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Celastrol prevents cadmium‐induced neuronal cell death by blocking reactive oxygen species‐mediated mammalian target of rapamycin pathway
Author(s) -
Zhang Ruijie,
Zhang Nana,
Zhang Hai,
Liu Chunxiao,
Dong Xiaoqing,
Wang Xiaoxue,
Zhu Yu,
Xu Chong,
Liu Lei,
Yang Sijun,
Huang Shile,
Chen Long
Publication year - 2017
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13655
Subject(s) - celastrol , pi3k/akt/mtor pathway , ampk , microbiology and biotechnology , programmed cell death , chemistry , apoptosis , protein kinase b , p70 s6 kinase 1 , viability assay , protein kinase a , reactive oxygen species , signal transduction , biology , phosphorylation , biochemistry
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 AMPKα prevented celastrol from hindering Cd‐induced dephosphorylation of AMPKα, 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.