Study of the effect of darbufelone on the anticonvulsant potential of classic antiepileptic drugs

Possible way to improve the control of multidrug-resistant epilepsy can be considered the use of drugs from other pharmacological groups as an adjunct to classical antiepileptic drugs (AEDs). One of the promising such medicines is an anti-inflammatory drug with a unique mechanism of action – the dual COX-2/5-LOG inhibitor darbufelone, for which per se a pronounced anticonvulsant effect was previously established. The aim of the work was to study the effect of the dual COX-2/5-LOG inhibitor darbufelone on the anticonvulsant potential of classical antiepileptic drugs: sodium valproate and carbamazepine. The study was conducted using 64 albino mice. Acute seizures were modeled by a single injection of the GABAA receptor antagonist pentylenetetrazole. Classical AEDs were administered intragastrically at ED50 and ½ ED50 30 min before pentylenetetrazole: sodium valproate – at doses of 300 and 150 mg/kg, respectively, carbamazepine – at doses of 100 and 50 mg/kg, respectively; darbufelone was administered at a previously determined effective anticonvulsant dose of 100 mg/kg. Pentylenetetrazole was administered at a dose of 80 mg/kg subcutaneously. It was found that the combination of darbufelone with sodium valproate at ½ ED50 provided a pronounced protective effect on the pentylenetetrazole-induced seizure model, which was verified by the prolongation of the latency period of the first seizures, a decrease in the number and severity of seizures. In addition, the combination of darbufelone with sodium valproate at ½ ED50 also provided protection of mice from death at the level of valproate at a conditionally effective dose, which significantly exceeded the effectiveness of monotherapy with valproate at ½ ED50 and darbufelone per se. Darbufelone also positively modulated the effect of carbamazepine at ½ ED50, not only reducing lethality (at the level of carbamazepine at a conditionally effective dose), but also protecting mice from severe tonic paroxysms, prolonging the latency period of the first seizures and the life span of animals. Thus, in the model of acute pentylenetetrazole-induced seizures, it was established that darbufelone not only has its own anticonvulsant properties but is also able to enhance the anticonvulsant potential of sodium valproate and carbamazepine in their subeffective doses. The results obtained provide grounds to consider darbufelone as an effective adjuvant anticonvulsant that provides a protective effect under conditions of the experimental equivalent of refractory epilepsy.