INVESTIGATION OF THE IMPACT OF FLUMAZENIL ON THE ANTICONVULSANT POTENTIAL OF DIGOXIN AND VALPROATE
DOI:
https://doi.org/10.11603/2312-0967.2025.4.15709Keywords:
digoxin, valproate, adjuvant, flumazenil, anticonvulsant effect, pentylenetetrazole-induced seizuresAbstract
The aim of the work – to investigate the impact of flumazenil on the anticonvulsant potential of the cardiac glycoside digoxin and its combination with sodium valproate.
Materials and methods. The study was conducted in 48 random-bred male albino mice (20–24 g). Depending on group assignment, animals received sodium valproate 150 mg/kg intragastrically, digoxin 0.8 mg/kg subcutaneously, and flumazenil 5 mg/kg intraperitoneally according to the protocol. Seizures were induced by subcutaneous pentylenetetrazole at 80 mg/kg. The following endpoints were assessed: latency to first seizure, number of seizures and their type (clonic / tonic), seizure severity, total duration of the seizure period, time to death, and overall lethality across experimental groups.
Results and discussion. In the acute pentylenetetrazole-induced seizure model, the selective benzodiazepine-site antagonist at the GABAA-receptor, flumazenil, potentiated the anticonvulsant action of a subeffective dose of valproate, partially attenuated the effect of digoxin, and markedly weakened the synergy of the valproate + digoxin combination. These findings indicate a significant contribution of GABAA-benzodiazepine-sensitive mechanisms to the protective effects of the studied medicines. The interactions are likely pharmacodynamic rather than pharmacokinetic in nature.
Conclusions. The results not only demonstrate the role of benzodiazepine (GABAA-receptor) mechanisms in mediating the anticonvulsant effects of valproate and its atypical adjuvant digoxin, but also substantiate the relevance of exploring the benzodiazepine-sensitive component as a distinct mechanism in the action of antiepileptic drugs.
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