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条新的途径。我们的中心假设是，与其他给药方法相比，慢性脑室或壳核内GDNF对受损的DA神经元具有更高的疗效、效力和更少的副作用。我们建议使用一种新型的留置泵，在自由移动的单侧1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)损伤猴体内长期输送GDNF，以评估两个输送部位：侧脑室和壳核。以往的研究表明，单次注射GDNF对大鼠和猴子的DA神经元具有神经保护和神经恢复作用，这些神经元定位于黑质，而不是纹状体。我们假设，基于初步研究，长期注射GDNF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程度的帕金森行为逆转。该计划项目拨款申请的项目1将使用体内微透析、体内电化学和高效液相结合电化学检测(HPLC-EC)进行定量的神经化学评估，以研究长期接受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。将进行冲刷研究，以确定慢性GDNF效应的持久性。还将进行重新声明研究，以确定GDNF是否可以维持或增加洗脱后的DA功能，并安全地重新给药。这些在慢性注射GDNF期间对猴纹状体的神经化学变化将与同一猴子的行为、免疫组织化学、束追踪和功能磁共振(FMRI)研究一起进行，并与项目2和3一起进行。这些研究将有助于更好地理解局部和持续传递一种有效的DA趋化因子对受损的DA神经元的影响。它们可能会为向帕金森氏症患者提供局部和长期的营养因子奠定基础。

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.