Role of nitric oxide in anticonvulsant effects of benzodiazepines in mice
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Published on: May 16, 2019
Sylwia Talarek1, Sylwia Fidecka
1Department of Pharmacodynamics, Medical University School, Staszica 4, PL 20-081 Lublin, Poland.
Abstract:
The influence of nitric oxide (NO) on anticonvulsant activity of diazepam and clonazepam was examined in the pentetrazole- and electroshock-induced seizure models in mice. Protective efficacy of the threshold dose of diazepam against pentetrazole-induced clonic and tonic seizures, and death was significantly increased by NG-nitro-L-arginine methyl ester hydrochloride (L-NAME) while 7-nitroindazole (7-NI) was slightly less effective. The above intensifying effect of L-NAME on antiepileptic activity of diazepam was reversed by L-arginine, a substrate for NO formation, but not by D-arginine. Methylene blue, the guanylate cyclase inhibitor, increased the protective efficacy of diazepam and clonazepam in the pentetrazole-induced seizures. 7-NI was able to potentiate the protective efficacy of diazepam and clonazepam in electroshock-induced tonic hindlimb extension. These findings suggest that the cGMP/NO system may participate in antiepileptic effects of benzodiazepines.
Insights
Nitric oxide (NO) influences the anticonvulsant effects of diazepam and clonazepam. Inhibiting NO pathways enhanced benzodiazepine efficacy against seizures, suggesting NO
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Benzodiazepines like diazepam and clonazepam are widely used anticonvulsants.
- The role of nitric oxide (NO) in modulating the efficacy of these drugs is not fully understood.
Purpose of the Study:
- To investigate the influence of the nitric oxide (NO)/cGMP system on the anticonvulsant activity of diazepam and clonazepam.
- To explore the potential of targeting the NO pathway to enhance benzodiazepine-based epilepsy treatment.
Main Methods:
- Utilized pentetrazole- and electroshock-induced seizure models in mice.
- Administered diazepam and clonazepam with NO pathway modulators (L-NAME, 7-NI, L-arginine, methylene blue).
- Assessed changes in seizure threshold, protection against seizures, and mortality.
Main Results:
- NG-nitro-L-arginine methyl ester hydrochloride (L-NAME) and 7-nitroindazole (7-NI) significantly potentiated the anticonvulsant effects of diazepam against pentetrazole-induced seizures.
- L-arginine reversed the L-NAME-induced potentiation, indicating NO pathway involvement.
- Methylene blue, a guanylate cyclase inhibitor, also enhanced the protective efficacy of both drugs in pentetrazole-induced seizures.
- 7-NI potentiated diazepam and clonazepam efficacy in electroshock-induced seizures.
Conclusions:
- The endogenous nitric oxide (NO)/cGMP system appears to play a role in the anticonvulsant mechanisms of benzodiazepines.
- Modulation of the NO pathway could be a potential strategy to augment the therapeutic effects of diazepam and clonazepam in epilepsy treatment.
