Pardoprunox reverses motor deficits but induces only mild dyskinesia in MPTP-treated common marmosets

Authors

  • Louisa Clare Johnston PhD,

    1. Neurodegenerative Diseases Research Centre, School of Health and Biomedical Sciences, King's College, London, United Kingdom
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    • Financial Disclosures: Louisa C. Johnston received funding from an Alzheimer's Drug Discovery Foundation grant awarded to Professor Susan Greenfield at the University of Oxford (Department of Pharmacology). This funding did not support the work presented in this manuscript. Louisa C. Johnston—PhD studies were funded by an educational grant from Solvay Pharmaceuticals. Andrew C. McCreary is an employee of Solvay Pharmaceuticals. Peter Jenner has received consultancy fees and honoraria for speaking at sponsored meetings, from Boehringer Ingelheim, Novartis, Orion Pharma, GlaxoSmithKline, Lundbeck, Teva, Merck Serono, FP Pharmaceuticals, Proximagen Neurosciences, and UCB. Peter Jenner—a consultancy agreement with Solvay Pharmaceuticals covering occasional speaking events and advisory meetings.

      Author Roles: L.C. Johnston—organization and execution of the research project; design and execution of the statistical analysis; review and critique of the manuscript. M.J. Jackson—organization and execution of the research project; design and execution of the statistical analysis; review and critique of the manuscript. S. Rose—organization of the research project; design, review and critique of the statistical analysis. A.C. McCreary—conception and organization of the research project and sourcing funding; design, review and critique of the statistical analysis; review and critique of the manuscript. P. Jenner—conception of the research project; design, review and critique of the statistical analysis; review and critique of the manuscript.

  • Michael John Jackson BSc,

    1. Neurodegenerative Diseases Research Centre, School of Health and Biomedical Sciences, King's College, London, United Kingdom
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    • Financial Disclosures: Louisa C. Johnston received funding from an Alzheimer's Drug Discovery Foundation grant awarded to Professor Susan Greenfield at the University of Oxford (Department of Pharmacology). This funding did not support the work presented in this manuscript. Louisa C. Johnston—PhD studies were funded by an educational grant from Solvay Pharmaceuticals. Andrew C. McCreary is an employee of Solvay Pharmaceuticals. Peter Jenner has received consultancy fees and honoraria for speaking at sponsored meetings, from Boehringer Ingelheim, Novartis, Orion Pharma, GlaxoSmithKline, Lundbeck, Teva, Merck Serono, FP Pharmaceuticals, Proximagen Neurosciences, and UCB. Peter Jenner—a consultancy agreement with Solvay Pharmaceuticals covering occasional speaking events and advisory meetings.

      Author Roles: L.C. Johnston—organization and execution of the research project; design and execution of the statistical analysis; review and critique of the manuscript. M.J. Jackson—organization and execution of the research project; design and execution of the statistical analysis; review and critique of the manuscript. S. Rose—organization of the research project; design, review and critique of the statistical analysis. A.C. McCreary—conception and organization of the research project and sourcing funding; design, review and critique of the statistical analysis; review and critique of the manuscript. P. Jenner—conception of the research project; design, review and critique of the statistical analysis; review and critique of the manuscript.

  • Sarah Rose PhD,

    1. Neurodegenerative Diseases Research Centre, School of Health and Biomedical Sciences, King's College, London, United Kingdom
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    • Financial Disclosures: Louisa C. Johnston received funding from an Alzheimer's Drug Discovery Foundation grant awarded to Professor Susan Greenfield at the University of Oxford (Department of Pharmacology). This funding did not support the work presented in this manuscript. Louisa C. Johnston—PhD studies were funded by an educational grant from Solvay Pharmaceuticals. Andrew C. McCreary is an employee of Solvay Pharmaceuticals. Peter Jenner has received consultancy fees and honoraria for speaking at sponsored meetings, from Boehringer Ingelheim, Novartis, Orion Pharma, GlaxoSmithKline, Lundbeck, Teva, Merck Serono, FP Pharmaceuticals, Proximagen Neurosciences, and UCB. Peter Jenner—a consultancy agreement with Solvay Pharmaceuticals covering occasional speaking events and advisory meetings.

      Author Roles: L.C. Johnston—organization and execution of the research project; design and execution of the statistical analysis; review and critique of the manuscript. M.J. Jackson—organization and execution of the research project; design and execution of the statistical analysis; review and critique of the manuscript. S. Rose—organization of the research project; design, review and critique of the statistical analysis. A.C. McCreary—conception and organization of the research project and sourcing funding; design, review and critique of the statistical analysis; review and critique of the manuscript. P. Jenner—conception of the research project; design, review and critique of the statistical analysis; review and critique of the manuscript.

