Objective/Rationale:
An important goal in Parkinson’s disease therapy is to reverse the loss of the dopaminergic neurons of the striatum. We have found that compounds that act as glycine uptake inhibitors promote the re-innervation of dopamine-depleted striatal areas in a toxin-based pre-clinical model of Parkinson’s disease. We will now examine whether this re-innervation is functional by evaluating dopamine content, release and uptake, and behavioral recovery.
Project Description:
The pre-clinical models will receive lesions using which destroy exclusively dopaminergic neurons. Several weeks following the lesion, a gradual and partial re-innervation occurs which is greatly enhanced by glycine uptake inhibitors. We will test the extent to which dopamine levels and activity are restored, and whether there is behavioral recovery. We will also perform tests to gain insight into the mechanism of action and to evaluate the safety of the compounds.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
If glycine uptake inhibitors promote a physiological and behavioral recovery in toxin-treated pre-clinical models and will not exacerbate toxin-induced lesions when co-applied, such inhibitors may be considered as an adjunct treatment in Parkinson’s disease.
Anticipated Outcome:
We expect to find that the glycine uptake inhibitor-related re-innervation of dopamine-depleted areas of the brain is functional in terms of restoring dopamine levels, release and uptake, and improving motor behavior. We will also learn from the proposed work about the mechanism of action of the compounds and whether they are safe in terms of neurotoxicity.
Progress Report
We have found that glycine uptake inhibitors promote the growth of dopaminergic processes into the dopamine-depleted striatum in a toxin-based pre-clinical model of Parkinson’s disease. This dopaminergic re-innervation was functional as a behavioral recovery paralleled the increase in dopamine fiber density. By creating models that lack NMDA glutamate receptors in dopamine cells, we could show that glycine uptake inhibitors act to promote fiber growth by activating NMDA receptors in dopamine neurons. Thus, glycine uptake inhibitors promote functional dopaminergic sprouting, a finding, that we think should be carefully examined as a new avenue for therapy development for Parkinson’s disease.
May 2012