Quantitative Neuropharmacoloqical.Studies of the Effects of Chronic Delivery of GDNF in Rhesus Monkeys The neurorestorative and neuroprotective trophic actions of GDNF on midbrain DA neurons provide a promising but controversial therapeutic approach for the treatment of Parkinson's disease (PD). Based on past work, we hypothesize that GDNF is affecting DA neurons through at least 3 major mechanisms: 1) Upregulation of existing DA neurons - direct effects on tyrosine hydroxylase and related proteins; 2) Repair of DA neurons - improved dendritic and neuronal fiber connections; and 3) Neurogenesis and/or gliogenesis. Project 1 will investigate DA function and repair of DA neurons, in conjunction with Projects 2 and 3. It is our central hypothesis that dual-site chronic intraputamenal/intranigral delivery of GDNF will improve function and restoration of damaged DA neurons with greater efficacy, potency and reduced side effects. In addition, we predict, based on preliminary data, that GDNF treatment in milder parkinsonian animals, a model of early stage PD patients, will lead to optimal restoration of the nigrostriatal DA neuronal system. We propose to use an indwelling pump that can deliver GDNF chronically in the freely-moving unilateral 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP)-lesioned middle-aged female monkeys. Project 1 of this revised program project grant will perform quantitative neurochemical assessments using in vivo microdialysis, Western immunoblot assays, immunohistochemical studies and high performance liquid chromatography coupled with electrochemical detection (HPLC-EC) to study DA neuronal systems in the striatum (putamen and caudate nucleus) and substantia nigra of Rhesus monkeys that have received chronic GDNF infusions. These neurochemical changes to the monkey striatum during chronic delivery of GDNF will be performed in conjunction with behavioral, immunohistochemical, histological and functional MRI (fMRI) studies of the same monkeys in conjunction with Projects 2 and 3. In addition, Project 1 will begin studies of glutamate regulation in the striatum, substantia nigra and globus pallidus of 6-OHDA- lesioned rats and the effects of GDNF infusion on glutamate regulation in the basal ganglia. This is as a new area of scientific growth of the Center. The investigation of the role of glutamate in relation of.DA function will improve our understanding of the essential role of this neurotransmitter to basal ganglia function in PD.
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