7-nitroindazole potentiates the antiseizure activity of some anticonvulsants in DBA/2 mice

被引:41
作者
De Sarro, G
Gareri, P
Falconi, U
De Sarro, A
机构
[1] Univ Catanzaro Magna Gracia, Policlin Mater Domini, Sch Med Catanzaro,Fac Med & Surg, Dept Expt & Clin Med,Chair Pharmacol, I-88100 Catanzaro, Italy
[2] Univ Messina, Fac Med, Inst Pharmacol, Chair Chemotherapy, Messina, Italy
关键词
nitric oxide (NO); epilepsy; 7-nitroindazole; carbamazepine; diazepam; lamotrigine; phenobarbital; phenytoin; valproate; anticonvulsant; audiogenic seizure; DBA/2; mouse;
D O I
10.1016/S0014-2999(00)00086-8
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 mu g/mouse, intracerebroventricularly (i.c.v.) did not show significant changes of ED50 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. (C) 2000 Elsevier Science B.V. All rights reserved.
引用
收藏
页码:275 / 288
页数:14
相关论文
共 96 条
[51]   SYNERGISM OF THE AMPA-ANTAGONIST NBQX AND THE NMDA-ANTAGONIST CPP WITH L-DOPA IN MODELS OF PARKINSONS-DISEASE [J].
LOSCHMANN, PA ;
LANGE, KW ;
KUNOW, M ;
RETTIG, KJ ;
JAHNIG, P ;
HONORE, T ;
TURSKI, L ;
WACHTEL, H ;
JENNER, P ;
MARSDEN, CD .
JOURNAL OF NEURAL TRANSMISSION-PARKINSONS DISEASE AND DEMENTIA SECTION, 1991, 3 (03) :203-213
[52]  
LOWRY OH, 1951, J BIOL CHEM, V193, P265
[53]  
MacDonald Robert L., 1995, P61
[54]   INHIBITION OF NITRIC-OXIDE SYNTHASE DRAMATICALLY POTENTIATES SEIZURES INDUCED BY KAINIC ACID AND PILOCARPINE IN RATS [J].
MAGGIO, R ;
FUMAGALLI, F ;
DONATI, E ;
BARBIER, P ;
RACAGNI, G ;
CORSINI, GU ;
RIVA, M .
BRAIN RESEARCH, 1995, 679 (01) :184-187
[55]   AMINO-ACID NEUROTRANSMITTERS AND NEW APPROACHES TO ANTICONVULSANT DRUG-ACTION [J].
MELDRUM, B .
EPILEPSIA, 1984, 25 :S140-S149
[56]  
MELDRUM BS, 1995, EPILEPSIA, V36, P30
[57]  
MELDRUM BS, 1996, EPILIPSIA, V37, P4
[58]   EVIDENCE THAT L-ARGININE POSSESSES PROCONVULSANT EFFECTS MEDIATED THROUGH NITRIC-OXIDE [J].
MOLLACE, V ;
BAGETTA, G ;
NISTICO, G .
NEUROREPORT, 1991, 2 (05) :269-272
[59]  
MONCADA C, 1992, NEUROREPORT, V3, P530
[60]   BIOSYNTHESIS OF NITRIC-OXIDE FROM L-ARGININE - A PATHWAY FOR THE REGULATION OF CELL-FUNCTION AND COMMUNICATION [J].
MONCADA, S ;
PALMER, RMJ ;
HIGGS, EA .
BIOCHEMICAL PHARMACOLOGY, 1989, 38 (11) :1709-1715