GDNF--INDUCED RECOVERY IN PARKINSONISM

描述：给药1-甲基-4-苯基-1，2，3，6-四氢吡啶 MPTP是一种对中脑多巴胺神经元具有高度选择性的神经毒素，可 非人灵长类产生一种多巴胺神经元丢失和运动的模式 类似于帕金森氏症的疾病。在这两种特发性中 帕金森病与MPTP诱导的帕金森病残馀功能状态 中脑多巴胺神经元尚不清楚。这项提案的重点是 残留多巴胺的结构和功能性质的表征 神经胶质细胞系源性神经营养因子作用前后的神经元 神经营养因子(GDNF)，一种有效的多巴胺能营养因子 帕金森病猴子的康复。在这个项目中，PI将特别 目的验证以下假说：1)GDNF发挥神经修复作用 对MPTP损伤的成人脑多巴胺神经元的影响。的变化 存活的黑质多巴胺神经元的特征 将使用光学分析器/体视学对GDNF治疗进行分析 一种确定细胞数量和定量图像的细胞计数方法 用于测量细胞大小的分析。2)帕金森症患者的改善 GDNF管理之后的功能与 酪氨酸羟化酶等多巴胺标志物表达上调 中脑多巴胺神经元中的多巴胺转运体。3)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 钾诱导的多巴胺释放和高亲和力多巴胺摄取将 GDNF处理组大鼠的壳核和黑质中的 赋形剂治疗帕金森病恒河猴的体内微透析 技巧。这些研究应该会增加对 非人灵长类动物中脑残留多巴胺神经元的特性 MPTP诱导的帕金森综合症。

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.