title: Involvement of oxidative stress-mediated ERK1/2 and p38 activation regulated mitochondria-dependent apoptotic signals in methylmercury-induced neuronal cell injury.
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 (50μg/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.
authors.affiliation: Graduate Institute of Drug Safety, College of Pharmacy, China Medical University, Taichung 404, Taiwan.
authors.forename: Tien-Hui
authors.initials: TH
authors.lastname: Lu
authors.forename: Shan-Yu
authors.initials: SY
authors.lastname: Hsieh
authors.forename: Cheng-Chien
authors.initials: CC
authors.lastname: Yen
authors.forename: Hsi-Chin
authors.initials: HC
authors.lastname: Wu
authors.forename: Kuo-Liang
authors.initials: KL
authors.lastname: Chen
authors.forename: Dong-Zong
authors.initials: DZ
authors.lastname: Hung
authors.forename: Chun-Hung
authors.initials: CH
authors.lastname: Chen
authors.forename: Chin-Ching
authors.initials: CC
authors.lastname: Wu
authors.forename: Yi-Chang
authors.initials: YC
authors.lastname: Su
authors.forename: Ya-Wen
authors.initials: YW
authors.lastname: Chen
authors.forename: Shing-Hwa
authors.initials: SH
authors.lastname: Liu
authors.forename: Chun-Fa
authors.initials: CF
authors.lastname: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D005434:Flow Cytometry; D005978:Glutathione / Q000032:analysis; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008767:Methylmercury Compounds / Q000009:adverse effects* / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*
chemical_list: D008767:Methylmercury Compounds; D017382:Reactive Oxygen Species; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D005978:Glutathione