Interference with nitric oxide production and action potentiates the antiseizure efficacy of flurazepam

The effect of inhibiting "downstream" consequences of NMDA receptor stimulation with 7-nitroindazole, an inhibitor of the neuronal form of nitric oxide synthase (NOS), and methylene blue, an inhibitor of the nitric oxide (NO)-sensitive soluble guanylyl cyclase, on electrically precipitated tonic hindlimb extension in mice was studied. Moreover, the abilities of these compounds to potentiate the antiseizure efficacy of flurazepam were also examined. When administered alone, 7-nitroindazole (10.0-100 mg/kg) and methylene blue (1.0-100 mg/kg) did not share the ability of MK-801 (0.1 to 1.0 mg/kg) to antagonize electrically precipitated tonic hindlimb extension. However, doses of MK-801 (0.18 mg/kg), 7-nitroindazole (100 mg/kg), and methylene blue (10.0 and 100 mg/kg) that were devoid of apparent antiseizure efficacy by themselves potentiated the ability of flurazepam to antagonize electrically precipitated seizures. NMDA receptor antagonists cause neuronal toxicity, interfere with acquisition of spatial memory and induction of long-term potentiation in the hippocampal CA1 region, and precipitate psychoses in susceptible individuals. Thus, the development of both open-channel blockers of the NMDA receptor complex that can be administered in lower doses, and inhibitors of the "downstream" consequences of NMDA receptor-gated transient elevations of intraneuronal calcium ions as potential adjunctive antiseizure medications should be considered. Moreover, administration of these compounds with benzodiazepines may attenuate some of the neurotoxicity that may result from NMDA receptor antagonism.