p53 inhibition during audiogenic kindling in Krushinsky-Molodkina rats attenuates seizure severity and prevents neurodegeneration in the hippocampus.

In the present study, we analyzed the effects of the p53 inhibitor pifithrin-α (PFT) on the expression of brainstem audiogenic seizures (AGS) and limbic seizures in Krushinsky-Molodkina (KM) rats genetically prone to AGS. To reproduce limbic/mesial temporal lobe epilepsy (TLE)-like condition in KM rats, we used repetitive AGS stimulations (audiogenic kindling) during 14 days. In parallel with AGS stimulations, KM rats received daily intraperitoneal injections of PFT. Our data demonstrated that PFT treatment significantly decreased the duration and severity of both brainstem AGS and limbic seizures. In addition, PFT partially prevented the kindling-induced neurodegeneration and activation of apoptotic mechanisms in the hippocampus of KM rats. Moreover, PFT treatment led to the persistent upregulation of anti-apoptotic Bcl-2, along with GluA2 and GluN2A, glutamate receptor subunits which are involved into the mechanisms supporting cell survival and preventing neuronal hyperexcitability. Altogether, our data confirm that p53 can be considered as a perspective target for the development of novel strategies to mitigate seizure activity and avert its deleterious consequences.