Pyrazolo[4,3-c]pyridine-4-one (PP-4-one) Exhibits Anti-Epileptogenic Effect in Rat Model of Traumatic Epilepsy by Mammalian Target of Rapamycin (mTOR) Signaling Pathway Downregulation.

BACKGROUND Post-traumatic epilepsy (PTE) is a common type of acquired epilepsies secondary to traumatic brain injury (TBI), accounting for approximately 10-25% of patients. The present study evaluated activity of PP-4-one against mTOR signaling activation in a rat model of FeCl2-induced post-traumatic epilepsy. MATERIAL AND METHODS Epilepsy in rats was induced by injecting 10 µl FeCl2 (concentration 100 mM) at a uniform rate of 1 µl/minute. The iNOS expression was detected using a Leica microscope connected to a digital camera system. Reverse transcription polymerase chain reaction (RT­PCR) was used for determination of NR1 mRNA expression. RESULTS The post-traumatic epilepsy induced neuronal degeneration in the hippocampus and frontal cortex of the rats. Treatment with PP-4-one prevented neuronal degeneration in the hippocampus and frontal cortex in rats with post-traumatic epilepsy. The data revealed markedly higher levels of p-mTOR and p-P70S6K in rat hippocampal tissues after induction of traumatic epilepsy. Treatment of post-traumatic epilepsy rats with PP-4-one significantly suppressed p-mTOR and p-P70S6K expression, and PP-4-one treatment reduced epileptic brain injury in the rats with post-traumatic epilepsy. CONCLUSIONS PP-4-one exhibits an anti-epileptogenic effect in the rat model of PTE by inhibiting behavioral seizures through suppression of iNOS and astrocytic proliferation. Moreover, PP-4-one treatment suppressed NR1 expression and targeted the mTOR pathway in PTE-induced rats. Thus, PP-4-one shows promise as a novel and effective therapeutic agent for treatment of epilepsy induced by PTE.