title: Microcystin-LR-caused ROS generation involved in p38 activation and tau hyperphosphorylation in neuroendocrine (PC12) cells.
abstract: Microcystin-LR (MC-LR), a potent specific hepatotoxin produced by cyanobacteria, has recently been reported to show neurotoxicity. Our previous study demonstrated that MC-LR caused the reorganization of cytoskeleton architectures and hyperphosphorylation of the cytoskeletal-associated proteins tau and HSP27 in neuroendocrine PC12 cell line by direct PP2A inhibition and indirect p38 mitogen-activated protein kinase (MAPK) activation. It has been shown that oxidative stress is extensively associated with MC-LR toxicity, mainly resulting from an excessive production of reactive oxygen species (ROS). However, the mechanisms by which ROS mediates the cytotoxic action of MC-LR are unclear. In the present study, we investigated whether ROS might play a critical role in MC-LR-induced hyperphosphorylation of microtubule-associated protein tau and the activation of the MAPKs in PC12 cell line. The results showed that MC-LR had time- and concentration-dependent effects on ROS generation, p38-MAPK activation and tau phosphorylation. The time-course studies indicated similar biphasic changes in ROS generation and tau hyperphosphorylation, which started to increase within 1 h and reached the maximum level at 3 h followed by a decrease after prolonged treatment. Furthermore, pretreatment with the antioxidants, N-acetylcysteine and vitamin C, significantly decreased MC-LR-induced ROS generation and effectively attenuated p38-MAPK activation as well as tau hyperphosphorylation. Taken together, these findings suggest that ROS generation triggered by MC-LR is a key intracellular event that contributes to an induction of p38-MAPK activation and tau phosphorylation, and that blockade of this ROS-mediated redox-sensitive signal cascades may attenuate the toxic effects of MC-LR.
authors.affiliation: Department of Clinical Laboratory, Tongde Hospital of Zhejiang Province, 234 Gucui Road, Hangzhou, 310012, China; Department of Biochemistry, School of Medicine, Zhejiang University, 866th Yu Hang Tang Road, Hangzhou, 310058, China.
authors.forename: Guanmin
authors.initials: G
authors.lastname: Meng
authors.forename: Jinghui
authors.initials: J
authors.lastname: Liu
authors.forename: Shuyan
authors.initials: S
authors.lastname: Lin
authors.forename: Zonglou
authors.initials: Z
authors.lastname: Guo
authors.forename: Lihong
authors.initials: L
authors.lastname: Xu
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D008387:Marine Toxins; D052998:Microcystins / Q000633:toxicity*; D010084:Oxidation-Reduction; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D008387:Marine Toxins; D052998:Microcystins; D017382:Reactive Oxygen Species; D016875:tau Proteins; D048051:p38 Mitogen-Activated Protein Kinases; C057862:cyanoginosin LR
keywords: microcystin-LR; p38 mitogen-activated protein kinase; reactive oxygen species; tau hyperphosphorylation