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Involvement of oxidative stress-mediated ERK1/2 and p38 activation regulated mitochondria-dependent apoptotic signals in methylmercury-induced neuronal cell injury |
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| Authors: | Lu Tien-Hui Hsieh Shan-Yu Yen Cheng-Chien Wu Hsi-Chin Chen Kuo-Liang Hung Dong-Zong Chen Chun-Hung Wu Chin-Ching Su Yi-Chang Chen Ya-Wen Liu Shing-Hwa Huang Chun-Fa |
| Affiliation: | a Graduate Institute of Drug Safety, College of Pharmacy, China Medical University, Taichung 404, Taiwan b School of Pharmacy, College of Pharmacy, China Medical University, Taichung 404, Taiwan c Department of Occupational Safety and Health, College of Health Care and Management, Chung Shan Medical University, Taichung 402, Taiwan d Department of Occupational Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan e Department of Urology, China Medical University Hospital, Taichung, Taiwan f Toxicology Center, China Medical University Hospital, Taichung 404, Taiwan g Department of Emergency, China Medical University Hospital, Taichung 404, Taiwan h Department of Public Health, China Medical University, Taichung 404, Taiwan i School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan j Department of Physiology, and Graduate Institute of Basic Medical Science, College of Medicine China Medical University, Taichung 404, Taiwan k Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100, Taiwan |
| Abstract: | Methylmercury (MeHg) is well-known for causing irreversible damage in the central nervous system as well as a risk factor for inducing neuronal degeneration. However, the molecular mechanisms of MeHg-induced neurotoxicity remain unclear. Here, we investigated the effects and possible mechanisms of MeHg in the mouse cerebrum (in vivo) and in cultured Neuro-2a cells (in vitro). In vivo study showed that the levels of LPO in the plasma and cerebral cortex significantly increased after administration of MeHg (50 μg/kg/day) for 7 consecutive weeks. MeHg could also decrease glutathione level and increase the expressions of caspase-3, -7, and -9, accompanied by Bcl-2 down-regulation and up-regulation of Bax, Bak, and p53. Moreover, treatment of Neuro-2a cells with MeHg significantly reduced cell viability, increased oxidative stress damage, and induced several features of mitochondria-dependent apoptotic signals, including increased sub-G1 hypodiploids, mitochondrial dysfunctions, and the activation of PARP, and caspase cascades. These MeHg-induced apoptotic-related signals could be remarkably reversed by antioxidant NAC. MeHg also increased the phosphorylation of ERK1/2 and p38, but not JNK. Pharmacological inhibitors NAC, PD98059, and SB203580 attenuated MeHg-induced cytotoxicity, ERK1/2 and p38 activation, MMP loss, and caspase-3 activation in Neuro-2a cells. Taken together, these results suggest that the signals of ROS-mediated ERK1/2 and p38 activation regulated mitochondria-dependent apoptotic pathways that are involved in MeHg-induced neurotoxicity. |
| Keywords: | LPO, lipid peroxidation PARP, poly (ADP-ribose) polymerase NAC, N-acetylcysteine MAPKs, mitogen-activated protein kinases ERK, extracellular signal-regulated kinases JNK, c-Jun N-terminal kinases MMP, mitochondrial membrane potential ROS, reactive oxygen species GSH, glutathione |
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