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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">JNK Inhibition Protects Dopamine Neurons and Provides Behavioral Improvement in a Rat 6-Hydroxydopamine Model of Parkinson’s Disease</title><author><name sortKey="Crocker, Candice E" sort="Crocker, Candice E" uniqKey="Crocker C" first="Candice E." last="Crocker">Candice E. Crocker</name><affiliation><nlm:aff id="aff2">Departments of Psychiatry and Pharmacology, Sir Charles Tuper Medical Building, Faculty of Medicine,<institution>Dalhousie University</institution>, 5850 College Street, Halifax, Nova Scotia, Canada B3H 1X5</nlm:aff></affiliation></author><author><name sortKey="Khan, Susan" sort="Khan, Susan" uniqKey="Khan S" first="Susan" last="Khan">Susan Khan</name><affiliation><nlm:aff id="aff1">Department of Molecular Therapeutics and Translational Research Institute,<institution>The Scripps Research Institute</institution>, Scripps Florida, 130 Scripps Way #A2A, Jupiter, Florida 33458, United States</nlm:aff></affiliation></author><author><name sortKey="Cameron, Michael D" sort="Cameron, Michael D" uniqKey="Cameron M" first="Michael D." last="Cameron">Michael D. Cameron</name><affiliation><nlm:aff id="aff1">Department of Molecular Therapeutics and Translational Research Institute,<institution>The Scripps Research Institute</institution>, Scripps Florida, 130 Scripps Way #A2A, Jupiter, Florida 33458, United States</nlm:aff></affiliation></author><author><name sortKey="Robertson, Harold A" sort="Robertson, Harold A" uniqKey="Robertson H" first="Harold A." last="Robertson">Harold A. Robertson</name><affiliation><nlm:aff id="aff2">Departments of Psychiatry and Pharmacology, Sir Charles Tuper Medical Building, Faculty of Medicine,<institution>Dalhousie University</institution>, 5850 College Street, Halifax, Nova Scotia, Canada B3H 1X5</nlm:aff></affiliation></author><author><name sortKey="Robertson, George S" sort="Robertson, George S" uniqKey="Robertson G" first="George S." last="Robertson">George S. Robertson</name><affiliation><nlm:aff id="aff2">Departments of Psychiatry and Pharmacology, Sir Charles Tuper Medical Building, Faculty of Medicine,<institution>Dalhousie University</institution>, 5850 College Street, Halifax, Nova Scotia, Canada B3H 1X5</nlm:aff></affiliation></author><author><name sortKey="Lograsso, Philip" sort="Lograsso, Philip" uniqKey="Lograsso P" first="Philip" last="Lograsso">Philip Lograsso</name><affiliation><nlm:aff id="aff1">Department of Molecular Therapeutics and Translational Research Institute,<institution>The Scripps Research Institute</institution>, Scripps Florida, 130 Scripps Way #A2A, Jupiter, Florida 33458, United States</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">21666838</idno><idno type="pmc">3110072</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110072</idno><idno type="RBID">PMC:3110072</idno><idno type="doi">10.1021/cn1001107</idno><date when="2011">2011</date><idno type="wicri:Area/Pmc/Corpus">000185</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000185</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">JNK Inhibition Protects Dopamine Neurons and Provides Behavioral Improvement in a Rat 6-Hydroxydopamine Model of Parkinson’s Disease</title><author><name sortKey="Crocker, Candice E" sort="Crocker, Candice E" uniqKey="Crocker C" first="Candice E." last="Crocker">Candice E. Crocker</name><affiliation><nlm:aff id="aff2">Departments of Psychiatry and Pharmacology, Sir Charles Tuper Medical Building, Faculty of Medicine,<institution>Dalhousie University</institution>, 5850 College Street, Halifax, Nova Scotia, Canada B3H 1X5</nlm:aff></affiliation></author><author><name sortKey="Khan, Susan" sort="Khan, Susan" uniqKey="Khan S" first="Susan" last="Khan">Susan Khan</name><affiliation><nlm:aff id="aff1">Department of Molecular Therapeutics and Translational Research Institute,<institution>The Scripps Research Institute</institution>, Scripps Florida, 130 Scripps Way #A2A, Jupiter, Florida 33458, United States</nlm:aff></affiliation></author><author><name sortKey="Cameron, Michael D" sort="Cameron, Michael D" uniqKey="Cameron M" first="Michael D." last="Cameron">Michael D. Cameron</name><affiliation><nlm:aff id="aff1">Department of Molecular Therapeutics and Translational Research Institute,<institution>The Scripps Research Institute</institution>, Scripps Florida, 130 Scripps Way #A2A, Jupiter, Florida 33458, United States</nlm:aff></affiliation></author><author><name sortKey="Robertson, Harold A" sort="Robertson, Harold