7-Nitroindazole potentiates the antiseizure activity of some anticonvulsants in DBA/2 mice.
7-Nitroindazole, a selective neuronal nitric oxide synthase inhibitor (25-200 mg kg(-1), intraperitoneally (i.p.)) antagonized audiogenic seizures in DBA/2 mice in a dose-dependent manner. We investigated the effects of 7-nitroindazole at a dose of 25 mg kg(-1) i.p., which per se did not show anticonvulsant activity against audiogenic seizures in DBA/2 mice, on the antiseizure activity of some conventional antiepileptic drugs. 7-Nitroindazole sometimes potentiated the anticonvulsant activity of carbamazepine, diazepam, lamotrigine, phenytoin, phenobarbital and valproate against audiogenic seizures in DBA/2 mice. The degree of potentiation by 7-nitroindazole was greatest for phenobarbital and diazepam, less for valproate and least for carbamazepine, lamotrigine and phenytoin. The increase in anticonvulsant activity was associated with a comparable increase in motor impairment. However, the therapeutic index of combined treatment with diazepam+7-nitroindazole, phenobarbital+7-nitroindazole or valproate+7-nitroindazole was more favourable than that of the diazepam+vehicle, phenobarbital+vehicle or valproate+vehicle treatment. The results indicate that 7-nitroindazole is able to increase the protective activity of some conventional antiepileptics and this effect appears not to result only from the impaired synthesis of nitric oxide. In fact, mice receiving 7-nitroindazole (25 mg kg(-1), i.p.) and L-arginine (30 microg/mouse, intracerebroventricularly (i.c.v.) did not show significant changes of ED(50) values in comparison to those of related groups of animals treated with 7-nitroindazole and anticonvulsants. 7-Nitroindazole was able to increase the brain levels of dopamine and noradrenaline and its anticonvulsant effects and changes in catecholamine content were antagonized by pretreatment with alpha-methyl-paratyrosine, an agent inhibiting the synthesis of catecholamines. The fact that alpha-methyl-paratyrosine reverses concomitantly both the increase in brain levels of dopamine and noradrenaline and the anticonvulsant properties of 7-nitroindazole strongly suggests an important role of catecholamines in the antiseizure activity of 7-nitroindazole. Since 7-nitroindazole did not significantly influence the total and free plasma levels of the anticonvulsant drugs studied, we suggest that pharmacokinetic interactions, in terms of total or free plasma levels, are not probable. 7-Nitroindazole did not significantly affect the hypothermic effects of the anticonvulsant compounds studied. 7-Nitroindazole showed an additive effect when administered in combination with some classical anticonvulsants, most notably diazepam, phenobarbital and valproate and its activity could be, in part, due to an increase of monoamine levels.
De Sarro
G
G
Chair of Pharmacology, Department of Experimental and Clinical Medicine, Faculty of Medicine and Surgery, School of Medicine at Catanzaro,University of Catanzaro "Magna Gracia" Policlinico Mater Domini,via T. Campanella, Catanzaro, Italy.
Gareri
P
P
Falconi
U
U
De Sarro
A
A
D000161:Acoustic Stimulation; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology*; D001120:Arginine / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D001923:Brain Chemistry / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008995:Monoamine Oxidase / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D009638:Norepinephrine / Q000378:metabolism
D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D007191:Indazoles; D001120:Arginine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D008995:Monoamine Oxidase; C080122:7-nitroindazole; D004298:Dopamine; D009638:Norepinephrine