Objective/Rationale:
Levodopa is the gold standard treatment for Parkinson’s disease. However, its continued use results in serious side effects including abnormal involuntary movements, or dyskinesias. There is therefore a continual search for novel classes of drugs for Parkinson's disease therapy. Our previous studies have shown that that a new class of drugs, type 7 phosphodiesterase (PDE7) inhibitors, restore normal movements in pre-clinical models of Parkinson’s disease. The goal of the present grant is to determine whether PDE7 inhibitors reduce parkinsonism in non-human primate models of PD while causing less dyskinesia than does levodopa.
Project Description:
We will first test a number of PDE7 inhibitor compounds for potency, safety, ability to enter the brain, and stability in control subjects. We will next test the most appropriate compound in parkinsonian non-human primate models for ability to improve motor symptoms with a minimum of dyskinesias. The optimal dose and timing of treatment will be assessed and the results will be compared to those obtained with levodopa. We will then continue treatment with the optimal dose for an additional four months to determine whether the therapeutic benefit is maintained and whether dyskinesias develop over time.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The use of PDE7 inhibitors represents a new research direction for the treatment of Parkinson's disease. This research may lead to novel therapeutic strategies employing PDE7 inhibitors, either as single agents or in combination with levodopa or dopaminergic agonists, to treat Parkinson's disease motor symptoms with the development of a minimum of the dyskinesias that occur with levodopa treatment.
Anticipated Outcome:
We anticipate that the proposed studies will increase our understanding of the usefulness of PDE7 inhibitors for the treatment of Parkinson's disease motor symptoms. They may provide a new class of drugs for Parkinson's disease therapy, with a minimum of adverse side effects such as the dyskinesias that occur with levodopa treatment.
Final Outcome
This project was motivated by the initial finding that selective inhibitors of the enzyme phosphodiesterase type 7 (PDE7) were effective in restoring the shortened stride length observed in rodent models treated with the dopaminergic neurotoxin MPTP. The testing of PDE7 inhibitors in a primate MPTP model was proposed in order to confirm the finding in the rodent model while also gaining a fuller understanding of the potential anti-parkinsonian action of PDE7 inhibitors as well as their potential to induce dyskinesias, as are observed with L-dopa.
Studies carried out by the researchers to date indicate that the improvement of stride length in rodents with the PDE7 inhibitor OMS182401 are not reflected in an improvement in Parkinson scores when it is administered to MPTP treated primates. In contrast to findings in the rodent, OMS182401 fails to reduce Parkinson scores when given by itself, and also does not enhance the effects of sub optimal doses of L-dopa. Potential reasons for this discrepancy include pre-clinical model-specific pharmacokinetic problems (e.g. compound access to the brain), a failure of the primate model to respond to agents acting via the dopaminergic D1 pathway, and/or a lack of expression of PDE7 in pre-clinical model striatum. All of these possibilities are under investigation.