Objective/Rationale:
Ample evidence suggests that the neurotrophin (NT) receptors, TrkB and TrkC, would be particularly effective therapeutic targets for Parkinson’s disease (PD). Both receptors are present on substantia nigra (SN) and striatal neurons, which are primarily affected in PD and their survival depends on NT signaling. We hypothesize that augmenting NT receptor signaling using a small molecule that binds to TrkB and TrkC receptors will reduce neurodegeneration and improve movement in a pre-clinical neurotoxin (MPTP) model of PD.
Project Description:
We identified a small molecule compound that specifically binds to and activates TrkB and TrkC. First, we will further elucidate this compound’s pharmacological properties and determine its dose-response effects on TrkB/C signaling. Next, we will examine whether it ameliorates motor deficits and prevents injury to healthy neurons in the MPTP model of PD. Finally, we will test if this compound can reverse the toxic effects of MPTP in the pre-clinical model.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The finding that our TrkB and TrkC compound improves motor ability and reduces pathology in the MPTP model would validate the targeting of TrkB/TrkC receptors as a disease-modifying therapy for PD. The finding that this prototype compound restores the health of injured neurons would be highly relevant to predicting the success of the compound or its derivatives in the clinic as the majority of PD patients are diagnosed after significant loss of dopamine neurons has already occurred.
Anticipated Outcome:
A successful outcome of this project will drive further optimization of new derivatives or our parent compound and possibly other TrkB/C ligands to provide new disease modifying/slowing therapies for PD.
Progress Report
In this study, we identified a compound that turns on two proteins, TrkB and TrkC, on the surface of nerve cells and thereby prevents the death of these cells. We aimed to test whether this compound, called LM22B-10, can protect brain cells from death and improve movement in pre-clinical models with Parkinson's features. So far, we have determined the properties of LM22B-10, its effects on the TrkB and TrkC proteins and cells that have these proteins as well as an optimal dose of the compound. We also found that LM22B-10 did not change features of the models. Preventative treatment with LM22B-10 improved movement in the models. We are currently testing the compound's ability to restore movement in the models and to prevent the death of brain cells.
February 2014