? ? The neurorestorative and neuroprotective trophic actions of glial cell line-derived neurotrophic factor (GDNF) on midbrain dopamine (DA) neurons provide a promising therapeutic approach for the treatment of Parkinson's disease (PD; Gill et al., 2003). Currently a Phase I FDA-approved trial in later stage PD patients is taking place in our Udall Center (Slevin et al., 2003). Based on previous studies and our Center studies over the last 4 years, we hypothesize that GDNF is affecting DA neurons through at least 3 major mechanisms: A) Upregulation of existing DA neurons (Projects 1, 2 and 3); B) Repair of DA neurons and connections (Projects 1, 2 and 3); and C) Neurogenesis and or gliogenesis (Project 3). We will investigate these three mechanisms in the proposed experiments in MPTP-treated nonhuman primates that best simulate the human parkinsonian state. In addition, in the next 5 years we plan to address two key issues. 1) We propose to chronically deliver GDNF in the freely-moving MPTP-lesioned monkey to evaluate multisite delivery of GDNF (putamen vs. putamen and substantia nigra) to improve the functional restoration of DA systems. 2) We will use the improved delivery approach, to investigate the effects of GDNF infusion on mild parkinsonian vs. severe parkinsonian monkeys, to determine if early intervention of GDNF treatment may contribute to better functional recovery of the nigrostriatal system. The highly integrated Projects and Cores will provide key data regarding the functional effects of chronic GDNF treatments to DA neurons, determine mechanisms of action of GDNF, and they will provide data that can be used to improve the use of GDNF in patients with PD. Project 1 will use microdialysis, postmortem HPLC-EC methods and Western immunoblot methods to study the nigrostriatal pathway of GDNF-treated unilateral MPTP-lesioned monkeys. Project 2 will investigate the behavioral consequences of the GDNF infusions and study potential functional changes to DA neurons using fMRI methods. Project 3 will carryout immunohistochemical measures of DA neurons in the same groups of monkeys. Cores A-C will provide needed support for the experiments outlined in Projects 1-3. Finally, Core D is a new translational Core, added to address the potential cognitive and sensory effects of GDNF in patients with advanced PD, as part of an ongoing FDA-approved Phase-I clinical trial. ? ? Project 1 ? ? Title: Quantitative Neuropharmacological Studies of the Effects of Chronic Delivery of ? GDNF in Rhesus Monkeys ? ? PI: Greg Gerhardt, PhD ? ? DESCRIPTION (provided by applicant): ? ? The neurorestorative and neuroprotective trophic actions of GDNF on midbrain DA neurons provide a promising therapeutic approach for the treatment of Parkinson's disease (PD), which is being addressed in part through a Phase I FDA-approved clinical trial in our Udall Center. Based on our past work, we hypothesize that GDNF is affecting DA neurons through at least 3 major mechanisms: 1) Upregulation of existing DA neurons; 2) Repair of DA neurons; and 3) Neurogenesis and/or gliogenesis. Project 1 will investigate upregulation of DA function and repair of DA neurons. These studies will be carried out in nonhuman primates, which best simulate the human parkinsonian state. It is our central hypothesis that dualsite chronic intraputamenal/intranigral delivery of GDNF will improve function and restoration of damaged DA neurons with greater efficacy and reduced side effects as compared to other methods of delivery. In addition, we predict, based on preliminary data, that GDNF treatment in mild parkinsonian animals, a model of early stage PD patients, will lead to optimal restoration of the nigrostriatal DA neuronal system. We propose to use a novel indwelling pump that can deliver GDNF chronically in the freely-moving unilateral 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP)-Iesioned monkey to evaluate the two major issues. Project 1 will perform quantitative neurochemical assessments using in vivo microdialysis, Western immunoblot assays 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 with Projects 2 and 3. In addition, Project 1 will begin studies of glutamate regulation in 6-OHDA-lesioned rats, as a new area of scientific growth of the Center. The investigation of the role of glutamate in relation to DA function will improve our understanding of the essential role of this neurotransmitter to basal ganglia function in PD and provide an improved understanding of the functional effects of GDNF on nigrostriatal circuitry. ? ?
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