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

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. © 2018 International Parkinson and Movement Disorder Society.

Keywords: PDE10A inhibitor; cyclic nucleotides; l-dopa-induced dyskinesia; nonhuman primate models; striatum.

Figure 1. MR1916 co-administration with L-Dopa reduces LID

(A) Time course of absolute LID scores following different doses of MR1916 or amantadine injected along with L-Dopa optimal dose (s.c.). (B–D) Normalized LID scores. All doses of MR1916 significantly reduced LID in all analyses: time course of LID (B), peak LID scored at 50 min after L-Dopa injection (C) and total LID scores calculated as the sum of scores from all postinjection time points (D). (E–H) LID scores following different doses of MR1916 or amantadine injected along with L-Dopa suboptimal dose (s.c.). Same graph details as in (A–D). MR1916 at 0.015 and 0.05 mg/kg significantly reduced LID in all analyses. Data are mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001 versus control (MR1916 0 mg/kg or vehicle injection). A: amantadine.

Figure 2. MR1916 cotherapy does not affect the antiparkinson action of L-Dopa

(A) Time course and (B) AUC (area under the curve) of MDS with different doses of MR1916 or amantadine injected along with L-Dopa optimal dose (s.c.). (C) Movement time (sec) in the Klüver board test (KBT) at 0 min (baseline) and 90 min following MR1916 or amantadine in combination with L-Dopa optimal dose (s.c.). None of MR1916 doses affected MDS or the time in KBT. (D–F) MDS and time in KBT with different doses of MR1916 or amantadine injected along with L-Dopa suboptimal dose (s.c.). Same graph details as in (A–C). Only 0.05 mg/kg of MR1916 had a significant effect on MDS. Data are mean ± SEM. *p < 0.05, **p < 0.01, versus control (MR1916 0 mg/kg). A: amantadine.

Figure 3. Pharmacokinetics

(A) Plasma concentrations of MR1916. Plasma levels of MR1916 in primates vary dose-dependently, and was not changed by L-Dopa co-administration. (B) Plasma concentrations of L-Dopa. Plasma levels of L-Dopa in primates did not change following co-administration of MR1916 (0.15 mg/kg). Data are mean ± SEM.

Figure 4. Chronic administration of MR1916 has sustained anti-LID effect

(A) Time course of absolute LID scores induced by (s.c.) suboptimal dose of L-Dopa alone at baseline or co-administered with 0.015 mg/kg of MR1916 (s.c.) after every week of daily MR1916 treatment for 5 weeks. (B–D) MR1916 significantly reduced LID at each time point during the 5-week treatment period in all analyses: time course of LID scored at every 20-minute interval (B), peak LID scored at 50 minutes following L-Dopa administration, and total LID scores calculated as the sum of scores from all post-administration time points. This effect was no longer detectable after a 1-week washout period (A–D). (E–H) LID scores induced by the oral maintenance dose of L-Dopa alone at baseline or co-administered with 0.015 mg/kg of MR1916 (s.c.) after every week of daily MR1916 treatment for 5 weeks. Same graph details as in (A–D). MR1916 significantly reduced LID in all analyses. Data are mean ± SEM. *p < 0.05, **p < 0.01, versus control (baseline, L-Dopa plus MR1916 0 mg/kg).

Figure 5. Chronic administration of MR1916 has no impact on parkinsonian motor disability

(A, C) Time course and (B, D) AUC (area under the curve) of MDS induced by (s.c.) suboptimal dose (A, B) or oral maintenance dose (C, D) of L-Dopa alone at baseline or co-administered with 0.015 mg/kg of MR1916 (s.c.) after every week of daily MR1916 treatment for 5 weeks. MDS induced by either s.c. or oral L-Dopa were not affected by chronic MR1916 therapy at any time point during the 5-week period.