Objective/Rationale:
The brain makes proteins that are required to keep nerve cell alive and healthy. They go down in Parkinson’s disease, and cannot get into the brain when ingested. To circumvent this problem we have synthesized two drugs that are orally active and keep nerve cells in the brain alive. They are therapeutically active in pre-clinical models of Alzheimer’s disease, ischemic stroke, and traumatic brain injury. The goal of this application is to test their efficacy in PD pre-clinical models.
Project Description:
The sole purpose of this application is to determine if two new drugs have therapeutic efficacy in rigorous models of PD. Two models will be used, one in which dopamine (DA) is depleted by MPTP over a period of four days, followed by gavage of the drug and behavioral assays on day eighteen. The other is models pre-treated for two weeks with the drugs, followed by a one-day acute MPTP treatment and feeding drug for one week. Models will be fed compounds CNB-001 and J147, and DA levels, tyrosine hydroxylase amount and the histological distribution of tyrosine hydroxylase determined. These experiments will take about 12 months to complete.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
There are no drugs that induce multiple growth factors, independently activate neurotrophin signaling pathways, and also have the outstanding medicinal chemical, pharmacological and safety properties of our two compounds. We therefore believe that they are truly unique drug candidates for the treatment of PD. If effective in the two models, they could immediately be moved into the FDA drug approval process because we have extensive pre-clinical and safety data on them.
Anticipated Outcome:
The sole objective is to find a compound that has therapeutic efficacy in pre-clinical PD models and move this compound into the clinic. Because of the novel drug discovery paradigm we used to make these compounds, their potency and mechanism of action, we believe that they will prevent the PD-like nerve cell death in the two pre-clinical PD models.