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Thus, it is important to find effective interventions for Cd\u2010induced oxidative stress in the CNS. Here, we have studied the effects of celastrol, a plant\u2010derived triterpene, on ROS production and cell death in neuronal cells, induced by Cd.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>PC12, SH\u2010SY5Y cells and primary murine neurons were used to study celastrol neuroprotection against Cd\u2010poisoning. Cd\u2010induced changes in cell viability, apoptosis, ROS and AMP\u2010activated 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Celastrol attenuated Cd\u2010induced 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 AMPK\u03b1 prevented celastrol from hindering Cd\u2010induced dephosphorylation of AMPK\u03b1, activation of mTOR and apoptosis. Inhibition of mTOR with rapamycin or knockdown of mTOR potentiated prevention by celastrol, of Cd\u2010induced phosphorylation of p70 S6 kinase 1\/eukaryotic initiation factor 4E binding protein 1 and apoptosis. Celastrol attenuated Cd\u2010induced cell death by suppressing induction of mitochondrial ROS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Celastrol prevented the inactivation of AMPK by mitochondrial ROS, thus attenuating Cd\u2010induced mTOR activation and neuronal apoptosis. Celastrol may be a promising agent for prevention of Cd\u2010induced oxidative stress and neurodegenerative diseases.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13655","type":"journal-article","created":{"date-parts":[[2016,10,20]],"date-time":"2016-10-20T16:42:40Z","timestamp":1476981760000},"page":"82-100","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Celastrol prevents cadmium\u2010induced neuronal cell death by blocking reactive oxygen species\u2010mediated mammalian target of rapamycin pathway"],"prefix":"10.1111","volume":"174","author":[{"given":"Ruijie","family":"Zhang","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences Nanjing Normal University  Nanjing 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