  • Andrew Christopher McCreary PhD,

    1. Solvay Pharmaceuticals Research Laboratories, Weesp, The Netherlands
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    • Financial Disclosures: Louisa C. Johnston received funding from an Alzheimer's Drug Discovery Foundation grant awarded to Professor Susan Greenfield at the University of Oxford (Department of Pharmacology). This funding did not support the work presented in this manuscript. Louisa C. Johnston—PhD studies were funded by an educational grant from Solvay Pharmaceuticals. Andrew C. McCreary is an employee of Solvay Pharmaceuticals. Peter Jenner has received consultancy fees and honoraria for speaking at sponsored meetings, from Boehringer Ingelheim, Novartis, Orion Pharma, GlaxoSmithKline, Lundbeck, Teva, Merck Serono, FP Pharmaceuticals, Proximagen Neurosciences, and UCB. Peter Jenner—a consultancy agreement with Solvay Pharmaceuticals covering occasional speaking events and advisory meetings.

      Author Roles: L.C. Johnston—organization and execution of the research project; design and execution of the statistical analysis; review and critique of the manuscript. M.J. Jackson—organization and execution of the research project; design and execution of the statistical analysis; review and critique of the manuscript. S. Rose—organization of the research project; design, review and critique of the statistical analysis. A.C. McCreary—conception and organization of the research project and sourcing funding; design, review and critique of the statistical analysis; review and critique of the manuscript. P. Jenner—conception of the research project; design, review and critique of the statistical analysis; review and critique of the manuscript.

  • Peter Jenner PhD, DSc, FRPharmS, FBPharmacolS, FKC

    Corresponding author
    1. Neurodegenerative Diseases Research Centre, School of Health and Biomedical Sciences, King's College, London, United Kingdom
    • Neurodegenerative Diseases Research Centre, School of Health and Biomedical Sciences, King's College, London SE1 1UL, United Kingdom.
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    • Financial Disclosures: Louisa C. Johnston received funding from an Alzheimer's Drug Discovery Foundation grant awarded to Professor Susan Greenfield at the University of Oxford (Department of Pharmacology). This funding did not support the work presented in this manuscript. Louisa C. Johnston—PhD studies were funded by an educational grant from Solvay Pharmaceuticals. Andrew C. McCreary is an employee of Solvay Pharmaceuticals. Peter Jenner has received consultancy fees and honoraria for speaking at sponsored meetings, from Boehringer Ingelheim, Novartis, Orion Pharma, GlaxoSmithKline, Lundbeck, Teva, Merck Serono, FP Pharmaceuticals, Proximagen Neurosciences, and UCB. Peter Jenner—a consultancy agreement with Solvay Pharmaceuticals covering occasional speaking events and advisory meetings.

      Author Roles: L.C. Johnston—organization and execution of the research project; design and execution of the statistical analysis; review and critique of the manuscript. M.J. Jackson—organization and execution of the research project; design and execution of the statistical analysis; review and critique of the manuscript. S. Rose—organization of the research project; design, review and critique of the statistical analysis. A.C. McCreary—conception and organization of the research project and sourcing funding; design, review and critique of the statistical analysis; review and critique of the manuscript. P. Jenner—conception of the research project; design, review and critique of the statistical analysis; review and critique of the manuscript.


  • Potential conflict of interest: Nothing to report.

Abstract

Long-acting full dopamine D2 agonists produce less dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates and in Parkinson's disease than effective antiparkinsonian doses of levodopa. They do not however, prevent priming for dyskinesia expression on subsequent levodopa exposure. In contrast, the effects of partial D2 receptor agonists on dyskinesia are unclear. We now examine the ability of the partial D2 agonist pardoprunox (SLV308) to improve motor function and its propensity to prime for dyskinesia in drug naïve, MPTP-treated common marmosets. Previously, drug naïve, MPTP-treated common marmosets were treated with equivalent doses of either pardoprunox (SLV308) (0.1 mg/kg po), ropinirole (0.18 mg/kg po), or levodopa (10 mg/kg po BID) for 28 days. All treatments induced a similar reduction of motor disability. Dyskinesia induced by levodopa was of greater intensity than that following administration of either pardoprunox (SLV308) or ropinirole. Administration of pardoprunox (SLV308) resulted in dyskinesia that was less intense and of shorter duration than either ropinirole or levodopa. At the end of drug treatment, acute challenge with levodopa resulted in the expression of marked dyskinesia in animals that had previously received chronic levodopa or ropinirole treatment. However, animals previously treated with pardoprunox (SLV308) showed only mild dyskinesia in response to the levodopa challenge. These results suggest that the partial D2 agonist pardoprunox (SLV308) is less likely to prime for dyskinesia or to lead to the expression of dyskinesia than either levodopa or full dopamine agonists. © 2010 Movement Disorder Society

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