumura
authors.forename: Kazue
authors.initials: K
authors.lastname: Kikuchi-Utsumi
authors.forename: Kentaro
authors.initials: K
authors.lastname: Sakamaki
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watabe
authors.forename: Koji
authors.initials: K
authors.lastname: Aoyama
authors.forename: Toshio
authors.initials: T
authors.lastname: Nakaki
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001640:Bicuculline / Q000009:adverse effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004597:Electroshock / Q000009:adverse effects; D007191:Indazoles / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010433:Pentylenetetrazole / Q000009:adverse effects; D010672:Phenytoin / Q000009:adverse effects; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D013331:Strychnine / Q000009:adverse effects
chemical_list: D000927:Anticonvulsants; D007191:Indazoles; D010672:Phenytoin; D013331:Strychnine; D010433:Pentylenetetrazole; D001640:Bicuculline