Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration
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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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Peter Teismann<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 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 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 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 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 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 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 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>Le document en format XML
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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></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">12702778</idno><idno type="pmc">154369</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC154369</idno><idno type="RBID">PMC:154369</idno><idno type="doi">10.1073/pnas.0837397100</idno><date when="2003">2003</date><idno type="wicri:Area/Pmc/Corpus">000215</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000215</idno><idno type="wicri:Area/Pmc/Curation">000213</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000213</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration</title><author><name sortKey="Teismann, Peter" sort="Teismann, Peter" uniqKey="Teismann P" first="Peter" last="Teismann">Peter Teismann</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></author><author><name sortKey="Tieu, Kim" sort="Tieu, Kim" uniqKey="Tieu K" first="Kim" last="Tieu">Kim Tieu</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></author><author><name sortKey="Choi, Dong Kug" sort="Choi, Dong Kug" uniqKey="Choi D" first="Dong-Kug" last="Choi">Dong-Kug Choi</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></author><author><name sortKey="Wu, Du Chu" sort="Wu, Du Chu" uniqKey="Wu D" first="Du-Chu" last="Wu">Du-Chu Wu</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></author><author><name sortKey="Naini, Ali" sort="Naini, Ali" uniqKey="Naini A" first="Ali" last="Naini">Ali Naini</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></author><author><name sortKey="Hunot, Stephane" sort="Hunot, Stephane" uniqKey="Hunot S" first="Stéphane" last="Hunot">Stéphane Hunot</name><affiliation wicri:level="1"><nlm:aff id="N0x9bf7258.0xaf0e928">Institut National de la Santé et de la Recherche Médicale U289, Hôpital de la Salpêtière, 75013 Paris, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut National de la Santé et de la Recherche Médicale U289, Hôpital de la Salpêtière, 75013 Paris</wicri:regionArea></affiliation></author><author><name sortKey="Vila, Miquel" sort="Vila, Miquel" uniqKey="Vila M" first="Miquel" last="Vila">Miquel Vila</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></author><author><name sortKey="Jackson Lewis, Vernice" sort="Jackson Lewis, Vernice" uniqKey="Jackson Lewis V" first="Vernice" last="Jackson-Lewis">Vernice Jackson-Lewis</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></author><author><name sortKey="Przedborski, Serge" sort="Przedborski, Serge" uniqKey="Przedborski S" first="Serge" 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><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Proc Natl Acad Sci U S A</journal-id><journal-id journal-id-type="publisher-id">PNAS</journal-id><journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title><issn pub-type="ppub">0027-8424</issn><issn pub-type="epub">1091-6490</issn><publisher><publisher-name>The National Academy of Sciences</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">12702778</article-id><article-id pub-id-type="pmc">154369</article-id><article-id pub-id-type="publisher-id">0837397100</article-id><article-id pub-id-type="publisher-id">7397</article-id><article-id pub-id-type="doi">10.1073/pnas.0837397100</article-id><article-categories><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Neuroscience</subject></subj-group></subj-group></article-categories><title-group><article-title>Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Teismann</surname><given-names>Peter</given-names></name><xref ref-type="aff" rid="N0x9bf7258.0xaf0e928">*</xref></contrib><contrib contrib-type="author"><name><surname>Tieu</surname><given-names>Kim</given-names></name><xref ref-type="aff" rid="N0x9bf7258.0xaf0e928">*</xref></contrib><contrib contrib-type="author"><name><surname>Choi</surname><given-names>Dong-Kug</given-names></name><xref ref-type="aff" rid="N0x9bf7258.0xaf0e928">*</xref></contrib><contrib contrib-type="author"><name><surname>Wu</surname><given-names>Du-Chu</given-names></name><xref ref-type="aff" rid="N0x9bf7258.0xaf0e928">*</xref></contrib><contrib contrib-type="author"><name><surname>Naini</surname><given-names>Ali</given-names></name><xref ref-type="aff" rid="N0x9bf7258.0xaf0e928">*</xref></contrib><contrib contrib-type="author"><name><surname>Hunot</surname><given-names>Stéphane</given-names></name><xref ref-type="aff" rid="N0x9bf7258.0xaf0e928">†</xref></contrib><contrib contrib-type="author"><name><surname>Vila</surname><given-names>Miquel</given-names></name><xref ref-type="aff" rid="N0x9bf7258.0xaf0e928">*</xref></contrib><contrib contrib-type="author"><name><surname>Jackson-Lewis</surname><given-names>Vernice</given-names></name><xref ref-type="aff" rid="N0x9bf7258.0xaf0e928">*</xref></contrib><contrib contrib-type="author"><name><surname>Przedborski</surname><given-names>Serge</given-names></name><xref ref-type="aff" rid="N0x9bf7258.0xaf0e928">*</xref><xref ref-type="aff" rid="N0x9bf7258.0xaf0e928">‡</xref><xref ref-type="aff" rid="N0x9bf7258.0xaf0e928">§</xref><xref ref-type="author-notes" rid="FN154">¶</xref></contrib></contrib-group><aff id="N0x9bf7258.0xaf0e928"><label>*</label>Neuroscience Research Laboratories of the Movement Disorder Division, Department of Neurology,<label>‡</label>Department of Pathology, and<label>§</label>Center for Neurobiology and Behavior, Columbia University, New York, NY 10032; and<label>†</label>Institut National de la Santé et de la Recherche Médicale U289, Hôpital de la Salpêtière, 75013 Paris, France</aff><author-notes><fn id="FN154"><label>¶</label><p>To whom correspondence should be addressed at: Departments of Neurology and Pathology, BB-307, Columbia University, 650 West 168th Street, New York, NY 10032. E-mail: <email>sp30@columbia.edu</email>.</p></fn><fn><p>Edited by Richard D. Palmiter, University of Washington School of Medicine, Seattle, WA, and approved February 14, 2003</p></fn></author-notes><pub-date pub-type="ppub"><day>29</day><month>4</month><year>2003</year></pub-date><pub-date pub-type="epub"><day>17</day><month>4</month><year>2003</year></pub-date><volume>100</volume><issue>9</issue><fpage>5473</fpage><lpage>5478</lpage><history><date date-type="received"><day>11</day><month>12</month><year>2002</year></date></history><copyright-statement>Copyright © 2003, The National Academy of Sciences</copyright-statement><copyright-year>2003</copyright-year><abstract><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></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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