Cyclooxygenase-2 is instrumental in Parkinson disease neurodegeneration

Peter Teismann, K. Tieu, D. -. K. Choi, D. C. Wu, A. Naini, S. Hunot, M. Vila, V. Jackson-Lewis, S. Przedborski

Research output: Contribution to journalArticle

531 Citations (Scopus)

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 E2 synthesis, is up-regulated in brain dopaminergic neurons of both PD and MPTP mice. COX-2 induction occurs through a JNK/c-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.

Original languageEnglish
Pages (from-to)5473-5478
Number of pages5
JournalPNAS
Volume100
Issue number9
Early online date17 Apr 2003
DOIs
Publication statusPublished - 29 Apr 2003

Keywords

  • nitric-oxide
  • mouse model
  • mptp
  • prostaglandin
  • expression
  • dopamine
  • neurons
  • kinase
  • oxidation
  • mechanism

Cite this

Teismann, P., Tieu, K., Choi, D. . K., Wu, D. C., Naini, A., Hunot, S., Vila, M., Jackson-Lewis, V., & Przedborski, S. (2003). Cyclooxygenase-2 is instrumental in Parkinson disease neurodegeneration. PNAS, 100(9), 5473-5478. https://doi.org/10.1073/pnas.0837397100