期刊
NEUROPHARMACOLOGY
卷 105, 期 -, 页码 270-284出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2016.01.030
关键词
Rapamycin; Cadmium; Apoptosis; MAPK; ROS; PP2A
资金
- National Natural Science Foundation of China [30971486, 81271416]
- NIH [CA115414]
- Scientific Research Foundation of the State Education Ministry of China [SEMR20091341]
- Project for the Priority Academic Program Development
- Natural Science Foundation of Jiangsu Higher Education Institutions of China [10KJA180027]
- American Cancer Society [RSG-08-135-01-CNE]
- Louisiana Board of Regents [NSF-2009-PFUND-144]
- Innovative Research Program of Jiangsu College Graduate of China [KYLX15_0733]
Cadmium (Cd) is a highly toxic metal that affects the central nervous system. Recently we have demonstrated that inhibition of mTOR by rapamycin rescues neuronal cells from Cd-poisoning. Here we show that rapamycin inhibited Cd-induced mitochondrial ROS-dependent neuronal apoptosis. Intriguingly, rapamycin remarkably blocked phosphorylation of JNK, Erk1/2 and p38 in neuronal cells induced by Cd, which was strengthened by co-treatment with Mito-TEMPO. Inhibition of JNK and Erk1/2 by SP600125 and U0126, respectively, potentiated rapamycin's prevention from Cd-induced apoptosis. Consistently, over-expression of dominant negative c-Jun or MKK1 also potently improved the inhibitory effect of rapamycin on Cd neurotoxicity. Furthermore, pretreatment with SP600125 or U0126, or expression of dominant negative c-Jun or MKK1 enhanced the inhibitory effects of rapamycin or Mito-TEMPO on Cd-induced ROS. Further investigation found that co-treatment with Mito-TEMPO/rapamycin more effectively rescued cells by preventing Cd inactivation of PP2A than treatment with rapamycin or Mito-TEMPO alone. Over-expression of wild-type PP2A reinforced rapamycin or Mito-TEMPO suppression of activated JNK and Erk1/2 pathways, as well as ROS production and apoptosis in neuronal cells in response to Cd. The findings indicate that rapamycin ameliorates Cd-evoked neuronal apoptosis by preventing mitochondrial ROS inactivation of PP2A, thereby suppressing activation of JNK and Erk1/2 pathways. Our results underline that rapamycin may have a potential in preventing Cd-induced oxidative stress and neurodegenerative diseases. (C) 2016 Elsevier Ltd. All rights reserved.
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