An important goal in Parkinson’s disease therapy is to restore the loss of the dopaminergic innervation of the striatum. Cell culture data from our lab indicate that activation of certain transmitter receptors (NMDA receptors) enhances the growth and branching of dopamine neurites. We will test whether newly developed compounds (glycine uptake inhibitors) that enhance NMDA receptor activity promote the regeneration of dopaminergic fibers in a toxin-based pre-clinical model of Parkinson’s disease.
Adult mice will receive unilateral lesions using 6-OHDA, which destroys exclusively dopaminergic neurons. Following the lesion a gradual and partial regeneration of the dopaminergic innervation occurs within the next 4 weeks. During this time, we will feed the mice with a new compound that enhances NMDA receptor–dependent transmission. We will assess functionally and anatomically whether this compound promotes regeneration on the dopaminergic projection.
Relevance to Diagnosis/Treatment of Parkinson's Disease:
If regeneration of the dopaminergic nigrostriatal projection will indeed be more pronounced in glycine uptake inhibitor-treated mice, we will have demonstrated the principle that glycine uptake inhibition promotes dopaminergic reinnervation and that such inhibitors may be considered as a treatment in Parkinson’s disease.</p>
We have found in cell culture experiments that neurite growth in dopamine neurons can be promoted by activation of certain transmitter receptors (NMDA receptors). We anticipate that oral application of compounds that activate these receptors will also encourage regeneration and growth of dopamine neurites in the intact brain.
We have found that glycine uptake inhibitors that enhance NMDA glutamate receptor activity promote striatal dopaminergic re-innervation in a toxin-based pre-clinical model of Parkinson’s disease. Adult mice received unilateral intrastriatal 6-OHDA injections. Three weeks after the lesion the dorsal striatum was devoid of dopamine neurites. After an additional four weeks, a gradual and partial dopaminergic re-innervation of the dorsal striatum occurred in untreated mice. This re-innervation was enhanced by 30% when mice were treated with a glycine uptake inhibitor beginning three weeks after the lesion. Dopamine release recordings indicated that this recovery was also functional. 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.