title: Activation of mTOR signaling mediates the increased expression of AChE in high glucose condition: in vitro and in vivo evidences.
abstract: Acetylcholinesterase (AChE) is impaired in brain of diabetic animals, which may be one of the reasons for diabetes-associated cognitive decline. However, the mechanism is still unknown. The present study was designed to investigate whether the increased expression of AChE in central neurons under high glucose (HG) condition was due to activation of mammalian target of rapamycin (mTOR) signaling. It was found that more production of reactive oxygen species, and higher levels of phospho-Akt, phospho-mTOR, phospho-p70S6K, and AChE were detected in HT-22 cells in HG group than normal glucose group after culture for 24 h, which were all attenuated by an antioxidant N-acetyl-L-cysteine. A PI3K inhibitor LY294002 significantly decreased the levels of phospho-Akt, phospho-mTOR, phospho-p70S6K, and AChE protein expression in HG-cultured HT-22 cells, and an mTOR inhibitor rapamycin markedly reduced the levels of phospho-mTOR, phospho-p70S6K, and AChE expression. Furthermore, compared with normal rats, diabetic rats showed remarkable increases in levels of AChE activity and expression, malondialdehyde, phospho-mTOR, phospho-p70S6K, and a significant decrease in total superoxide dismutase activity in both hippocampus and cerebral cortex. However, much lower levels of phospho-mTOR, phospho-p70S6K, and AChE expression occurred in both brain regions of diabetic rats treated with rapamycin when compared with untreated ones. These results indicated that mTOR signaling was activated through the activation of PI3K/Akt pathway mediated by oxidative stress in HG-cultured HT-22 cells and diabetic rat brains, which contributed to the elevated protein expression of AChE in central neurons under the condition of HG.
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical College, No. 209, Tongshan Road, Xuzhou, 221004, Jiangsu, China.
authors.forename: Yao-Wu
authors.initials: YW
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical College, No. 209, Tongshan Road, Xuzhou, 221004, Jiangsu, China.|Department of Pharmacy, the People's Hospital of Hebi, Henan, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical College, No. 209, Tongshan Road, Xuzhou, 221004, Jiangsu, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical College, No. 209, Tongshan Road, Xuzhou, 221004, Jiangsu, China.
authors.forename: Ya-Qin
authors.initials: YQ
authors.lastname: Cheng
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical College, No. 209, Tongshan Road, Xuzhou, 221004, Jiangsu, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical College, No. 209, Tongshan Road, Xuzhou, 221004, Jiangsu, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical College, No. 209, Tongshan Road, Xuzhou, 221004, Jiangsu, China. yinxx@xzmc.edu.cn.
authors.forename: Xiao-Xing
authors.initials: XX
authors.lastname: Yin
mesh_terms: D000110:Acetylcholinesterase / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000008:administration & dosage / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D002867:Chromones; C549075:LY 290042; D009025:Morpholines; D017382:Reactive Oxygen Species; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D000110:Acetylcholinesterase; D005947:Glucose; D020123:Sirolimus
keywords: Acetylcholinesterase; High glucose; Mammalian target of rapamycin; Oxidative stress; PI3K/Akt pathway