Phosphodiesterase 9 inhibition prolongs the antiparkinsonian action of l-DOPA in parkinsonian non-human primates

Phosphodiesterase 9 (PDE9) degrades selectively the second messenger cGMP, which is an important molecule of dopamine signaling pathways in striatal projection neurons (SPNs). In this study, we assessed the effects of a selective PDE9 inhibitor (PDE9i) in the primate model of Parkinson's disease (PD). Six macaques with advanced parkinsonism were used in the study. PDE9i was administered as monotherapy and co-administration with l-DOPA at two predetermined doses (suboptimal and threshold s.c. doses of l-Dopa methyl ester plus benserazide) using a controlled blinded protocol to assess motor disability, l-DOPA -induced dyskinesias (LID), and other neurologic drug effects. While PDE9i was ineffective as monotherapy, 2.5 and 5 mg/kg (s.c.) of PDE9i significantly potentiated the antiparkinsonian effects of l-DOPA with a clear prolongation of the “on” state (p