A" uniqKey="Robertson H" first="Harold A." last="Robertson">Harold A. Robertson</name><affiliation><nlm:aff id="aff2">Departments of Psychiatry and Pharmacology, Sir Charles Tuper Medical Building, Faculty of Medicine,<institution>Dalhousie University</institution>, 5850 College Street, Halifax, Nova Scotia, Canada B3H 1X5</nlm:aff></affiliation></author><author><name sortKey="Robertson, George S" sort="Robertson, George S" uniqKey="Robertson G" first="George S." last="Robertson">George S. Robertson</name><affiliation><nlm:aff id="aff2">Departments of Psychiatry and Pharmacology, Sir Charles Tuper Medical Building, Faculty of Medicine,<institution>Dalhousie University</institution>, 5850 College Street, Halifax, Nova Scotia, Canada B3H 1X5</nlm:aff></affiliation></author><author><name sortKey="Lograsso, Philip" sort="Lograsso, Philip" uniqKey="Lograsso P" first="Philip" last="Lograsso">Philip Lograsso</name><affiliation><nlm:aff id="aff1">Department of Molecular Therapeutics and Translational Research Institute,<institution>The Scripps Research Institute</institution>, Scripps Florida, 130 Scripps Way #A2A, Jupiter, Florida 33458, United States</nlm:aff></affiliation></author></analytic><series><title level="j">ACS Chemical Neuroscience</title><idno type="ISSN">1948-7193</idno><idno type="eISSN">1948-7193</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p content-type="toc-graphic"><graphic xlink:href="cn-2010-001107_0003" id="ab-tgr1"></graphic></p><p>Parkinson’s disease (PD) results from the loss of dopamine neurons located in the substantia nigra pars compacta (SNpc) that project to the striatum. A therapeutic has yet to be identified that halts this neurodegenerative process, and as such, development of a brain penetrant small molecule neuroprotective agent would represent a significant advancement in the treatment of the disease. To fill this void, we developed an aminopyrimidine JNK inhibitor (SR-3306) that reduced the loss of dopaminergic cell bodies in the SNpc and their terminals in the striatum produced by unilateral injection of 6-hydroxydopamine (6-OHDA) into the nigrostriatal pathway. Administration of SR-3306 [10 mg/kg/day (s.c.) for 14 days] increased the number of tyrosine hydroxylase immunoreactive (TH<sup>+</sup>) neurons in the SNpc by 6-fold and reduced the loss of the TH<sup>+</sup> terminals in the striatum relative to the corresponding side of 6-OHDA-lesioned rats that received only vehicle (<italic>p</italic> < 0.05). In addition, SR-3306 [10 mg/kg/day (s.c.) for 14 days] decreased d-amphetamine-induced circling by 87% compared to 6-OHDA-lesioned animals given vehicle. Steady-state brain levels of SR-3306 at day 14 were 347 nM, which was approximately 2-fold higher than the cell-based IC<sub>50</sub> for this compound. Finally, immunohistochemical staining for phospho-c-jun (p-c-jun) revealed that SR-3306 [10 mg/kg/day (s.c.) for 14 days] produced a 2.3-fold reduction of the number of immunoreactive neurons in the SNpc relative to vehicle treated rats. Collectively, these data suggest that orally bioavailable JNK inhibitors may be useful neuroprotective agents for the treatment of Parkinson’s disease.</p></div></front></TEI><pmc article-type="research-article" xml:lang="EN"><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">ACS Chem Neurosci</journal-id><journal-id journal-id-type="iso-abbrev">ACS Chem Neurosci</journal-id><journal-id journal-id-type="publisher-id">cn</journal-id><journal-id journal-id-type="coden">acncdm</journal-id><journal-title-group><journal-title>ACS Chemical Neuroscience</journal-title></journal-title-group><issn pub-type="ppub">1948-7193</issn><issn pub-type="epub">1948-7193</issn><publisher><publisher-name>American Chemical Society</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">21666838</article-id><article-id pub-id-type="pmc">3110072</article-id><article-id pub-id-type="doi">10.1021/cn1001107</article-id><article-categories><subj-group><subject>Research Article</subject></subj-group></article-categories><title-group><article-title>JNK Inhibition Protects Dopamine Neurons and Provides Behavioral Improvement in a Rat 6-Hydroxydopamine Model of Parkinson’s Disease</article-title></title-group><contrib-group><contrib contrib-type="author" id="ath1"><name><surname>Crocker</surname><given-names>Candice E.</given-names></name><xref rid="aff2" ref-type="aff">‡</xref></contrib><contrib contrib-type="author" id="ath2"><name><surname>Khan</surname><given-names>Susan</given-names></name><xref rid="aff1" ref-type="aff">†</xref></contrib><contrib contrib-type="author" id="ath3"><name><surname>Cameron</surname><given-names>Michael D.