Reversible neurochemical changes mediated by delayed intrastriatal glial cell line‐derived neurotrophic factor gene delivery in a partial Parkinson's disease rat model
Identifieur interne : 000965 ( Main/Exploration ); précédent : 000964; suivant : 000966Reversible neurochemical changes mediated by delayed intrastriatal glial cell line‐derived neurotrophic factor gene delivery in a partial Parkinson's disease rat model
Auteurs : Xin Yang [Belgique] ; Birgit Mertens [Belgique] ; Enni Lehtonen [Belgique] ; Linda Vercammen [Belgique] ; Olivier Bockstael [Belgique] ; Abdelwahed Chtarto [Belgique] ; Marc Levivier [Belgique, Suisse] ; Jacques Brotchi [Belgique] ; Yvette Michotte [Belgique] ; Veerle Baekelandt [Belgique] ; Sophie Sarre [Belgique] ; Liliane Tenenbaum [Belgique]Source :
- The Journal of Gene Medicine [ 1099-498X ] ; 2009-10.
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Abstract
Background: Efficient protection of dopaminergic neurons against a subsequent 6‐hydroxydopamine lesion by glial cell line‐derived neurotrophic factor (GDNF) gene delivery has been demonstrated. By contrast, the neurorestorative effects of GDNF administered several weeks after the toxin have been less characterized. In particular, whether these were permanent or dependent on the continuous presence of GDNF remains elusive. Methods: A tetracycline‐inducible adeno‐associated virus (AAV)‐1 vector expressing human GDNF cDNA was administered unilaterally in the rat striatum 5 weeks after 6‐hydroxydopamine. Rats were treated with doxycycline (dox) or untreated from the day of vector injection until sacrifice (4 or 14 weeks). A sub‐group was dox‐treated for 7 weeks then untreated until 14 weeks. The motor behavior was assessed by amphetamine‐induced rotations and spontaneous forelimb asymmetry. The amounts of tyrosine hydroxylase (TH), serine‐40‐phosphorylated TH (S40‐TH) and aromatic amino acid decarboxylase (AADC) proteins were compared by western blotting and the dopamine levels quantified by high‐performance liquid chromatography. Results: Dox‐dependent behavioral improvements were demonstrated 4 weeks post‐vector injection. At later time points, spontaneous partial recovery was observed in all rats, but no further improvement was found in dox‐treated animals. TH levels were significantly increased in dox‐treated rats at all time points. By contrast, striatal dopamine and S40‐TH were increased at 4 weeks, but not 14 weeks, and AADC remained unchanged. Dox withdrawal after 7 weeks, resulted in TH levels comparable to the controls at 14 weeks. Conclusions: Delayed GDNF gene delivery only transiently improved dopaminergic function. Over the long term, TH was more abundant, but not functional, and the increase was lost when GDNF gene expression was switched off. Copyright © 2009 John Wiley & Sons, Ltd.
