Effects of carbamazepine and phenytoin in Krushinsky-Molodkina rats: further validation of the audiogenic kindling model of epilepsy.

In the present study, we evaluated the effects of the clinically approved anti-seizure medications (ASMs) carbamazepine (CBZ) and phenytoin (PHT) on brainstem audiogenic seizures (AGS) and limbic seizures in Krushinsky-Molodkina (KM) audiogenic rats. In order to analyze the effects of ASMs on the standard AGS, KM rats received single intraperitoneal injection of CBZ (50 mg/kg), PHT (25 mg/kg), or vehicle prior to the single AGS stimulation. The further three groups of KM rats were exposed to 14 daily AGS stimulations (audiogenic kindling), resulting in the stable development of limbic clonus. The following day, these rats received the same injections before the 15th AGS stimulation. Naïve vehicle-treated KM rats were recruited as well as non-seizure control. The results showed that administration of CBZ and PHT led to a substantial reduction in the severity of the standard AGS in both experiments. Moreover, after the development of the limbic seizures, the administration of both CBZ and PHT effectively prevented limbic clonus, with the effect on the brainstem component being more pronounced, than that observed for standard AGS. Additionally, both ASMs attenuated Ca2+-dependent signaling markers and modulated cRaf/ERK1/2 signaling in the hippocampus of kindled KM rats. Meanwhile, CBZ additionally suppressed the seizure-induced increase in the hippocampal glutamate/GABA ratio, while PHT specifically affected the markers of cyclic AMP-dependent signaling. Together with the previous results, the present data indicate that audiogenic kindling in KM rats is a valid approach, reproducing the development of limbic seizures, which can be used to investigate new strategies for epilepsy treatment.