</given-names></name><xref rid="aff1" ref-type="aff">†</xref></contrib><contrib contrib-type="author" id="ath4"><name><surname>Robertson</surname><given-names>Harold A.</given-names></name><xref rid="aff2" ref-type="aff">‡</xref></contrib><contrib contrib-type="author" id="ath5"><name><surname>Robertson</surname><given-names>George S.</given-names></name><xref rid="aff2" ref-type="aff">‡</xref></contrib><contrib contrib-type="author" corresp="yes" id="ath6"><name><surname>LoGrasso</surname><given-names>Philip</given-names></name><xref rid="cor1" ref-type="other">*</xref><xref rid="aff1" ref-type="aff">†</xref></contrib><aff id="aff1"><label>†</label>Department of Molecular Therapeutics and Translational Research Institute,<institution>The Scripps Research Institute</institution>, Scripps Florida, 130 Scripps Way #A2A, Jupiter, Florida 33458, United States</aff><aff id="aff2"><label>‡</label>Departments of Psychiatry and Pharmacology, Sir Charles Tuper Medical Building, Faculty of Medicine,<institution>Dalhousie University</institution>, 5850 College Street, Halifax, Nova Scotia, Canada B3H 1X5</aff></contrib-group><author-notes><corresp id="cor1"><label>*</label>Telephone: <phone>561-228-2230</phone>. Fax: <fax>561-228-3081</fax>. E-mail: <email>lograsso@scripps.edu</email>.</corresp></author-notes><pub-date pub-type="epub"><day>07</day><month>02</month><year>2011</year></pub-date><pub-date pub-type="collection"><day>20</day><month>04</month><year>2011</year></pub-date><volume>2</volume><issue>4</issue><fpage>207</fpage><lpage>212</lpage><history><date date-type="received"><day>16</day><month>12</month><year>2010</year></date><date date-type="accepted"><day>13</day><month>01</month><year>2011</year></date></history><permissions><copyright-statement>Copyright © 2011 American Chemical Society</copyright-statement><copyright-year>2011</copyright-year><copyright-holder>American Chemical Society</copyright-holder></permissions><abstract><p content-type="toc-graphic"><graphic xlink:href="cn-2010-001107_0003" id="ab-tgr1"></graphic></p><p>Parkinson’s disease (PD) results from the loss of dopamine neurons located in the substantia nigra pars compacta (SNpc) that project to the striatum. A therapeutic has yet to be identified that halts this neurodegenerative process, and as such, development of a brain penetrant small molecule neuroprotective agent would represent a significant advancement in the treatment of the disease. To fill this void, we developed an aminopyrimidine JNK inhibitor (SR-3306) that reduced the loss of dopaminergic cell bodies in the SNpc and their terminals in the striatum produced by unilateral injection of 6-hydroxydopamine (6-OHDA) into the nigrostriatal pathway. Administration of SR-3306 [10 mg/kg/day (s.c.) for 14 days] increased the number of tyrosine hydroxylase immunoreactive (TH<sup>+</sup>) neurons in the SNpc by 6-fold and reduced the loss of the TH<sup>+</sup> terminals in the striatum relative to the corresponding side of 6-OHDA-lesioned rats that received only vehicle (<italic>p</italic> < 0.05). In addition, SR-3306 [10 mg/kg/day (s.c.) for 14 days] decreased d-amphetamine-induced circling by 87% compared to 6-OHDA-lesioned animals given vehicle. Steady-state brain levels of SR-3306 at day 14 were 347 nM, which was approximately 2-fold higher than the cell-based IC<sub>50</sub> for this compound. Finally, immunohistochemical staining for phospho-c-jun (p-c-jun) revealed that SR-3306 [10 mg/kg/day (s.c.) for 14 days] produced a 2.3-fold reduction of the number of immunoreactive neurons in the SNpc relative to vehicle treated rats. Collectively, these data suggest that orally bioavailable JNK inhibitors may be useful neuroprotective agents for the treatment of Parkinson’s disease.</p></abstract><kwd-group><kwd>JNK</kwd><kwd>6-OHDA</kwd><kwd>neuroprotection</kwd><kwd>Parkinson’s disease</kwd></kwd-group><funding-group><funding-statement><funding-source>National Institutes of Health, United States</funding-source></funding-statement></funding-group><custom-meta-group><custom-meta><meta-name>document-id-old-9</meta-name><meta-value>cn1001107</meta-value></custom-meta><custom-meta><meta-name>document-id-new-14</meta-name><meta-value>cn-2010-001107</meta-value></custom-meta><custom-meta><meta-name>ccc-price</meta-name><meta-value></meta-value></custom-meta></custom-meta-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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