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Anticonvulsant effects of 7‐nitroindazole in rodents with reflex epilepsy may result from L‐arginine accumulation or a reduction in nitric oxide or L‐citrulline formation
Author(s) -
Smith S.E.,
Man C.M.,
Yip P.K.,
Tang E.,
Chapman A.G.,
Meldrum B.S.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15690.x
Subject(s) - nitric oxide , anticonvulsant , ed50 , nitric oxide synthase , arginine , chemistry , epilepsy , pharmacology , citrulline , endocrinology , medicine , biochemistry , amino acid , in vitro , psychiatry
1 To investigate the role of nitric oxide in epilepsy we have studied the effects of agents which affect nitric oxide synthesis in sound‐induced seizures in DBA/2 mice and in genetically epilepsy‐prone (GEP) rats. 2 The neuronal selective nitric oxide synthase inhibitor, 7‐nitroindazole (7‐NI) is anticonvulsant in these models with ED 50 values against clonic seizures in mg kg −1 i.p. (times following injection) of: 74 (+0.25 h), 120 (+1 h) in DBA/2 mice, and 56 (+0.25 h), 42 (+0.5 h), 36 (+1 h), 28 (+2 h), 38 (+4 h), 93 (+8 h) in GEP rats. 3 Therapeutic indices (locomotor deficit ED 50 /anticonvulsant ED 50 ) for 7‐NI are low, ranging from 0.6 to 1.1 at +0.25 h to +1 h after administration in GEP rats, but are more favourable at later times (1.6 at +2 h and 2.9 at +4 h). 4 The substrate for nitric oxide synthase, L‐arginine (500–5000 mg kg −1 , i.p. or 100–300 μg, i.c.v.) but not D‐arginine (300 μg i.c.v.) is anticonvulsant in DBA/2 mice. L‐Arginine (500–5000 mg kg −1 , i.p. or 1800–6000 μg, i.c.v.) is a more potent anticonvulsant than D‐arginine (1500–2500 mg kg −1 , i.p. or 6000 μg, i.c.v.) in GEP rats. 5 In DBA/2 mice, L‐arginine (30 μg i.c.v.) reverses the anticonvulsant effect of 7‐NI (50 mg kg −1 , i.p.). 6 In GEP rats, low dose L‐arginine (25–50 mg kg −1 , i.p.) but not D‐arginine (50 mg kg −1 , i.p.) reverses the anticonvulsant effect of low dose 7‐NI (25 mg kg −1 , i.p.). A higher dose of L‐arginine (500 mg kg −1 , i.p.) or 7‐NI (50 mg kg −1 , i.p.) produces summation of anticonvulsant effect. 7 The product for nitric oxide synthase, L‐citrulline (250–831 μg i.c.v.), is convulsant in DBA/2 mice. 8 The anticonvulsant effect of the neuronal selective nitric oxide synthase inhibitor, 7‐nitroindazole, may therefore be mediated by L‐arginine accumulation, as well as by a reduction in nitric oxide and L‐citrulline formation in rodent models of reflex epilepsy.