AGING AND 6 HYDROXYDOPAMINE NEUROTOXICITY

描述：(逐字摘自申请者的摘要)黑质纹状体 大脑中的多巴胺系统在控制脑血管紧张素转换酶活性中起重要作用。 有动静。黑质纹状体DA神经元在正常衰老过程中逐渐丧失 在人类身上，许多老年人表现出一种或多种 帕金森氏病而不患此病。这可能表明这些 人们黑质纹状体DA的丢失比正常情况下更严重。一种动物模型 随着DA神经元的部分丧失而衰老(脑室注射6-羟基多巴胺， 6-OHDA)目前正在由申请人开发。实验中的实验 目前的建议将使用这一模型来确定自发程度 青年、中老年人突触前多巴胺能功能的恢复 老鼠。此外，强大的多巴胺能因子神经胶质细胞的作用 线源性神经营养因子(GDNF)也将在这个模型中被检测。它 假设老年大鼠的黑质纹状体DA系统将具有 与6-OHDA的神经毒性效应相比，6-OHDA的恢复能力降低 幼小的老鼠。进一步假设GDNF在老年人中的效果会较差 动物与幼年动物相比，其对6-OHDA的保护能力 并促进损伤后的恢复。第一个具体目标将检查 青年(4个月大)、中年(14个月大)自然恢复，以及 老年(24月龄)雄性和雌性Fischer-344大鼠 双侧病变用6-羟基多巴胺。运动活动、基础水平和诱发 多巴胺及其代谢物在纹状体中的溢出(用 微透析)和酪氨酸羟基酶免疫组织化学研究 在损伤后的几个时间点进行，以确定损伤的程度 恢复。对组织单胺类物质的尸检结果分析如下 井。第二个具体目标将评估GDNF预防或 减少6-OHDA引起的运动活动和突触前改变 多巴胺能功能的三个年龄段，而第三个特定的目标 将检验GDNF促进行为和神经化学的能力 三个年龄段患者的皮损愈合情况。这些研究的结果 实验将有助于确定黑质纹状体DA系统是否在衰老 大脑从神经毒性的侮辱中恢复的能力与 更年轻的动物，并将开始评估与年龄相关的反应差异 黑质纹状体DA神经元对神经营养因子的作用。

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.