The herbicide paraquat induces dopaminergic nigral apoptosis through sustained activation of the JNK pathway

J Biol Chem. 2004 Jul 30;279(31):32626-32. doi: 10.1074/jbc.M404596200. Epub 2004 May 20.

Abstract

Environmental exposure to the oxidant-producing herbicide paraquat has been implicated as a risk factor in Parkinson's disease. Although intraperitoneal paraquat injections in mice cause a selective loss of dopaminergic neurons in the substantia nigra pars compacta, the exact mechanism involved is still poorly understood. Our data show that paraquat induces the sequential phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun and the activation of caspase-3 and sequential neuronal death both in vitro and in vivo. These effects are diminished by the specific JNK inhibitor SP600125 and the antioxidant manganese(III) tetrakis (4-benzoic acid) porphyrin in vitro. Furthermore, JNK pathway inhibitor CEP-11004 effectively blocks paraquat-induced dopaminergic neuronal death in vivo. These results suggest that the JNK signaling cascade is a direct activator of the paraquat-mediated nigral dopaminergic neuronal apoptotic machinery and provides a molecular linkage between oxidative stress and neuronal apoptosis.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anthracenes / pharmacology
  • Antioxidants / pharmacology
  • Apoptosis*
  • Blotting, Western
  • Caspase 3
  • Caspases / metabolism
  • Cell Death
  • Cell Line
  • Cell Survival
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • Free Radical Scavengers / pharmacology
  • Herbicides / pharmacology*
  • Immunohistochemistry
  • JNK Mitogen-Activated Protein Kinases*
  • MAP Kinase Kinase 4
  • Male
  • Metalloporphyrins / pharmacology
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / metabolism*
  • Mitogen-Activated Protein Kinases / metabolism
  • Neurons / metabolism
  • Paraquat / pharmacology*
  • Phosphorylation
  • Rats
  • Receptors, Dopamine / metabolism*
  • Substantia Nigra / drug effects*
  • Substantia Nigra / pathology
  • Time Factors
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Anthracenes
  • Antioxidants
  • Free Radical Scavengers
  • Herbicides
  • Metalloporphyrins
  • Receptors, Dopamine
  • manganese(III)-tetrakis(4-benzoic acid)porphyrin
  • pyrazolanthrone
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Mitogen-Activated Protein Kinase Kinases
  • Casp3 protein, mouse
  • Casp3 protein, rat
  • Caspase 3
  • Caspases
  • Paraquat