Url:
DOI: 10.1002/jgm.1377
Affiliations:
- Belgique, Suisse
- Canton de Vaud, Région de Bruxelles-Capitale
- Bruxelles, Lausanne
- Université libre de Bruxelles
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Pharmaceutical Chemistry, Drug Analysis and Drug Information (Research Group Experimental Neuropharmacology), Vrije Universiteit Brussel, Brussels</wicri:regionArea><placeName><settlement type="city">Bruxelles</settlement><region nuts="2">Région de Bruxelles-Capitale</region></placeName></affiliation></author><author><name sortKey="Lehtonen, Enni" sort="Lehtonen, Enni" uniqKey="Lehtonen E" first="Enni" last="Lehtonen">Enni Lehtonen</name><affiliation wicri:level="4"><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Experimental Neurosurgery, Université Libre de Bruxelles, Brussels</wicri:regionArea><placeName><settlement type="city">Bruxelles</settlement><region nuts="2">Région de Bruxelles-Capitale</region></placeName><orgName type="university">Université libre de Bruxelles</orgName></affiliation><affiliation wicri:level="4"><country xml:lang="fr">Belgique</country><wicri:regionArea>Multidisciplinary Research Institute (IRIBHM), Université Libre de Bruxelles, Brussels</wicri:regionArea><placeName><settlement type="city">Bruxelles</settlement><region nuts="2">Région de Bruxelles-Capitale</region></placeName><orgName type="university">Université libre de Bruxelles</orgName></affiliation></author><author><name sortKey="Vercammen, Linda" sort="Vercammen, Linda" uniqKey="Vercammen L" first="Linda" last="Vercammen">Linda Vercammen</name><affiliation wicri:level="1"><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory for Neurobiology and Gene Therapy, Katholieke Universiteit Leuven, Leuven</wicri:regionArea><wicri:noRegion>Leuven</wicri:noRegion></affiliation></author><author><name sortKey="Bockstael, Olivier" sort="Bockstael, Olivier" uniqKey="Bockstael O" first="Olivier" last="Bockstael">Olivier Bockstael</name><affiliation wicri:level="4"><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Experimental Neurosurgery, Université Libre de Bruxelles, Brussels</wicri:regionArea><placeName><settlement 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nuts="2">Région de Bruxelles-Capitale</region></placeName><orgName type="university">Université libre de Bruxelles</orgName></affiliation><affiliation wicri:level="4"><country xml:lang="fr">Belgique</country><wicri:regionArea>Multidisciplinary Research Institute (IRIBHM), Université Libre de Bruxelles, Brussels</wicri:regionArea><placeName><settlement type="city">Bruxelles</settlement><region nuts="2">Région de Bruxelles-Capitale</region></placeName><orgName type="university">Université libre de Bruxelles</orgName></affiliation></author><author><name sortKey="Levivier, Marc" sort="Levivier, Marc" uniqKey="Levivier M" first="Marc" last="Levivier">Marc Levivier</name><affiliation wicri:level="4"><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Experimental Neurosurgery, Université Libre de Bruxelles, Brussels</wicri:regionArea><placeName><settlement type="city">Bruxelles</settlement><region nuts="2">Région de Bruxelles-Capitale</region></placeName><orgName type="university">Université libre de Bruxelles</orgName></affiliation><affiliation wicri:level="3"><country xml:lang="fr">Suisse</country><wicri:regionArea>Present address: Department of Neurosurgery, CHUV, Lausanne</wicri:regionArea><placeName><settlement type="city">Lausanne</settlement><region nuts="3" type="region">Canton de Vaud</region></placeName></affiliation></author><author><name sortKey="Brotchi, Jacques" sort="Brotchi, Jacques" uniqKey="Brotchi J" first="Jacques" last="Brotchi">Jacques Brotchi</name><affiliation wicri:level="4"><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Experimental Neurosurgery, Université Libre de Bruxelles, Brussels</wicri:regionArea><placeName><settlement type="city">Bruxelles</settlement><region nuts="2">Région de Bruxelles-Capitale</region></placeName><orgName type="university">Université libre de Bruxelles</orgName></affiliation></author><author><name sortKey="Michotte, Yvette" sort="Michotte, Yvette" uniqKey="Michotte