Microcystin-LR-Caused ROS generation involved in p38 activation and tau hyperphosphorylation in neuroendocrine (PC12) cells

Guanmin Meng, Jinghui Liu, Shuyan Lin, Zonglou Guo, Lihong Xu

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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.

Original languageEnglish
Pages (from-to)366-374
Number of pages9
JournalEnvironmental Toxicology
Volume30
Issue number3
DOIs
StatePublished - Mar 1 2015

Bibliographical note

Publisher Copyright:
© 2013 Wiley Periodicals, Inc.

Keywords

  • Microcystin-LR
  • P38 mitogen-activated protein kinase
  • Reactive oxygen species
  • Tau hyperphosphorylation

ASJC Scopus subject areas

  • Toxicology
  • Management, Monitoring, Policy and Law
  • Health, Toxicology and Mutagenesis

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