25 October 2016 : Animal Research
Long-Term Alcohol-Induced Activation of Mammalian Target of Rapamycin is a Key Risk Factor of Epilepsy
Xiaoling FuBCDEF, Zhe GuoBCDEF, Chang GaoBCDF, Qinying ChuBDF, Jianhua LiBD, Hongying MaDF, Gangming ShuACEDOI: 10.12659/MSM.897018
Med Sci Monit 2016; 22:3975-3980
Abstract
BACKGROUND: The aim of this study was to determine whether activation of mammalian target of rapamycin (mTOR) is a key epileptogenic mechanism in the development of alcohol-related seizure.
MATERIAL AND METHODS: C57BL/6 mice were administered 10% ethanol in drinking water for 9 weeks. Video-electroencephalography (EEG) monitoring was then used to assess seizure frequency after alcohol and rapamycin treatment. In addition, mouse neuroblastoma NG108-15 cells were treated ethanol for 3 days and subsequently treated with AKT inhibitor LY294002 for 2–12 h. The in vitro kinase assay was performed for determining mTOR activity. Western blot analysis was used to determine the expression of P-AKT, P-S6K, and P-S6.
RESULTS: Long-term ethanol treatment markedly increased the seizure frequency of C57/BL6 mice over time. Moreover, ethanol treatment increased the expression level of P-S6 over time. Ethanol-induced seizure can be reversed by rapamycin. In addition, the in vitro kinase assay showed mTOR activity was activated by ethanol. Compared with NG108-15 cells treated without both ethanol and LY294002, ethanol increased the expression level of P-AKT, P-S6K, and P-S6, whereas LY294002 had opposite effects on expression levels of these proteins.
CONCLUSIONS: Our findings indicate that long-term alcohol intake increases the risk of epilepsy via activation of mTOR signaling. Moreover, ethanol-induced mTOR activation may be dependent on the AKT-mTOR signaling pathway. The key molecules involved in AKT-mTOR signaling pathway may serve as potential targets in the treatment of epilepsy.
Keywords: Chromones - pharmacology, Enzyme Inhibitors - pharmacology, Epilepsy - etiology, Ethanol - administration & dosage, Morpholines - pharmacology, Phosphorylation - drug effects, Proto-Oncogene Proteins c-akt - metabolism, Risk Factors, Seizures - etiology, Signal Transduction - physiology, Sirolimus - pharmacology, TOR Serine-Threonine Kinases - metabolism
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