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

Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration.

Author information

1
Neuroscience Research Laboratories of the Movement Disorder Division, Department of Neurology, Columbia University, New York, NY 10032, USA.

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.

PMID:
12702778
PMCID:
PMC154369
DOI:
10.1073/pnas.0837397100
[Indexed for MEDLINE]
Free PMC Article

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