Drugs called GLP1 agonists for their ability to activate protein GLP1 receptor were originally developed to treat type 2 diabetes mellitus. However, they can travel to the brain and may have beneficial effects in the brain through mechanisms other than their anti-diabetes action. A clinical trial has demonstrated that people with Parkinson's disease (PD) benefited from the treatment with GLP1 agonist exenatide. How activation of the GLP1 receptor may protect cells from neurodegeneration will predict whether the GLP1 receptor and other molecules with which it interacts are valid targets for the treatment for Parkinson's disease.
Our aim is to describe the mechanism of action of GLP1 agonists in Parkinson's models. In particular, we aim to determine how GLP1 agonists influence different interactions of molecules (pathways) in brain cells and how this may ultimately affect the health of cells.
We have designed this study to include two stages. First, we will study exenatide in the cerebrospinal fluid -- the fluid that bathes the brain and spinal cord -- and blood samples. Next, we will use a human cell model of PD to determine the molecular pathways influenced by GLP1 agonists. We plan to determine exactly what pathways are responsible for the neuroprotective effects of GLP1 in models of inherited Parkinson's and identify people who may benefit from GLP1 agonists.
Impact on Diagnosis/Treatment of Parkinson's Disease:
This study will help us understand the connection between two different effects of GLP1 agonists: anti-diabetes and neuroprotective effects. The nature of this connection would further suggest metabolic pathways targeted in PD.
Next Steps for Development:
Clinical trials studying the use of GLP1 agonists to treat Parkinson's and other neurodegenerative diseases are underway. This study will suggest which GLP1 agonist may be more effective and which of the molecular interaction of GLP1 may be targeted with the best therapeutic outcome. It will also identify molecules that can serve as a measure of GLP1 agonist efficacy, which would greatly improve clinical trial design.