Effect of NG-nitro-L-arginine on the anticonvulsant action of four second-generation antiepileptic drugs in pentetrazole-induced clonic seizures in mice.
The exact role of compounds modulating nitric oxide (NO) content in the brain during seizure phenomena is under intensive investigation. This study was aimed at determining the effect of NG-nitro-L-arginine (L-NA; a non-selective NO synthase inhibitor) on the anticonvulsant activity of four second-generation antiepileptic drugs (AEDs: gabapentin [GBP], oxcarbazepine [OXC], tiagabine [TGB] and vigabatrin [VGB]) in the mouse pentetrazole (PTZ)-induced seizure model. The acute adverse-effect liability of the studied AEDs in combinations with L-NA were evaluated in the chimney test (motor coordination). Results indicate that L-NA (40 mg/kg; ip) significantly reduced the anticonvulsant activity of OXC in the PTZ test, by increasing its ED50 from 20.9 to 29.8 mg/kg (p < 0.05). Similarly, L-NA at doses of 20 and 40 mg/kg considerably attenuated the antiseizure effects of VGB by raising its ED50 from 595 to 930 mg/kg (p < 0.05), and 1022 mg/kg (p < 0.01), respectively. L-NA at lower doses of 10 and 20 mg/kg did not affect significantly the anticonvulsant effects of VGB and OXC in PTZ-induced seizures. Likewise, the co-administration of L-NA(40 mg/kg; ip) with GBP and TGB was associated with no significant changes in their anticonvulsant activities in PTZ-induced seizures in mice. Moreover, none of the examined combinations of L-NA (40 mg/kg; ip) and second-generation AEDs (at their ED50 values) affected motor coordination in the chimney test. Based on this preclinical study, one can conclude that L-NA reduced the anticonvulsant activities of VGB and OXC in the mouse PTZ-induced seizure model. Only, GBP and TGB were resistant to the action of L-NA in this model.
Łuszczki
Jarogniew J
JJ
Department of Pathophysiology, Medical Institute of Lublin, Jaczewskiego 8, PL 20-090 Lublin, Poland. jarogniew.luszczki@am.lublin.pl
Szadkowski
Marcin
M
Czuczwar
Stanisław J
SJ
D000588:Amines / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002220:Carbamazepine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000077206:Gabapentin; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D009557:Nipecotic Acids / Q000008:administration & dosage / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000008:administration & dosage / Q000494:pharmacology*; D000078330:Oxcarbazepine; D010433:Pentylenetetrazole / Q000008:administration & dosage / Q000633:toxicity; D011597:Psychomotor Performance / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control*; D000078308:Tiagabine; D013997:Time Factors; D020888:Vigabatrin / Q000008:administration & dosage / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000494:pharmacology
D000588:Amines; D000927:Anticonvulsants; D003509:Cyclohexanecarboxylic Acids; D004791:Enzyme Inhibitors; D009557:Nipecotic Acids; D019335:Nitroarginine; D002220:Carbamazepine; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D019001:Nitric Oxide Synthase; D020888:Vigabatrin; D000078330:Oxcarbazepine; D010433:Pentylenetetrazole; D000078308:Tiagabine