A 2-Min Transient Ischemia Confers Cerebral Ischemic Tolerance in Non-Obese Gerbils, but Results in Neuronal Death in Obese Gerbils by Increasing Abnormal mTOR Activation-Mediated Oxidative Stress and Neuroinflammation

Cells

Minah Song¹  InKoo Hwang²  JoonHa Park³  DaeWon Kim⁴  Sungwoo Ryoo⁵  SooYoung Choi⁶  JiHyeon Ahn⁶  IlJun Kang⁷  Young-Myeong Kim⁸  Jae-Chul Lee⁹  CheolWoo Park⁹  YoungEun Park⁹  Moo-Ho Won⁹  Tae-Kyeong Lee⁹  Choong-Hyun Lee^1,10  BingChun Yan^1,11  Hyunjung Kim^1,12 

[1] Center for Virus Research and Testing, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea;Department of Anatomy and Cell Biology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08826, Korea;Department of Anatomy, College of Korean Medicine, Dongguk University, Gyeongju, Gyeongbuk 38066, Korea;Department of Biochemistry and Molecular Biology, and Research Institute of Oral Sciences, College of Dentistry, Gangneung-Wonju National University, Gangneung, Gangwon 25457, Korea;Department of Biological Sciences, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon 24341, Korea;Department of Biomedical Science and Research Institute for Bioscience and Biotechnology, Hallym University, Chuncheon, Gangwon 24252, Korea;Department of Food Science and Nutrition, Hallym University, Chuncheon, Gangwon 24252, Korea;Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24341, Korea;Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24341, Korea;Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan, Chungnam 31116, Korea;Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Medical college of Yangzhou University, Yangzhou 225001, China;Knotus Co. Ltd., Incheon 22014, Korea;

关键词: obesity;    brief transient ischemia;    neuronal death;    oxidative stress;    neuroinflammation;    mammalian target of rapamycin;   

DOI  :  10.3390/cells8101126

来源: DOAJ

【 摘 要 】

A brief episode of transient ischemia (TI) can confer cerebral ischemic tolerance against a subsequent severer TI under standard condition. The brain under obesity’s conditions is more sensitive to ischemic injury. However, the impact of a brief episode of TI under obesity’s conditions has not been fully addressed yet. Thus, the objective of this study was to determine the effect of a brief TI in the hippocampus of high-fat diet (HFD)-induced obese gerbils and related mechanisms. Gerbils were maintained on HFD or normal diet (ND) for 12 weeks and subjected to 2 min TI. HFD gerbils were heavier, with higher blood glucose, serum total cholesterol, triglycerides, and leptin levels. Massive loss of pyramidal neurons occurred in the hippocampal cornu ammonis 1 (CA1) field of HFD animals at 5 days after 2 min of TI, but 2 min of TI did not elicit death of pyramidal neurons in ND gerbils. The HFD group showed significantly increased levels of oxidative stress indicators (dihydroethidium and 4-hydroxynonenal) and proinflammatory cytokines (tumor necrosis factor-α and interleukin-1β) and microglial activation in pre- and/or post-ischemic phases compared to the ND group. Levels of mammalian target of rapamycin (mTOR) and phosphorylated-mTOR in the CA1 field of the HFD group were also significantly higher than the ND group. On the other hand, inhibition of mTOR activation by rapamycin (an allosteric mTOR inhibitor) significantly attenuated neuronal death induced by HFD, showing reduction of HFD-induced increases of oxidative stress indicators and proinflammatory cytokines, and microglia activation. Taken together, a brief episode of TI can evoke neuronal death under obesity’s conditions. It might be closely associated with an abnormal increase of mTOR activation-mediated, severe oxidative stress and neuroinflammation in pre- and/or post-ischemic phases.

【 授权许可】

Unknown