USE AND DRUG DEPENDENT NEUROPROTECTION--TROPIC FACTORS

帕金森氏症（PD）对我们社会的大部分人的健康构成严重威胁。在专注于帕金森病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问题上。目前的项目是这一努力的一个组成部分，重点是在PD动物模型中诱导内源性神经保护机制的策略。这项工作源于我们实验室最近的证据，表明通常在单侧黑质纹状体多巴胺（DA）投射损伤后的对侧运动忽视可以通过强制使用对侧肢体来改善。此外，我们发现这种行为节约伴随着DA损失的急剧减少。我们假设，运动行为的强制执行对PD具有神经保护作用，这是运动行为、损伤以及一种或多种营养因子（如GDNF）和激素（如雌激素）可用性增加之间的相互作用的结果。我们的项目利用6-羟多巴胺（6-OHDA）治疗的PD啮齿动物模型，有五个具体目标：(1)我们将确定强制使用/停用对DA神经元解剖和功能状态的影响，包括使用微透析来测量体内DA外排。(2)我们将通过使用反义寡核苷酸来降低表达，融合蛋白作为这些因子的诱饵，以及a缺乏的动物来确定使用依赖性神经保护与营养因子表达增加之间的关系

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.