Evaluation of a Specific DAT Inhibitor in Pre-clinical Models of Parkinson's Disease

Objective/Rationale: 
MLR-1017 is a psychostimulant drug used clinically for a variety of neuropsychiatric and other applications, but has never been tested in Parkinson’s disease (PD). Levodopa is a commonly used drug to treat PD. However, long-term use induces complications such as movement disorders, sleep disturbances (nightmares, nocturnal confusion), and psychosis. We propose that MLR-1017, in combination with levodopa, would reduce the amount of levodopa required for treatment, thereby also reducing side effects such as movement and sleep disorders.

Project Description: 
Pre-clinical models of PD, as well as other Symptoms & Side Effects models, will be used to test the hypothesis that MLR-1017 can reduce the amount of levodopa needed by PD patients to control their PD symptoms and related side effects. Because PD is a multi-symptom disease with deficits in motor, sleep, cognitive, and other systems, we propose to establish a “platform” of models to test the effectiveness of MLR-1017. We will compare the effectiveness of MLR-1017 with and without levodopa against untreated models in normalizing sleep/wake activity, cognitive and motor function, gastrointestinal function, and in improving responsiveness in a model of depression.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:  
It is proposed that MLR-1017 administered in combination with levodopa may improve PD treatment in multiple ways. During the day, MLR-1017 administration would promote wakefulness and minimize nighttime sleep disturbances. MLR-1017 use may also normalize brain dopamine levels following levodopa administration, allowing lower levodopa doses to be used. MLR-1017 may thereby reduce side-effects of levodopa treatment such as movement disorders and psychological dysfunction. Finally, sydnocarb may be neuroprotective, thus slowing the progression of PD. 

Anticipated Outcome: 
Parkinson’s is a devastating disease waiting for more effective drugs to halt its progression and improve its symptoms. This project will determine if a potent drug used in other neurological disorders will also be useful in PD. Another important aspect of this proposal is the establishment of an efficient and comprehensive pre-clinical evaluation system, including relevant pre-clinical models and imaging endpoints, which can be used to identify additional drugs for treatment of PD.