Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration
Identifieur interne : 003548 ( Main/Merge ); précédent : 003547; suivant : 003549Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration
Auteurs : Peter Teismann ; Kim Tieu ; Dong-Kug Choi ; Du-Chu Wu ; Ali Naini ; Stéphane Hunot [France] ; Miquel Vila ; Vernice Jackson-Lewis ; Serge Przedborski [États-Unis]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2003.
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 E2 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.
Url:
DOI: 10.1073/pnas.0837397100
PubMed: 12702778
PubMed Central: 154369
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last="Przedborski">Serge Przedborski</name><affiliation><nlm:aff id="N0x9bf7258.0xaf0e928">Neuroscience Research Laboratories of the Movement Disorder Division, Department of Neurology,</nlm:aff><wicri:noCountry code="subfield">Department of Neurology</wicri:noCountry></affiliation><affiliation><nlm:aff wicri:cut=", and" id="N0x9bf7258.0xaf0e928">Department of Pathology</nlm:aff></affiliation><affiliation wicri:level="2"><nlm:aff wicri:cut="; and" id="N0x9bf7258.0xaf0e928">Center for Neurobiology and Behavior, Columbia University, New York, NY 10032</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>Center for Neurobiology and Behavior, Columbia University, New York</wicri:cityArea></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2003">2003</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>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<sub>2</sub> have been implicated in neurodegeneration in several pathological settings. Here we show that COX-2, the rate-limiting enzyme in prostaglandin E<sub>2</sub> 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.</p></div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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