Study Rationale:
The two main types of the enzyme 5α-reductase (5αR) play a key role in the production of steroids in the brain and other organs. In pre-clinical testing, we found that inhibitors of both major types of this enzyme prevent damage to brain cells that occur in Parkinson's disease and reduce the severity of dyskinesias. Dyskinesias are one of the major complications of standard treatment with levodopa. Though we inhibited both enzyme types, our preliminary data suggests that we may only need to inhibit type 1. Thus, we will test the specific role of this enzyme as a therapeutic target for Parkinson's, using selective blockers of this enzyme that were already found to be clinically safe and well-tolerated.
Hypothesis:
We hypothesize that 5αR type 1 is a therapeutic target for early-stage Parkinson's progression as well as levodopa-induced dyskinesias.
Study Design:
Our studies include two aims: Aim 1 will determine the efficacy of two selective 5αR type 1 inhibitors in reducing the neurotoxic effects of the Parkinson's-inducing toxin MPTP in pre-clinical models. Aim 2 will determine the efficacy of these drugs in reducing levodopa-induced dyskinesias in pre-clinical models. In addition to the behavioral effects of these drugs, we will begin analyzing some of the molecular mechanisms that may account for their therapeutic efficacy.
Impact on Diagnosis/Treatment of Parkinson's disease:
Current treatments for Parkinson's and levodopa-induced dyskinesias have very limited efficacy. Given that 5αR type 1 inhibitors are safe in humans, this project could lead to disease-modifying therapies that improve the prognosis and quality of life of Parkinson's patients.
Next Steps for Development:
The next steps of this research will confirm our results in models of Parkinson's and levodopa-induced dyskinesias with the goal of ultimately testing these drugs in Parkinson's patients. Further studies will also aim at identifying what steroids and dopamine-related targets are directly responsible for the role of 5αR type 1 in Parkinson's and levodopa-induced dyskinesias.