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Author Notes:

Stella M. Papa, M.D., YNPRC, Emory University School of Medicine, 954 Gatewood Road, Atlanta, GA 30329,Tel: (+1) 404-727-1737. Fax: (+1) 404-727-9294. spapa@emory.edu.

1. Research Project: A. Conception, B. Organization, C. Execution.

2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique.

3. Manuscript Preparation: A. Writing the First Draft, B. Review and Critique.

G.B.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B; S.M.: 1B, 1C, 3A, 3B; P.C.: 1C, 2B, 3B; S.M.P.: 1A, 1B, 2C, 3B;

We thank Drs. Keita Arakawa and Motohiko Kometani for their technical assistance as well as their discussion and comments on the manuscript.

Dr. Papa has received research support from NIH-NINDS;Michael J. Fox Foundation; Pfizer, Inc.; EnVivo Pharmaceuticals, Inc., Forum Pharmaceuticals, Inc.; GeneGraft, LTD.; Key Neurosciences; and Mochida Pharmaceuticals Co. LTD.

She has been a consultant for Teva Neuroscience.

There is no conflict of interest with the present manuscript.

Subjects:

Research Funding:

NIH grants NS45962, NS073994, NCRR RR000165 ;and ORIP/OD OD011132 (S.M.P.)

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Clinical Neurology
  • Neurosciences & Neurology
  • PDE10A inhibitor
  • l-dopa-induced dyskinesia
  • striatum
  • cyclic nucleotides
  • nonhuman primate models
  • LEVODOPA-INDUCED DYSKINESIAS
  • HEMIPARKINSONIAN RATS
  • IMMUNOHISTOCHEMICAL LOCALIZATION
  • INVOLUNTARY MOVEMENTS
  • MOLECULAR-MECHANISMS
  • THERAPEUTIC APPROACH
  • MOTOR FLUCTUATIONS
  • NONHUMAN-PRIMATES
  • FOSB EXPRESSION
  • DISEASE

A Selective Phosphodiesterase 10A Inhibitor Reduces L-Dopa-Induced Dyskinesias in Parkinsonian Monkeys

Journal Title:

Movement Disorders

Volume:

Volume 33, Number 5

Publisher:

, Pages 805-814

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Background: Phosphodiesterase 10A is a member of the phosphodiesterase family whose brain expression is restricted to the striatum. Phosphodiesterase 10A regulates cyclic adenosine monophosphate and cyclic guanosine monophosphate, which mediate responses to dopamine receptor activation, and the levels of these cyclic nucleotides are decreased in experimental models of l-dopa-induced dyskinesia. The elevation of cyclic adenosine monophosphate/cyclic guanosine monophosphate levels by phosphodiesterase 10A inhibition may thus be targeted to reduce l-dopa-induced dyskinesia. Objectives: The present study was aimed at determining the potential antidyskinetic effects of phosphodiesterase 10A inhibitors in a primate model of Parkinson's disease (PD). The experiments performed in this model were also intended to provide translational data for the design of future clinical trials. Methods: Five MPTP-treated macaques with advanced parkinsonism and reproducible l-dopa-induced dyskinesia were used. MR1916, a selective phosphodiesterase 10A inhibitor, at doses 0.0015 to 0.05 mg/kg, subcutaneously, or its vehicle (control test) was coadministered with l-dopa methyl ester acutely (predetermined optimal and suboptimal subcutaneous doses) and oral l-dopa chronically as daily treatment for 5 weeks. Standardized scales were used to assess motor disability and l-dopa-induced dyskinesia by blinded examiners. Pharmacokinetics was also examined. Results: MR1916 consistently reduced l-dopa-induced dyskinesia in acute tests of l-dopa optimal and suboptimal doses. Significant effects were present with every MR1916 dose tested, but the most effective was 0.015 mg/kg. None of the MR1916 doses tested affected the antiparkinsonian action of l-dopa at the optimal dose. The anti-l-dopa-induced dyskinesia effect of MR1916 (0.015 mg/kg, subcutaneously) was sustained with chronic administration, indicating that tolerance did not develop over the 5-week treatment. No adverse effects were observed after MR1916 administration acutely or chronically. Conclusions: Results show that regulation of striatal cyclic nucleotides by phosphodiesterase 10A inhibition could be a useful therapeutic approach for l-dopa-induced dyskinesia, and therefore data support further studies of selective phosphodiesterase 10A inhibitors for PD therapy.

Copyright information:

© 2018 International Parkinson and Movement Disorder Society

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