Quantitative neurochemical studies of effects of chronic delivery of GDNF

GDNF对中脑多巴胺（DA）神经元的神经修复和神经保护作用为帕金森病的治疗提供了一种有希望的治疗方法。 我们的中心假设是，与其他递送方法相比，慢性脑室内或壳核内GDNF将对受损的DA神经元产生更大的功效、效力和减少的副作用。 我们建议使用一种新的留置泵，可以提供GDNF长期在自由移动的单侧1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）病变的猴子评估两个网站的交付：侧脑室和壳核。 先前的研究表明，GDNF的单次输注对DA神经元产生神经保护和神经恢复作用，DA神经元定位于黑质而不是大鼠和猴子的纹状体。 基于初步研究，我们假设GDNF的长期递送将恢复黑质和纹状体区域的DA功能，产生比以前单次注射更大的帕金森病行为逆转。 本计划项目资助申请的项目1将使用体内微透析，体内电化学和高效液相色谱-电化学检测（HPLC-EC）进行定量神经化学评估，以研究接受慢性GDNF输注的年轻成年恒河猴纹状体（壳核和尾状核）和黑质中的DA神经元系统。 将进行洗脱研究以确定慢性GDNF效应的寿命。还将进行恢复研究以确定GDNF是否可以在洗脱后维持或增加DA功能并安全地重新给药。在GDNF慢性递送期间对猴纹状体的这些神经化学变化将与项目2和3中相同猴的行为、免疫组织化学、束追踪和功能性MRI（fMRI）研究一起进行。 这些研究应导致更好地了解局部和持续提供一个强大的DA热带因子受损DA神经元的影响。 他们可能会为帕金森病患者的局部和慢性营养因子输送奠定基础。

The neurorestorative and neuroprotective tropic actions of GDNF on midbrain dopamine (DA) neurons provide a promising therapeutic approach for the treatment of Parkinson's disease. It is our central hypothesis that chronic intracerebroventricular or intraputamenal GDNF will produce effects on damaged DA neurons with greater efficacy, potency and reduced side effects as compared to other methods of delivery. 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)-lesions monkey to evaluate two sites of delivery: the lateral ventricle and the putamen. Prior studies have shown that single infusions of GDNF produce neuroprotection and neurorestorative effects to DA neurons, which are localized to the substantia nigra and not the striatum of rats and monkeys. We hypothesize, based on preliminary studies, tha chronic delivery of GDNF will restore DA function in regions of the substantia nigra and striatum, producing a greater reversal of parkinsonian behavior than previously seen with single injections. Project 1 of this program project grant application will perform quantitative neurochemical assessments using in vivo micordialysis, in vivo electrochemical, 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 young adult Rhesus monkeys that have received chronic GDNF infusions. Washout studies will be performed to determine the longevity of the chronic GDNF effects. Re-instatement studies will also be performed to determine if GDNF can sustain or increase DA funciton following washout and be safely re-administered. These neurochemical changes to the monkey striatum during chronic delivery of GDNF will be performed in conjunction with behavioral, immunohistochemical, tract tracing and functional MRI (fMRI) studies of the same monkeys in conjunction with Project 2 and 3. These studies should lead to a greater understanding of the effects of focal and sustained delivery of a potent DA tropic factor to damaged DA neurons. They will likely lay the foundation for focal and chronic delivery of trophic factors to patients with Parkinson's disease.