The Monoamine Re-Uptake Inhibitor UWA-101 Improves Motor Fluctuations in the MPTP-Lesioned Common Marmoset
Identifieur interne : 001116 ( Main/Exploration ); précédent : 001115; suivant : 001117The Monoamine Re-Uptake Inhibitor UWA-101 Improves Motor Fluctuations in the MPTP-Lesioned Common Marmoset
Auteurs : Philippe Huot [Canada] ; Tom H. Johnston [Canada] ; Michael N. Gandy [Australie] ; M. Gabriela Reyes [Canada] ; Susan H. Fox [Canada] ; Matthew J. Piggott [Australie] ; Jonathan M. Brotchie [Canada]Source :
- PLoS ONE [ 1932-6203 ] ; 2012.
Abstract
The wearing-OFF phenomenon is a common motor complication of chronic L-3,4-dihydroxyphenylalanine (L-DOPA) therapy for Parkinson’s disease. We recently described the discovery of UWA-101, a dual serotonin (SERT) and dopamine (DAT) transporter inhibitor, which increases the duration of “good quality” ON-time provided by L-DOPA in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. Here, we further characterise the effects of UWA-101 on this extension of ON-time in terms of L-DOPA-induced side-effects in the MPTP-lesioned common marmoset.
Marmosets were rendered parkinsonian by MPTP injection and “primed” by repeated L-DOPA administration, to exhibit dyskinesia and psychosis-like behaviours. Animals were then administered acute challenges of L-DOPA in combination with UWA-101 (1, 3, 6 and 10 mg/kg) or vehicle.
In combination with L-DOPA, UWA-101 (3, 6 and 10 mg/kg) significantly increased duration of ON-time (by 28%, 28%, and 33%, respectively; all
Our results demonstrate that dual SERT/ DAT inhibitors can effectively enhance L-DOPA anti-parkinsonian action, without exacerbating dyskinesia and, as such, represent a promising new therapeutic class for wearing-OFF. However, at higher doses, dual SERT/ DAT inhibitors may exacerbate dopaminergic psychosis.
Url:
DOI: 10.1371/journal.pone.0045587
PubMed: 23029119
PubMed Central: 3447761
Affiliations:
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Brotchie</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Toronto Western Research Institute, University Health Network, Toronto, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">23029119</idno><idno type="pmc">3447761</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3447761</idno><idno type="RBID">PMC:3447761</idno><idno type="doi">10.1371/journal.pone.0045587</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">000A84</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000A84</idno><idno type="wicri:Area/Pmc/Curation">000A84</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000A84</idno><idno type="wicri:Area/Pmc/Checkpoint">000755</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000755</idno><idno type="wicri:Area/Ncbi/Merge">001266</idno><idno type="wicri:Area/Ncbi/Curation">001266</idno><idno type="wicri:Area/Ncbi/Checkpoint">001266</idno><idno type="wicri:Area/Main/Merge">001136</idno><idno type="wicri:Area/Main/Curation">001116</idno><idno type="wicri:Area/Main/Exploration">001116</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The Monoamine Re-Uptake Inhibitor UWA-101 Improves Motor Fluctuations in the MPTP-Lesioned Common Marmoset</title><author><name sortKey="Huot, Philippe" sort="Huot, Philippe" uniqKey="Huot P" first="Philippe" last="Huot">Philippe Huot</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Toronto Western Research Institute, University Health Network, Toronto, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Division of Neurology, Movement Disorder Clinic, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Division of Neurology, Movement Disorder Clinic, Toronto Western Hospital, University Health Network, Toronto, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation></author><author><name sortKey="Johnston, Tom H" sort="Johnston, Tom H" uniqKey="Johnston T" first="Tom H." last="Johnston">Tom H. Johnston</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Toronto Western Research Institute, University Health Network, Toronto, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation></author><author><name sortKey="Gandy, Michael N" sort="Gandy, Michael N" uniqKey="Gandy M" first="Michael N." last="Gandy">Michael N. Gandy</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>School of Chemistry and Biochemistry, The University of Western Australia, Perth, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>School of Chemistry and Biochemistry, The University of Western Australia, Perth</wicri:regionArea><wicri:noRegion>Perth</wicri:noRegion></affiliation></author><author><name sortKey="Reyes, M Gabriela" sort="Reyes, M Gabriela" uniqKey="Reyes M" first="M. Gabriela" last="Reyes">M. Gabriela Reyes</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Toronto Western Research Institute, University Health Network, Toronto, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation></author><author><name sortKey="Fox, Susan H" sort="Fox, Susan H" uniqKey="Fox S" first="Susan H." last="Fox">Susan H. Fox</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Toronto Western Research Institute, University Health Network, Toronto, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Division of Neurology, Movement Disorder Clinic, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Division of Neurology, Movement Disorder Clinic, Toronto Western Hospital, University