The progressive death of brain neurons containing the neurochemical dopamine is the hallmark of Parkinson's disease. The symptoms of PD can be improved by levodopa, a drug which transiently restores levels of dopamine in the brain. For reasons that are poorly understood, levodopa loses efficacy and induces uncontrolled motor dysregulation, known as dyskinesia, after prolonged use. Thus, adjunct treatments which would reduce dependence upon levodopa, prolong the lifetime of levodopa's useful effects, and/or reduce the severity or incidence of levodopa-related dyskinesia, would represent a significant contribution to the care of PD patients.
Scientists at Intra-Cellular Therapies Inc (ITI) are developing novel therapeutic molecules that mimic and potentiate the normal actions of dopamine. These compounds are potent, highly selective small-molecule inhibitors of phosphodiesterases (PDEs), enzymes that are enriched in the precise brain neurons that lose dopamine input in PD. We hypothesize that these compounds will potentiate the actions of levodopa in PD patients, enabling effective relief of motor symptoms with lower doses of levodopa and reducing the incidence of dyskinesias.
In collaboration with colleagues at The Karolinska Institute (Stockholm, Sweden), we propose to test this hypothesis by studying the ability of PDE inhibitors to improve motor behavior in a pre-clinical model of Parkinson's disease, assessing their benefit in correcting motor behavior and their potential for reducing or ameliorating dyskinetic behavior during long-term levodopa treatment. Small-molecule therapeutics targeted to enzymes that modulate the impact of dopamine in the brain offer the potential to improve the motor symptoms of PD with lower risk of dyskinesia.
A phosphodiesterase (PDE) inhibitor compound was identified that exhibited good potency and selectivity and good bioavailability. The compound was capable of potentiating LDOPA-induced motor restoration in 6-OHDA-lesioned mice and reducing the expression of established levodopa-induced dyskinesias. MJFF has provided additional support for studies testing the efficacy of PDE inhibitors in other relevant disease models.