Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration

Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5473-8. doi: 10.1073/pnas.0837397100. Epub 2003 Apr 17.

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder of uncertain pathogenesis characterized by the loss of the nigrostriatal dopaminergic neurons, which can be modeled by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Increased expression of cyclooxygenase type 2 (COX-2) and production of prostaglandin E(2) have been implicated in neurodegeneration in several pathological settings. Here we show that COX-2, the rate-limiting enzyme in prostaglandin E(2) synthesis, is up-regulated in brain dopaminergic neurons of both PD and MPTP mice. COX-2 induction occurs through a JNKc-Jun-dependent mechanism after MPTP administration. We demonstrate that targeting COX-2 does not protect against MPTP-induced dopaminergic neurodegeneration by mitigating inflammation. Instead, we provide evidence that COX-2 inhibition prevents the formation of the oxidant species dopamine-quinone, which has been implicated in the pathogenesis of PD. This study supports a critical role for COX-2 in both the pathogenesis and selectivity of the PD neurodegenerative process. Because of the safety record of the COX-2 inhibitors, and their ability to penetrate the blood-brain barrier, these drugs may be therapies for PD.

Publication types

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

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / pharmacology
  • Animals
  • Catalysis
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / pharmacology
  • Enzyme Activation
  • Humans
  • Immunohistochemistry
  • Isoenzymes / metabolism*
  • JNK Mitogen-Activated Protein Kinases
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Microglia / drug effects
  • Mitogen-Activated Protein Kinases / metabolism
  • Parkinson Disease / enzymology
  • Parkinson Disease / pathology*
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Isoenzymes
  • Membrane Proteins
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases