Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration
Identifieur interne : 000325 ( Ncbi/Merge ); précédent : 000324; suivant : 000326Cyclooxygenase-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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<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>
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<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>
<affiliations><list><country><li>France</li>
<li>États-Unis</li>
</country>
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<li>Île-de-France</li>
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</settlement>
</list>
<tree><noCountry><name sortKey="Choi, Dong Kug" sort="Choi, Dong Kug" uniqKey="Choi D" first="Dong-Kug" last="Choi">Dong-Kug Choi</name>
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<name sortKey="Naini, Ali" sort="Naini, Ali" uniqKey="Naini A" first="Ali" last="Naini">Ali Naini</name>
<name sortKey="Teismann, Peter" sort="Teismann, Peter" uniqKey="Teismann P" first="Peter" last="Teismann">Peter Teismann</name>
<name sortKey="Tieu, Kim" sort="Tieu, Kim" uniqKey="Tieu K" first="Kim" last="Tieu">Kim Tieu</name>
<name sortKey="Vila, Miquel" sort="Vila, Miquel" uniqKey="Vila M" first="Miquel" last="Vila">Miquel Vila</name>
<name sortKey="Wu, Du Chu" sort="Wu, Du Chu" uniqKey="Wu D" first="Du-Chu" last="Wu">Du-Chu Wu</name>
</noCountry>
<country name="France"><region name="Île-de-France"><name sortKey="Hunot, Stephane" sort="Hunot, Stephane" uniqKey="Hunot S" first="Stéphane" last="Hunot">Stéphane Hunot</name>
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<country name="États-Unis"><region name="État de New York"><name sortKey="Przedborski, Serge" sort="Przedborski, Serge" uniqKey="Przedborski S" first="Serge" last="Przedborski">Serge Przedborski</name>
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