AGING AND 6 HYDROXYDOPAMINE NEUROTOXICITY

描述：（来自申请人摘要的逐字记录） 多巴胺（DA）系统的大脑中起着重要的作用，在控制 运动黑质纹状体DA能神经元在正常衰老过程中逐渐丧失 在人类中，许多老年人显示出一种或多种 帕金森氏病而不患此病。这可能表明， 人的黑质纹状体DA的损失大于正常。 伴随DA神经元部分丧失的衰老（ICV注射6-羟基多巴胺， 6-OHDA）目前正在由申请人开发。中的实验 目前的建议将使用这个模型来确定自发的程度， 青年、中年和老年人突触前多巴胺能功能的恢复 大鼠此外，强效多巴胺能因子神经胶质细胞的作用 也将在该模型中检查系源性神经营养因子（GDNF）。它 假设老年大鼠的黑质纹状体DA系统将有一个 从6-OHDA的神经毒性作用中恢复的能力降低， 年轻的老鼠进一步假设GDNF在老年人中的有效性较低， 动物相比，年轻的动物，无论是在其能力，保护对6-OHDA 并促进损伤后的恢复。第一个具体目标将审查 年轻人（4个月）和中年人（14个月）的自发恢复，以及 部分给药后，老年（24月龄）雄性和雌性Fischer-344大鼠 双侧病变6-OHDA。自发活动，基础水平和诱发 DA及其代谢产物在纹状体中的溢出（如用 微透析），酪氨酸羟化酶免疫组织化学研究将是 在病变后的几个时间点进行，以确定 复苏组织单胺的尸检测量值将分析为 好.第二个具体目标将评估GDNF预防或治疗肿瘤的能力。 减少6-OHDA诱导的自发活动和突触前神经元的变化 多巴胺能功能在三个年龄组，而第三个具体目标 将研究GDNF促进行为和神经化学的能力， 在三个年龄组中从损伤中恢复。的结果予以 实验将有助于确定是否黑质纹状体DA系统的老化 大脑从神经毒性损伤中恢复的能力与 年轻的动物，并将开始评估与年龄相关的反应差异 黑质纹状体DA能神经元对神经营养因子的反应。

DESCRIPTION: (Verbatim from the Applicant's Abstract) The nigrostriatal dopamine (DA) system of the brain plays a major role in the control of movement. A gradual loss of nigrostriatal DA neurons occurs during normal aging in humans, and many elderly persons display one or more of the signs of Parkingson's disease without having the disease. This may indicate that these people have a greater than normal loss of nigrostriatal DA. An animal model of aging with a partial loss of DA neurons (ICV injection of 6-hydroxydopamine, 6-OHDA) is currently being developed by the applicant. The experiments in the present proposal will use this model to determine the extent of spontaneous recovery of presynaptic dopaminergic functioning in young, middle-aged and aged rats. In addition, the effects of the potent dopaminergic factor glial cell line-derived neurotrophic factor (GDNF) will also be examined in this model. It is hypothesized that the nigrostriatal DA system in aged rats will have a reduced capacity to recover from the neurotoxic effects of 6-OHDA compared to young rats. It is further hypothesized that GDNF will be less effective in aged animals compared to young animals both in its ability to protect against 6-OHDA and to promote recovery after the lesion. The first specific aim will examine spontaneous recovery in young (4 months old) middle-aged (14 months old), and aged (24 months old) male and female Fischer-344 rats following partial bilateral lesions with 6-OHDA. Locomotor activity, basal levels and evoked overflow of DA and its metabolites in the striata (as measured with microdialysis), and tyrosine hydroxylase immunohistochemistry studies will be carried out at several time points after the lesion to determine extent of recovery. Post-mortem measurements of tissue monoamines will be analyzed as well. The second specific aim will evaluate the ability of GDNF to prevent or reduce 6-OHDA-induced changes in locomotor activity and presynaptic dopaminergic function in the three age groups, while the third specific aim will examine the ability of GDNF to promote behavioral and neurochemical recovery from the lesion in the three age groups. The results of these experiments will help determine if the nigrostriatal DA system of the aging brain has the same capacity to recover from a neurotoxic insult as that of younger animals, and will begin to evaluate age-related differences in response of nigrostriatal DA neurons to neurotrophic factors.