USE AND DRUG DEPENDENT NEUROPROTECTION--TROPIC FACTORS

帕金森病（PD）对我们社会的很大一部分人的健康构成严重威胁。在关注了PD临床前阶段的代偿性变化之后，我们现在将精力集中在神经保护的问题上。本项目是这一努力的一个组成部分，并侧重于在PD动物模型中诱导内源性神经保护机制的策略。这项工作来自我们实验室最近的证据表明，对侧运动忽视通常是在黑质纹状体多巴胺（DA）投射单侧损伤后，可以通过强迫使用对侧肢体来改善。此外，我们发现这种行为保留伴随着DA损失的急剧减少。我们假设，强制执行否则会受到PD损害的运动行为是神经保护性的，并且这是由于运动行为，损伤和伴随的一种或多种营养因子（例如，GDNF）和激素（例如雌激素）。我们的项目利用6-羟基多巴胺（6-OHDA）处理的啮齿动物模型的PD，并有五个具体的目标：（1）我们将确定强制使用/停用对DA神经元的解剖和功能状态的影响，包括使用微透析来测量体内DA流出。(2)我们将通过使用反义寡核苷酸减少营养因子的表达，融合蛋白作为因子的诱饵，以及缺乏反义寡核苷酸的动物来确定使用依赖性神经保护和营养因子表达增加之间的关系。 营养因子信号的关键蛋白质。(3)我们将研究雌激素发挥神经保护作用的能力，以及这种影响对运动影响的可能作用。(4)我们将使用微阵列与更经典的技术，以检查其他营养因子及其受体在纹状体的动物受到损害和/或铸造的变化。稍后，我们还将研究黑质和没有神经保护作用的区域。(5)最后，我们将研究年龄对营养因子诱导的神经保护作用的影响，首先确定在年轻成年大鼠中诱导的神经保护作用是否随着动物进入老年而继续有效，然后询问在年轻成年人中起作用的神经保护策略是否也可以用于减少6-OHDA对老年大鼠的影响。

Parkinson's disease (PD) poses a serious threat to the health of a large segment of our society. Having focused on the compensatory changes that underlie the preclinical phase of PD, we are now concentrating our efforts on the issue of neuroprotection. The present project is one component of this effort and focuses on strategies for inducing endogenous neuroprotective mechanisms in animal models of PD. The work derives from recent evidence from our labs indicating that the contralateral motor neglect normally following unilateral damage to the nigrostriatal dopamine (DA) projection can be ameliorated by forced use of the contralateral limb. Moreover, we find that this behavioral sparing is accompanied by a dramatic reduction in the loss of DA. We hypothesize that forced execution of a motor act that is otherwise compromised by PD is neuroprotective, and that this results from an interaction between the motor act, injury, and concomitant increase in the availability of one or more trophic factors (e.g., GDNF) and hormones (e.g. estrogen). Our project utilizes 6-hydroxydopamine (6-OHDA)-treated rodent models of PD and has five specific aims: (1) We will determine the impact of forced use/disuse on the anatomical and functional state of DA neurons, including the use of microdialysis to measure in vivo DA efflux. (2) We will determine the relationship between use-dependent neuroprotection and increased trophic factor expression by using antisense oligonucleotides to reduce expression, fusion proteins to serve as decoys for the factors, and animals deficient in a protein key to trophic factor signaling. (3) We will examine the ability of estrogen to exert a neuroprotective influence and the possible role of that influence on the impact of exercise. (4) We will use microarrays together with more classical techniques to examine changes in other trophic factors and their receptors in striatum of animals subjected to lesions and/or casting. Later we will also look at substantia nigra and at regions where no neuroprotection is seen. (5) Finally, we will examine the impact of age on neuroprotection induced by trophic factors by first determining whether neuroprotection induced in young adult rats continues to be effective as animals reach old age, and then ask whether neuroprotective strategies that work in young adults can also be used to reduce the impact of 6-OHDA in aged rats.