Journal Article

Cyclooxygenase-2 Is Instrumental in Parkinson's Disease Neurodegeneration

Tieu, Kim, Wu, Du-Chu, Teismann, Peter, Vila, Miquel, Choi, Dong-Kug, Naini, Ali, Jackson-Lewis, Vernice, Przedborski, Serge, Hunot, Stéphane

2003

Overview

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 E2have been implicated in neurodegeneration in several pathological settings. Here we show that COX-2, the rate-limiting enzyme in prostaglandin E2synthesis, 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.

• Publisher: National Academy of Sciences,National Acad Sciences,The National Academy of Sciences
• Subject: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - pharmacology / Animals / Biological Sciences / Catalysis / Cyclooxygenase 2 / Cyclooxygenase 2 Inhibitors / Cyclooxygenase inhibitors / Cyclooxygenase Inhibitors - pharmacology / Dopaminergic neurons / Enzyme Activation / Enzymes / Humans / Immunohistochemistry / Isoenzymes - metabolism / JNK Mitogen-Activated Protein Kinases / Membrane Proteins / Messenger RNA / Mice / Mice, Inbred C57BL / Microglia - drug effects / Midbrain / Mitogen-Activated Protein Kinases - metabolism / Neurological disorders / Neurons / Neurotoxicity / Neurotoxins / Oxidizing agents / Parkinson Disease - enzymology / Parkinson Disease - pathology / Parkinson's disease / Particle accelerators / Prostaglandin-Endoperoxide Synthases - metabolism / Prostaglandins / Reverse Transcriptase Polymerase Chain Reaction / Up regulation