SP600125, a new JNK inhibitor, protects dopaminergic neurons in the MPTP model of Parkinson's disease

Neurosci Res. 2004 Feb;48(2):195-202. doi: 10.1016/j.neures.2003.10.012.

Abstract

Increasing evidence suggests that c-Jun N-terminal kinase (JNK) is an important kinase mediating neuronal apoptosis in Parkinson's disease (PD) model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In order to study roles of JNK activity in neuronal apoptosis in this model, we blocked JNK activity in vivo using a specific inhibitor of JNK, SP600125. Our data showed that MPTP-induced phospho-c-Jun of substantial nigral neurons, caused apoptosis of dopaminergic neurons, and decreased the dopamine level in striatal area. We found that inhibiting JNK with SP600125 reduced the levels of c-Jun phosphorylation, protected dopaminergic neurons from apoptosis, and partly restored the level of dopamine in MPTP-induced PD in C57BL/6N mice. These results indicate that JNK pathway is the major mediator of the neurotoxic effects of MPTP in vivo and inhibiting JNK activity may represent a new and effective strategy to treat PD.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology
  • Animals
  • Anthracenes / pharmacology
  • Anthracenes / therapeutic use*
  • Corpus Striatum / drug effects
  • Corpus Striatum / enzymology
  • Dopamine / metabolism*
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • JNK Mitogen-Activated Protein Kinases
  • MPTP Poisoning / drug therapy*
  • MPTP Poisoning / enzymology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinases / metabolism
  • Neurons / drug effects
  • Neurons / enzymology

Substances

  • Anthracenes
  • Enzyme Inhibitors
  • pyrazolanthrone
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Dopamine