PMID- 31546722 OWN - NLM STAT- MEDLINE DCOM- 20200615 LR - 20211204 IS - 2073-4409 (Electronic) IS - 2073-4409 (Linking) VI - 8 IP - 10 DP - 2019 Sep 22 TI - 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. LID - 10.3390/cells8101126 [doi] LID - 1126 AB - 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-alpha and interleukin-1beta) 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. FAU - Park, Joon Ha AU - Park JH AD - Department of Anatomy, College of Korean Medicine, Dongguk University, Gyeongju, Gyeongbuk 38066, Korea. parkfamilyda@hanmail.net. FAU - Ahn, Ji Hyeon AU - Ahn JH AD - Department of Biomedical Science and Research Institute for Bioscience and Biotechnology, Hallym University, Chuncheon, Gangwon 24252, Korea. jh-ahn@hallym.ac.kr. FAU - Song, Minah AU - Song M AD - Center for Virus Research and Testing, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea. zlscydn@naver.com. FAU - Kim, Hyunjung AU - Kim H AD - Knotus Co. Ltd., Incheon 22014, Korea. nicolehkim@naver.com. FAU - Park, Cheol Woo AU - Park CW AD - Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24341, Korea. flfhflfh@naver.com. FAU - Park, Young Eun AU - Park YE AD - Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24341, Korea. taeparo@naver.com. FAU - Lee, Tae-Kyeong AU - Lee TK AD - Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24341, Korea. xorud312@naver.com. FAU - Lee, Jae-Chul AU - Lee JC AD - Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24341, Korea. anajclee@kangwon.ac.kr. FAU - Kim, Dae Won AU - Kim DW AD - Department of Biochemistry and Molecular Biology, and Research Institute of Oral Sciences, College of Dentistry, Gangneung-Wonju National University, Gangneung, Gangwon 25457, Korea. kimdw@gwnu.ac.kr. FAU - Lee, Choong-Hyun AU - Lee CH AD - Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan, Chungnam 31116, Korea. anaphy@dankook.ac.kr. FAU - Hwang, In Koo AU - Hwang IK AUID- ORCID: 0000-0002-0533-4638 AD - Department of Anatomy and Cell Biology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 08826, Korea. vetmed2@snu.ac.kr. FAU - Yan, Bing Chun AU - Yan BC AD - 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. bcyan@yzu.edu.cn. FAU - Ryoo, Sungwoo AU - Ryoo S AD - Department of Biological Sciences, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon 24341, Korea. ryoosw08@kangwon.ac.kr. FAU - Kim, Young-Myeong AU - Kim YM AD - Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24341, Korea. ymkim@kangwon.ac.kr. FAU - Kang, Il Jun AU - Kang IJ AUID- ORCID: 0000-0003-0314-5195 AD - Department of Food Science and Nutrition, Hallym University, Chuncheon, Gangwon 24252, Korea. ijkang@hallym.ac.kr. FAU - Won, Moo-Ho AU - Won MH AUID- ORCID: 0000-0002-7178-6501 AD - Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon 24341, Korea. mhwon@kangwon.ac.kr. FAU - Choi, Soo Young AU - Choi SY AD - Department of Biomedical Science and Research Institute for Bioscience and Biotechnology, Hallym University, Chuncheon, Gangwon 24252, Korea. sychoi@hallym.ac.kr. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190922 PL - Switzerland TA - Cells JT - Cells JID - 101600052 RN - 0 (Interleukin-1beta) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Case-Control Studies MH - Cell Death MH - Diet, High-Fat/adverse effects MH - Disease Models, Animal MH - Gerbillinae MH - Hippocampus/cytology/metabolism/*pathology MH - Interleukin-1beta/metabolism MH - Ischemic Attack, Transient/*complications/metabolism/pathology MH - Male MH - Neurons/cytology/metabolism MH - Obesity/chemically induced/*metabolism/*pathology MH - Oxidative Stress/drug effects MH - Phosphorylation MH - Sirolimus/pharmacology MH - TOR Serine-Threonine Kinases/*metabolism MH - Tumor Necrosis Factor-alpha/metabolism MH - Up-Regulation PMC - PMC6830098 OTO - NOTNLM OT - brief transient ischemia OT - mammalian target of rapamycin OT - neuroinflammation OT - neuronal death OT - obesity OT - oxidative stress COIS- The authors have no financial conflict of interest. EDAT- 2019/09/25 06:00 MHDA- 2020/06/17 06:00 PMCR- 2019/10/01 CRDT- 2019/09/25 06:00 PHST- 2019/08/24 00:00 [received] PHST- 2019/09/19 00:00 [revised] PHST- 2019/09/20 00:00 [accepted] PHST- 2019/09/25 06:00 [entrez] PHST- 2019/09/25 06:00 [pubmed] PHST- 2020/06/17 06:00 [medline] PHST- 2019/10/01 00:00 [pmc-release] AID - cells8101126 [pii] AID - cells-08-01126 [pii] AID - 10.3390/cells8101126 [doi] PST - epublish SO - Cells. 2019 Sep 22;8(10):1126. doi: 10.3390/cells8101126.