A study on the protective mechanism of mTOR inhibitor Everolimus on brain injury after epilepsy

Abstract

Background: Epilepsy is a common acute and severe disease in infants and children. Recurrent seizures or status epilepticus can cause irreversible brain damage. While the PI3K/Akt/mTOR pathway regulates various physiological processes of neurons and glia, it may also lead to abnormal neuronal signal transduction under pathological conditions, including that of epilepsy. Everolimus (Eve) is an mammalian target of repamycin (mTOR) inhibitor that may affect neuronal excitability and have a therapeutic effect on epilepsy. Therefore, this study aimed to investigate the protective effect of Everolimus on post-epileptic brain injury and the regulation mechanism of the PI3K/Akt/mTOR and NF-kB/IL-6 signaling pathway. Intraperitoneal administration of kanic acid (KA) 15mg/kg was used to induce epilepsy in the developing rat and Everolimus (1, 2, 5mg/kg) was injected intraperitoneally 2 hours before KA injection. Cerebral cortex tissue was sampled at 24 hours post-epilepsy.Results: The protein and mRNA levels of PI3K、AKt、mTOR、NF-kB and IL-6 as well as microglia activation significantly increased after KA-induced epilepsy, however these effects were inhibited by Everolimus treatment. Furthermore, pretreatment with Everolimus decreased seizure scores and increased seizure latency. This study demonstrates that mTOR inhibitor.Conclusions: Everolimus can decrease the PI3K/Akt/mTOR and NF-kB/IL-6 signaling pathway, reduce microglia activation, and attenuate seizure susceptibility and intensity, thus having a protective effect on post-epileptic brain damage.