Testing PDE-1 Inhibitor in MPTP-treated Macaques

Promising Outcomes of Original Grant:
Our goal is to develop novel therapeutic molecules that promote normal dopamine neurotransmission in the brain affected by PD. We hypothesize that these molecules will augment the beneficial actions of low-dose levodopa therapy and reduce adverse dyskinesias. To this end, we tested a small-molecule inhibitor of the brain-enriched phosphodiesterase-1 (PDE1) for its ability to reverse akinesia and attenuate motor dyskinesias in a pre-clinical model of PD. This model displayed better spontaneous motor activity in the presence of levodopa and significantly fewer dyskinetic behaviors.

Objectives for Supplemental Investigation: 
A critical step in translating our observation in this first pre-clinical model into a viable human pharmacotherapy for PD is confirmation in a second pre-clinical model.  The current project will evaluate the utility of this therapeutic approach in a higher pre-clinical model, by testing the motor benefits of a PDE1 inhibitor. In the proposed studies we will first perform a pharmacokinetic study in the higher pre-clinical model intended to establish optimal dosing conditions for our PDE1 inhibitor. Motor dyskinesias will be elicited in an MPTP-treated pre-clinical model by chronic levodopa administration. The pre-clinical model will then be treated with levodopa in the absence or presence of a PDE1 inhibitor in order to determine if PDE1 inhibition attenuates the expression of motor dyskinesias evoked by levodopa, without compromising normal movement.   These experiments will test whether, analogous to our previous studies, pharmacological inhibition of PDE1 effectively reduces the expression of motor side effects associated with chronic levodopa treatment in a higher pre-clinical model.

Importance of This Research for the Development of a New PD Therapy: 
The appearance of motor dyskinesias represents a major, debilitating side effect of chronic levodopa treatment and a significant challenge for the long-term management of PD. To date, no pharmacological therapies have yet been approved for the maintenance of motor dyskinesias. PDE1 inhibition represents a novel pharmacological approach to promote the positive motor effects of levodopa, while reducing the expression of dyskinesias.  If successful in a higher pre-clinical model, this therapy will be poised to continue pre-clinical development and enter human clinical evaluation as an anti-dyskinetic medication in PD.