Y" first="Yvette" last="Michotte">Yvette Michotte</name><affiliation wicri:level="3"><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information (Research Group Experimental Neuropharmacology), Vrije Universiteit Brussel, Brussels</wicri:regionArea><placeName><settlement type="city">Bruxelles</settlement><region nuts="2">Région de Bruxelles-Capitale</region></placeName></affiliation></author><author><name sortKey="Baekelandt, Veerle" sort="Baekelandt, Veerle" uniqKey="Baekelandt V" first="Veerle" last="Baekelandt">Veerle Baekelandt</name><affiliation wicri:level="1"><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory for Neurobiology and Gene Therapy, Katholieke Universiteit Leuven, Leuven</wicri:regionArea><wicri:noRegion>Leuven</wicri:noRegion></affiliation></author><author><name sortKey="Sarre, Sophie" sort="Sarre, Sophie" uniqKey="Sarre S" first="Sophie" last="Sarre">Sophie Sarre</name><affiliation wicri:level="3"><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Pharmaceutical Chemistry, Drug Analysis and Drug Information (Research Group Experimental Neuropharmacology), Vrije Universiteit Brussel, Brussels</wicri:regionArea><placeName><settlement type="city">Bruxelles</settlement><region nuts="2">Région de Bruxelles-Capitale</region></placeName></affiliation></author><author><name sortKey="Tenenbaum, Liliane" sort="Tenenbaum, Liliane" uniqKey="Tenenbaum L" first="Liliane" last="Tenenbaum">Liliane Tenenbaum</name><affiliation wicri:level="4"><country xml:lang="fr">Belgique</country><wicri:regionArea>Laboratory of Experimental Neurosurgery, Université Libre de Bruxelles, Brussels</wicri:regionArea><placeName><settlement type="city">Bruxelles</settlement><region nuts="2">Région de Bruxelles-Capitale</region></placeName><orgName type="university">Université libre de Bruxelles</orgName></affiliation><affiliation wicri:level="4"><country xml:lang="fr">Belgique</country><wicri:regionArea>Multidisciplinary Research Institute (IRIBHM), Université Libre de Bruxelles, Brussels</wicri:regionArea><placeName><settlement type="city">Bruxelles</settlement><region nuts="2">Région de Bruxelles-Capitale</region></placeName><orgName type="university">Université libre de Bruxelles</orgName></affiliation></author></analytic><monogr></monogr><series><title level="j">The Journal of Gene Medicine</title><title level="j" type="sub">A cross‐disciplinary journal for research on the science of gene transfer and its clinical applications</title><title level="j" type="abbrev">J. Gene Med.</title><idno type="ISSN">1099-498X</idno><idno type="eISSN">1521-2254</idno><imprint><publisher>John Wiley & Sons, Ltd.</publisher><pubPlace>Chichester, UK</pubPlace><date type="published" when="2009-10">2009-10</date><biblScope unit="volume">11</biblScope><biblScope unit="issue">10</biblScope><biblScope unit="page" from="899">899</biblScope><biblScope unit="page" to="912">912</biblScope></imprint><idno type="ISSN">1099-498X</idno></series><idno type="istex">46E9D4E8670597F82A94241CD0F6E714CB70A427</idno><idno type="DOI">10.1002/jgm.1377</idno><idno type="ArticleID">JGM1377</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1099-498X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>6‐hydroxydopamine</term><term>Parkinson's disease</term><term>adeno‐associated viral vector</term><term>glial cell line‐derived neurotrophic factor</term><term>phosphorylation</term><term>tetracycline‐inducible</term><term>tyrosine hydroxylase</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Background: Efficient protection of dopaminergic neurons against a subsequent 6‐hydroxydopamine lesion by glial cell line‐derived neurotrophic factor (GDNF) gene delivery has been demonstrated. By contrast, the neurorestorative effects of GDNF administered several weeks after the toxin have been less characterized. In particular, whether these were permanent or dependent on the continuous presence of GDNF remains elusive. Methods: A tetracycline‐inducible adeno‐associated virus (AAV)‐1 vector expressing human GDNF cDNA was administered unilaterally in the rat striatum 5 weeks after 6‐hydroxydopamine. Rats were treated