Project 3

The neurorestorative and neuroprotective trophic actions of GDNF on midbrain dopamine (DA) neurons provide a promising but controversial therapeutic approach for the treatment of Parkinson's disease. We specifically plan to address the following major issues in the next 5 years of support for the University of Kentucky Udall Center: 1) We hypothesize that GDNF is affecting DA neurons through at least 3 major mechanisms: A) Upregulation of existing DA neurons - direct effects on tyrosine hydroxylase and related proteins (Project 1); B) Repair of DA neurons and connections - improved dendritic and neuronal fiber connections (Projects 2 and 3); and C) Neurogenesis and/or gliogenesis (Project 3). We will investigate these three mechanisms in the proposed experiments in nonhuman primate models of PD. 2) We propose to use a novel indwelling pump that can deliver GDNF chronically in the freely-moving MPTP-Iesioned monkey to evaluate multisite delivery of GDNF (putamen vs. putamen + substantia nigra) to improve the functional restoration of DA systems. 3) Recent studies in PD patients involving a Phase 2 clinical trial have yielded controversial data regarding potential GDNF antibody formation and preliminary toxicology studies in rhesus monkeys support a potential toxicity of GDNF to cerebellar Purkinje cells and granule cells, when chronically administered in high doses (100 I-Ig/day) and subsequently withdrawn. In conjunction with Projects 2 and 3, we will investigate the potential toxic effects of GDNF on dopamine and non-dopamine containing cells in the CNS. In addition, we will investigate potential antibody formation from chronic GDNF administration. 4) Finally, we will use an improved delivery approach, to investigate the effects of GDNF infusion on milder parkinsonism in unilateral MPTP-treated monkeys, to investigate if earlier intervention of GDNF treatment may contribute to better functional recovery of the nigrostriatal system. We will utilize a recently developed stable, unilateral milder parkinsonian monkey model for these studies, which may be an "earlystage" model of PD. The different highly integrated Projects and Cores will provide key data regarding the functional effects of chronic GDNF treatments to DA neurons, mechanisms of action of GDNF both positive and negative, and will provide data that may be useful to gain a better understanding of the effects of trophic factors on dead or dying neurons.