Selective mGluR3 Positive Allosteric Modulators as Neuroprotective Agents for Parkinson's Disease Supplement

Study Rationale:                   
mGluR3 is a novel target leading to neuroprotection through production of neurotrophic factors. We have recently demonstrated that selective mGluR3 positive allosteric modulators (PAMs) mimic neuroprotective and neurotrophic factor production effects induced by mGluR3 activation. Moreover, an mGluR3 PAM candidate with excellent pharmacokinetic properties and in vitro activities was recently nominated for proof-of-concept studies. The goal of the current project is to evaluate this molecule in pre-clinical models to test its capacity to modulate central GDNF levels.

Hypothesis:
The objective of the present study is to see if a bioavailable mGluR3 PAM, given orally, can upregulate GDNF levels in the striatum of pre-clinical models.

Study Design:
Our mGluR3 PAM candidate will be given orally at different doses. After different time-points following treatment administration, brain structures will be isolated and ELISA analyses will be performed to measure GDNF levels in the different areas. These experiments can be performed on naïve and/or on challenged (MPTP-treated, alpha-synuclein-treated or aged) models.

Impact on Diagnosis/Treatment of Parkinson’s Disease:             
The present study will constitute the first in vivo proof-of-concept that GDNF can be upregulated in the brain following oral administration of a small molecule mGluR3 PAM. This will demonstrate that the present mechanism of action constitute a viable alternative to the challenging neurotrophic factor central delivery. 

Next Steps for Development:
If positive, the next step will consist in reproducing these experiments using mGluR3 knockout models to fully demonstrate the implication of this glutamate receptor in the GDNF induction. Then, neuroprotective role of mGluR3 PAMs will have to be demonstrated using an appropriate model.