Health Network, Toronto, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation></author><author><name sortKey="Piggott, Matthew J" sort="Piggott, Matthew J" uniqKey="Piggott M" first="Matthew J." last="Piggott">Matthew J. Piggott</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>School of Chemistry and Biochemistry, The University of Western Australia, Perth, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>School of Chemistry and Biochemistry, The University of Western Australia, Perth</wicri:regionArea><wicri:noRegion>Perth</wicri:noRegion></affiliation></author><author><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M" last="Brotchie">Jonathan M. Brotchie</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Toronto Western Research Institute, University Health Network, Toronto, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>The wearing-OFF phenomenon is a common motor complication of chronic L-3,4-dihydroxyphenylalanine (L-DOPA) therapy for Parkinson’s disease. We recently described the discovery of UWA-101, a dual serotonin (SERT) and dopamine (DAT) transporter inhibitor, which increases the duration of “good quality” ON-time provided by L-DOPA in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. Here, we further characterise the effects of UWA-101 on this extension of ON-time in terms of L-DOPA-induced side-effects in the MPTP-lesioned common marmoset.</p></sec><sec><title>Methods</title><p>Marmosets were rendered parkinsonian by MPTP injection and “primed” by repeated L-DOPA administration, to exhibit dyskinesia and psychosis-like behaviours. Animals were then administered acute challenges of L-DOPA in combination with UWA-101 (1, 3, 6 and 10 mg/kg) or vehicle.</p></sec><sec><title>Results</title><p>In combination with L-DOPA, UWA-101 (3, 6 and 10 mg/kg) significantly increased duration of ON-time (by 28%, 28%, and 33%, respectively; all <italic>P</italic><0.05). UWA-101 (10 mg/kg) significantly extended duration of ON-time without disabling dyskinesia (by 62%, <italic>P</italic><0.01). UWA-101 did not exacerbate the severity of dyskinesia (<italic>P</italic>>0.05). However, at the highest doses (6 and 10 mg/kg), UWA-101 increased the severity of psychosis-like behaviours (<italic>P</italic><0.05).</p></sec><sec><title>Conclusions</title><p>Our results demonstrate that dual SERT/ DAT inhibitors can effectively enhance L-DOPA anti-parkinsonian action, without exacerbating dyskinesia and, as such, represent a promising new therapeutic class for wearing-OFF. However, at higher doses, dual SERT/ DAT inhibitors may exacerbate dopaminergic psychosis.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Hornykiewicz, O" uniqKey="Hornykiewicz O">O Hornykiewicz</name></author><author><name sortKey="Kish, Sj" uniqKey="Kish S">SJ Kish</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fahn, S" uniqKey="Fahn S">S Fahn</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hely, Ma" uniqKey="Hely M">MA Hely</name></author><author><name sortKey="Morris, Jg" uniqKey="Morris J">JG Morris</name></author><author><name sortKey="Reid, Wg" uniqKey="Reid W">WG Reid</name></author><author><name sortKey="Trafficante, R" uniqKey="Trafficante R">R Trafficante</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hely, Ma" uniqKey="Hely M">MA Hely</name></author><author><name sortKey="Morris, Jg" uniqKey="Morris 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van Eimeren</name></author><author><name sortKey="Zurowski, M" uniqKey="Zurowski M">M Zurowski</name></author><author><name sortKey="Rusjan, Pm" uniqKey="Rusjan P">PM Rusjan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Huot, P" uniqKey="Huot P">P Huot</name></author><author><name sortKey="Johnston, Th" uniqKey="Johnston T">TH Johnston</name></author><author><name sortKey="Darr, T" uniqKey="Darr T">T Darr</name></author><author><name sortKey="Hazrati, Ln" uniqKey="Hazrati L">LN Hazrati</name></author><author><name sortKey="Visanji, Np" uniqKey="Visanji N">NP Visanji</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Australie</li><li>Canada</li></country></list><tree><country name="Canada"><noRegion><name sortKey="Huot, Philippe" sort="Huot, Philippe" uniqKey="Huot P" first="Philippe" last="Huot">Philippe Huot</name></noRegion><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M" last="Brotchie">Jonathan M. Brotchie</name><name sortKey="Fox, Susan H" sort="Fox, Susan H" uniqKey="Fox S" first="Susan H." last="Fox">Susan H. Fox</name><name sortKey="Fox, Susan H" sort="Fox, Susan H" uniqKey="Fox S" first="Susan H." last="Fox">Susan H. Fox</name><name sortKey="Huot, Philippe" sort="Huot, Philippe" uniqKey="Huot P" first="Philippe" last="Huot">Philippe Huot</name><name sortKey="Johnston, Tom H" sort="Johnston, Tom H" uniqKey="Johnston T" first="Tom H." last="Johnston">Tom H. Johnston</name><name sortKey="Reyes, M Gabriela" sort="Reyes, M Gabriela" uniqKey="Reyes M" first="M. Gabriela" last="Reyes">M. Gabriela Reyes</name></country><country name="Australie"><noRegion><name sortKey="Gandy, Michael N" sort="Gandy, Michael N" uniqKey="Gandy M" first="Michael N." last="Gandy">Michael N. Gandy</name></noRegion><name sortKey="Piggott, Matthew J" sort="Piggott, Matthew J" uniqKey="Piggott M" first="Matthew J." last="Piggott">Matthew J. 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