Pifithrin-α Inhibits Neural Differentiationof Newborn Cells in the Subgranular Zone of the Dentate Gyrus atInitial Stages of Audiogenic Kindling in Krushinsky–Molodkina RatStrain

One of the main challenges of modern neurobiology is finding approaches to prevent structural abnormalities in the brain, specifically, in the hippocampus affected by epileptic activity. It is well known that epilepsy leads to an increase in proliferation in the hippocampal neurogenic niche, the subgranular layer of the dentate gyrus. In the recent years, there is a prevalent idea that newborn neural cells contribute to epileptogenesis to a larger extent than prevent neurodegenerative disorders associated with increased cell death. We hypothesized that a proapoptotic protein p53 can be one of the possible therapeutic targets in treating epilepsy and its neurodegenerative consequences. In the present work, we used the Krushinsky–Molodkina (KM) inbred rats, which are genetically prone to audiogenic seizures (AGS). Audiogenic kindling, a commonly accepted model of epileptogenesis, induces epileptiform activity in the limbic system and cerebral cortex. In KM rats, it has been shown that 4 AGS lead to an increase in proliferation, aberrant migration of newborn cells to the hilus, and accelerated neural differentiation of these cells. We revealed abnormalities neither in apoptosis nor in autophagy levels at the initial stages of temporal lobe (limbic) epilepsy. Treatment with pifithrin-α, a chemical p53 inhibitor, did not change apoptosis and autophagy levels but caused an increase in proliferation and migration of newborn cells to the granule cell layer of the dentate gyrus and to the hilus. However, a week after the last seizure, p53 inactivation entailed a decrease in the number of differentiating cells, as compared to the vehicle control group, despite a significant increase in the number of newborn cells. These data indicate a decrease in the neural differentiation rate of newborn cells, thus allowing pifitrin-α to be considered as a potential therapeutic agent to alleviate neurodegenerative disorders in epilepsy.