GDNF--INDUCED RECOVERY IN PARKINSONISM

描述：1-甲基-4-苯基-1，2，3，6四氢吡啶给药 （MPTP），一种对中脑多巴胺神经元具有高度选择性的神经毒素， 非人类灵长类动物产生多巴胺神经元丢失和运动的模式 类似于帕金森病的疾病。 在特发性 帕金森综合征和MPTP诱导的帕金森综合征，残留的功能状态 中脑多巴胺神经元尚不清楚。 该提案的重点是 表征残留多巴胺的结构和功能特性 暴露于胶质细胞系源性神经营养素之前和之后的神经元 GDNF是一种有效的多巴胺能营养因子， 帕金森病猴子的康复 在本项目中，PI将特别 目的是验证以下假设：1）GDNF发挥神经修复作用， 对MPTP损伤的多巴胺神经元的影响。 变化 黑质多巴胺神经元存活的特征 GDNF治疗将使用光学解剖器/体视学分析仪进行分析。 细胞计数法测定细胞数量和定量图像 分析以测量细胞大小。 2)帕金森病的改善 GDNF给药后的特征与 多巴胺标记物如酪氨酸羟化酶的上调， 中脑多巴胺神经元中的多巴胺转运体。 3)大脑内 给予GDNF显著改变黑质纹状体多巴胺 新陈代谢. 多巴胺及其代谢物的基础水平，特征 钾诱发的多巴胺释放和高亲和力多巴胺摄取将 在GDNF处理的壳核和黑质中进行分析， 使用静脉内微透析的载体治疗的帕金森病恒河猴 技术. 这些研究应增进对 非人灵长类动物中脑残留多巴胺神经元的特性 MPTP诱发的帕金森症

DESCRIPTION: Administration of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), a neurotoxin highly selective for midbrain dopamine neurons, to nonhuman primates produces a pattern of dopamine neuron loss and movement disorders similar to that seen in Parkinson's disease. In both idiopathic parkinsonism and MPTP-induced parkinsonism, the functional state of residual midbrain dopamine neurons is unclear. This proposal focuses on characterizing the structural and functional properties of residual dopamine neurons before and after exposure to glial cell line-derived neurotrophic factor (GDNF), a potent dopaminergic trophic factor which induces functional recovery in parkinsonian monkeys. In this project, the PI will specifically aim to test the following hypotheses: 1) That GDNF exerts neurorestorative effects on MPTP-injured dopamine neurons in the adult brain. Changes in the characteristics of surviving substantia nigra dopamine neurons following GDNF treatment will be analyzed using an optical dissector/stereological cell counting approach to determine cell number and quantitative image analysis to measure cell size. 2) That improvements in parkinsonian features following GDNF administration correlate closely with the upregulation of dopamine markers such as tyrosine hydroxylase and the dopamine transporter in midbrain dopamine neurons. 3) That intracerebral administration of GDNF significantly alters nigrostriatal dopamine metabolism. Basal levels of dopamine and its metabolites, characteristics of potassium-evoked dopamine release and high affinity dopamine uptake will be analyzed in the putamen and substantia nigra of GDNF-treated and vehicle-treated parkinsonian rhesus monkeys using iv vivo microdialysis techniques. These studies should increase the understanding of the properties of residual midbrain dopamine neurons in nonhuman primates with MPTP-induced parkinsonism.