title: Long-Term Alcohol-Induced Activation of Mammalian Target of Rapamycin is a Key Risk Factor of Epilepsy.
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.
authors: Cardre Ward 2, The First Affiliated Hospital of Chinese PLA General Hospital, Beijing, China (mainland).
authors: Xiaoling
authors: X
authors: Fu
authors: Department of Nuclear Medicine, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, China (mainland).
authors: Zhe
authors: Z
authors: Guo
authors: Cardre Ward 2 , The First Affiliated Hospital of Chinese PLA General Hospital, Beijing, China (mainland).
authors: Chang
authors: C
authors: Gao
authors: Cardre Ward 2, The First Affiliated Hospital of Chinese PLA General Hospital, Beijing, China (mainland).
authors: Qinying
authors: Q
authors: Chu
authors: Cardre Ward 2, The First Affiliated Hospital of Chinese PLA General Hospital, Beijing, China (mainland).
authors: Jianhua
authors: J
authors: Li
authors: Cardre Ward 2, The First Affiliated Hospital of Chinese PLA General Hospital, Beijing, China (mainland).
authors: Hongying
authors: H
authors: Ma
authors: Cardre Ward 2, The First Affiliated Hospital of Chinese PLA General Hospital, Beijing, China (mainland).
authors: Gangming
authors: G
authors: Shu
mesh_terms: D000818:Animals; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004827:Epilepsy / Q000201:enzymology* / Q000209:etiology; D000431:Ethanol / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D012307:Risk Factors; D012640:Seizures / Q000201:enzymology / Q000209:etiology; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000431:Ethanol; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus