PMID- 27764525 OWN - NLM STAT- MEDLINE DCOM- 20171106 LR - 20211204 IS - 1476-5381 (Electronic) IS - 0007-1188 (Print) IS - 0007-1188 (Linking) VI - 174 IP - 1 DP - 2017 Jan TI - Celastrol prevents cadmium-induced neuronal cell death by blocking reactive oxygen species-mediated mammalian target of rapamycin pathway. PG - 82-100 LID - 10.1111/bph.13655 [doi] AB - BACKGROUND AND PURPOSE: Increasing evidence has suggested cadmium (Cd), as an inducer of ROS, is a potential pathogenic factor in human neurodegenerative diseases. Thus, it is important to find effective interventions for Cd-induced oxidative stress in the CNS. Here, we have studied the effects of celastrol, a plant-derived triterpene, on ROS production and cell death in neuronal cells, induced by Cd. EXPERIMENTAL APPROACH: PC12, SH-SY5Y cells and primary murine neurons were used to study celastrol neuroprotection against Cd-poisoning. Cd-induced changes in cell viability, apoptosis, ROS and AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway in the cells were analysed by Trypan blue exclusion, DAPI and TUNEL staining, ROS imaging, immunofluorescence staining and Western blotting. Pharmacological and genetic approaches were employed to investigate the mechanisms underlying Cd neurotoxicity. RESULTS: Celastrol attenuated Cd-induced apoptosis by suppressing Cd activation of mTOR, which was attributed to preventing Cd inactivation of AMPK. Inhibition of AMPK with compound C or expression of dominant negative AMPKalpha prevented celastrol from hindering Cd-induced dephosphorylation of AMPKalpha, activation of mTOR and apoptosis. Inhibition of mTOR with rapamycin or knockdown of mTOR potentiated prevention by celastrol, of Cd-induced phosphorylation of p70 S6 kinase 1/eukaryotic initiation factor 4E binding protein 1 and apoptosis. Celastrol attenuated Cd-induced cell death by suppressing induction of mitochondrial ROS. CONCLUSIONS AND IMPLICATIONS: Celastrol prevented the inactivation of AMPK by mitochondrial ROS, thus attenuating Cd-induced mTOR activation and neuronal apoptosis. Celastrol may be a promising agent for prevention of Cd-induced oxidative stress and neurodegenerative diseases. CI - (c) 2016 The British Pharmacological Society. FAU - Zhang, Ruijie AU - Zhang R AD - Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, China. FAU - Zhang, Nana AU - Zhang N AD - Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, China. FAU - Zhang, Hai AU - Zhang H AD - Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, China. FAU - Liu, Chunxiao AU - Liu C AD - Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, China. FAU - Dong, Xiaoqing AU - Dong X AD - Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, China. FAU - Wang, Xiaoxue AU - Wang X AD - Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, China. FAU - Zhu, Yu AU - Zhu Y AD - Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, China. FAU - Xu, Chong AU - Xu C AD - Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, China. FAU - Liu, Lei AU - Liu L AD - Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA. AD - Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, USA. FAU - Yang, Sijun AU - Yang S AD - ABSL-III Laboratory for Animal Experiment Center, State Key Laboratory of Virology, Wuhan University School of Medicine, Wuhan, China. FAU - Huang, Shile AU - Huang S AD - Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, USA. AD - Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, USA. FAU - Chen, Long AU - Chen L AD - Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, China. LA - eng GR - R01 CA115414/CA/NCI NIH HHS/United States PT - Journal Article DEP - 20161121 PL - England TA - Br J Pharmacol JT - British journal of pharmacology JID - 7502536 RN - 0 (Pentacyclic Triterpenes) RN - 0 (Reactive Oxygen Species) RN - 0 (Triterpenes) RN - 00BH33GNGH (Cadmium) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - L8GG98663L (celastrol) SB - IM MH - Animals MH - Apoptosis/drug effects MH - Cadmium/*toxicity MH - Cell Death/*drug effects MH - Dose-Response Relationship, Drug MH - Humans MH - Mitochondria/drug effects/metabolism MH - Neurons/*drug effects/metabolism MH - Pentacyclic Triterpenes MH - Rats MH - Reactive Oxygen Species/*metabolism MH - Structure-Activity Relationship MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism MH - Triterpenes/*pharmacology MH - Tumor Cells, Cultured PMC - PMC5341486 EDAT- 2016/10/21 06:00 MHDA- 2017/11/07 06:00 PMCR- 2018/01/01 CRDT- 2016/10/21 06:00 PHST- 2016/07/06 00:00 [received] PHST- 2016/09/06 00:00 [revised] PHST- 2016/10/12 00:00 [accepted] PHST- 2016/10/21 06:00 [pubmed] PHST- 2017/11/07 06:00 [medline] PHST- 2016/10/21 06:00 [entrez] PHST- 2018/01/01 00:00 [pmc-release] AID - BPH13655 [pii] AID - 10.1111/bph.13655 [doi] PST - ppublish SO - Br J Pharmacol. 2017 Jan;174(1):82-100. doi: 10.1111/bph.13655. Epub 2016 Nov 21.