Caspase-11 mediates inflammatory dopaminergic cell death in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease

J Neurosci. 2004 Feb 25;24(8):1865-72. doi: 10.1523/JNEUROSCI.3309-03.2004.

Abstract

The present study was designed to elucidate the inflammatory and apoptotic mechanisms of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in a model of Parkinson's disease. Our results showed that mutant mice lacking the caspase-11 gene were significantly more resistant to the effects of acute treatment with MPTP than their wild-type mice. Thus, the neurotoxicity of MPTP seems to be mediated by the induction of both mitochondrial dysfunction and free radical generation. Previously, we showed that overexpression of the Apaf-1 dominant-negative inhibitor inhibited the mitochondrial apoptotic cascade in chronic MPTP treatment but not in acute MPTP treatment. The present results indicate that MPTP neurotoxicity may be mediated via activation of the caspase-11 cascade and inflammatory cascade, as well as the mitochondrial apoptotic cascade.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics*
  • Caspase Inhibitors
  • Caspases / genetics
  • Caspases / metabolism*
  • Caspases, Initiator
  • Cell Count
  • Disease Models, Animal
  • Dopamine / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Immunoblotting
  • Immunohistochemistry
  • Inflammation Mediators / metabolism
  • Interleukin-1 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / drug effects
  • Microglia / metabolism
  • Microglia / pathology
  • Neostriatum / drug effects
  • Neostriatum / pathology
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Nitric Oxide Synthase / drug effects
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type II
  • Parkinsonian Disorders / chemically induced
  • Parkinsonian Disorders / pathology
  • Parkinsonian Disorders / physiopathology*
  • Substantia Nigra / drug effects
  • Substantia Nigra / pathology
  • Time Factors
  • Up-Regulation

Substances

  • Caspase Inhibitors
  • Enzyme Inhibitors
  • Inflammation Mediators
  • Interleukin-1
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Casp4 protein, mouse
  • Caspases
  • Caspases, Initiator
  • Dopamine