Funded Studies
Objective/Rationale:
GDNF is a potent trophic factor for dopamine neurons in the adult brain. Exogenous GDNF supplementation strategies, however, are fraught with technical difficulties associated with the perfusion of a large, immunogenic protein into the adult brain by cannulation. Pharmacological up-regulation of endogenous GDNF productions could overcome many of these challenges.
Project Description:
Based on preliminary results we hypothesize that low molecular weight compounds that were developed as mimetics of the sonic hedgehog signaling (Shh) pathway could be utilized to regulate GDNF expression from endogenous sources in the adult brain. We wish to test this hypothesis in the MPTP model of Parkinson’s disease: In animals with limited toxin exposure we shall assess whether the semi chronic, pharmacological modulation of Shh signaling will exacerbate or ameliorate the neurological phenotype.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The beneficial effects of increased GDNF signaling on the protection of dopamine neurons in the adult brain have been demonstrated previously. Finding pharmacological strategies to boost endogenous expression of GDNF could make GDNF therapy feasible as a general treatment for the stabilization of remaining dopamine neurons in Parkinson’s disease. Agonists and antagonists of Shh signaling have been developed and are already in clinical trials as anticancer treatments. Hence positive results from this proof of principle study could be translated quickly into a clinical setting.
Anticipated Outcome:
We anticipate that the partial inhibition of Shh signaling in the adult basal ganglia will lead to an increase in GDNF expression, a reduced sensitivity of dopamine neurons towards the neurotoxin MPTP and/or increased recovery of dopamine neurons from the neurotoxic insult.
Progress Report
GDNF is a potent trophic factor for dopamine neurons in the adult brain. Exogenous GDNF supplementation strategies, however, are fraught with technical difficulties associated with the delivery of a large, immunogenic protein into the adult brain. Pharmacological up-regulation of endogenous GDNF productions could overcome many of these challenges. We tested these ideas using the MPTP model of Parkinson’s disease. We first established a “semi – chronic” MPTP injection paradigm that achieves a toxin induced degeneration of about 40 percent of DA neurons. We then repeated the MPTP injections in models that are chronically perfused with cyclopamine, a potent signaling antagonist, to up-regulate GDNF. Currently, we are quantifying the survival of DA neurons as a function of cyclopamine concentration in the face of MPTP intoxication.