with doxycycline (dox) or untreated from the day of vector injection until sacrifice (4 or 14 weeks). A sub‐group was dox‐treated for 7 weeks then untreated until 14 weeks. The motor behavior was assessed by amphetamine‐induced rotations and spontaneous forelimb asymmetry. The amounts of tyrosine hydroxylase (TH), serine‐40‐phosphorylated TH (S40‐TH) and aromatic amino acid decarboxylase (AADC) proteins were compared by western blotting and the dopamine levels quantified by high‐performance liquid chromatography. Results: Dox‐dependent behavioral improvements were demonstrated 4 weeks post‐vector injection. At later time points, spontaneous partial recovery was observed in all rats, but no further improvement was found in dox‐treated animals. TH levels were significantly increased in dox‐treated rats at all time points. By contrast, striatal dopamine and S40‐TH were increased at 4 weeks, but not 14 weeks, and AADC remained unchanged. Dox withdrawal after 7 weeks, resulted in TH levels comparable to the controls at 14 weeks. Conclusions: Delayed GDNF gene delivery only transiently improved dopaminergic function. Over the long term, TH was more abundant, but not functional, and the increase was lost when GDNF gene expression was switched off. Copyright © 2009 John Wiley & Sons, Ltd.</div></front></TEI><affiliations><list><country><li>Belgique</li><li>Suisse</li></country><region><li>Canton de Vaud</li><li>Région de Bruxelles-Capitale</li></region><settlement><li>Bruxelles</li><li>Lausanne</li></settlement><orgName><li>Université libre de Bruxelles</li></orgName></list><tree><country name="Belgique"><region name="Région de Bruxelles-Capitale"><name sortKey="Yang, Xin" sort="Yang, Xin" uniqKey="Yang X" first="Xin" last="Yang">Xin Yang</name></region><name sortKey="Baekelandt, Veerle" sort="Baekelandt, Veerle" uniqKey="Baekelandt V" first="Veerle" last="Baekelandt">Veerle Baekelandt</name><name sortKey="Bockstael, Olivier" sort="Bockstael, Olivier" uniqKey="Bockstael O" first="Olivier" last="Bockstael">Olivier Bockstael</name><name sortKey="Bockstael, Olivier" sort="Bockstael, Olivier" uniqKey="Bockstael O" first="Olivier" last="Bockstael">Olivier Bockstael</name><name sortKey="Brotchi, Jacques" sort="Brotchi, Jacques" uniqKey="Brotchi J" first="Jacques" last="Brotchi">Jacques Brotchi</name><name sortKey="Chtarto, Abdelwahed" sort="Chtarto, Abdelwahed" uniqKey="Chtarto A" first="Abdelwahed" last="Chtarto">Abdelwahed Chtarto</name><name sortKey="Chtarto, Abdelwahed" sort="Chtarto, Abdelwahed" uniqKey="Chtarto A" first="Abdelwahed" last="Chtarto">Abdelwahed Chtarto</name><name sortKey="Lehtonen, Enni" sort="Lehtonen, Enni" uniqKey="Lehtonen E" first="Enni" last="Lehtonen">Enni Lehtonen</name><name sortKey="Lehtonen, Enni" sort="Lehtonen, Enni" uniqKey="Lehtonen E" first="Enni" last="Lehtonen">Enni Lehtonen</name><name sortKey="Levivier, Marc" sort="Levivier, Marc" uniqKey="Levivier M" first="Marc" last="Levivier">Marc Levivier</name><name sortKey="Mertens, Birgit" sort="Mertens, Birgit" uniqKey="Mertens B" first="Birgit" last="Mertens">Birgit Mertens</name><name sortKey="Michotte, Yvette" sort="Michotte, Yvette" uniqKey="Michotte Y" first="Yvette" last="Michotte">Yvette Michotte</name><name sortKey="Sarre, Sophie" sort="Sarre, Sophie" uniqKey="Sarre S" first="Sophie" last="Sarre">Sophie Sarre</name><name sortKey="Tenenbaum, Liliane" sort="Tenenbaum, Liliane" uniqKey="Tenenbaum L" first="Liliane" last="Tenenbaum">Liliane Tenenbaum</name><name sortKey="Tenenbaum, Liliane" sort="Tenenbaum, Liliane" uniqKey="Tenenbaum L" first="Liliane" last="Tenenbaum">Liliane Tenenbaum</name><name sortKey="Vercammen, Linda" sort="Vercammen, Linda" uniqKey="Vercammen L" first="Linda" last="Vercammen">Linda Vercammen</name><name sortKey="Yang, Xin" sort="Yang, Xin" uniqKey="Yang X" first="Xin" last="Yang">Xin Yang</name></country><country name="Suisse"><region name="Canton de Vaud"><name sortKey="Levivier, Marc" sort="Levivier, Marc" uniqKey="Levivier M" first="Marc" last="Levivier">Marc Levivier</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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