Stress stimulated peptides in forced use neuroprotection

描述(由申请人提供)： 在帕金森病的单侧6-羟基多巴胺(6-OHDA)损伤模型中，强制使用受损的前肢可以改善行为不对称，并在神经毒性侮辱后立即开始恢复纹状体中的多巴胺(DA)含量。然而，强迫肢体使用改善行为和神经化学功能的机制尚不清楚。虽然强迫受损的肢体使用对受损的大脑有积极的影响，但它可以被视为一种约束压力。因此，像其他应激性刺激一样，我们可以预测，铸造动物的前肢将刺激下丘脑-垂体-肾上腺轴(HPA轴)。对HPA轴的刺激导致多肽(例如，促肾上腺皮质激素释放)释放到门脉血流中，在那里它们被输送到垂体的前叶和中叶，刺激源自前阿片皮质素的几种多肽[例如，促肾上腺皮质激素(ACTH)、黑素细胞刺激激素(α、β和伽马-MSH)和ACTH4-10]的释放。ACTH刺激肾上腺皮质释放皮质酮(CORT)。我的初步数据表明，单侧前肢铸型会增加纹状体循环皮质醇水平以及GDNF和BDNF蛋白水平。因此，我建议探索运动-营养因子-神经保护联系可能发生的方式的一个方面。具体地说，我将研究强迫运动对多肽的影响，这些多肽可以通过刺激HPA轴来启动释放。我将重点介绍与ACTH相关的多肽(即？-MSH和CORT)。虽然这些肽和相关的HPA轴是最常见的与应激有关的，通常被认为是有毒的，我将概述证据，事实上激活HPA轴也可以起到关键的神经保护功能，并且更好地了解这一功能可能导致新的和重要的治疗帕金森病的策略。因此，本提案的总体目标是研究强制使用前肢对多肽的影响，这些多肽的释放可以通过激活HPA轴来启动，以及它们在强迫使用肢体诱导的保护中的作用。为了实现这一目标，我提出了两个具体目标：(1)确定强迫肢体使用对皮质醇水平的影响，以及在6-OHDA啮齿动物模型中，皮质醇水平、神经营养因子表达和强迫使用诱导的神经保护之间是否存在因果关系，以及(2)确定强迫肢体使用诱导的神经保护与特定黑素皮质素表达增加之间的关系。更好地了解运动预防6-OHDA神经毒性的机制将为此类疗法的发展提供见解，包括为物理治疗和药物发现的靶点提供合理的基础。

DESCRIPTION (provided by applicant): Forced use of the impaired forelimb in a unilateral 6-hydroxydopamine (6-OHDA) lesion model of Parkinson's disease, ameliorates behavioral asymmetry and restores dopamine (DA) content in the striatum when commenced immediately after neurotoxic insult. However, the mechanism by which forced-limb use improves behavioral and neurochemical functioning is unknown. Although forced impaired limb use has positive effects on the compromised brain, it can be regarded as a form of restraint stress. Thus, like other stressful stimuli, we might predict that casting the forelimb of animals will stimulate the hypothalamic-pituitary-adrenal axis (HPA axis). Stimulation of the HPA axis results in the release of peptides (e.g. corticotrophin-releasing) into the portal bloodstream where they are transported to the anterior and intermediate lobe of the pituitary stimulating the release of several peptides derived from pro-opiornelanocortin [e.g. adrenocorticotrophin (ACTH), melanocyte-stimulating hormones (alpha, beta and gamma-MSH) and ACTH4-10]. ACTH stimulates the adrenal cortex to release corticosterone (CORT). My preliminary data indicates that unilateral forelimb casting produces an increase in circulating CORT levels and GDNF and BDNF protein levels in the striatum. Thus, I propose to explore one aspect of the manner in which an exercise-trophic-factor-neuroprotection link might occur. Specifically, I will examine the impact of forced exercise on peptides whose release can be initiated through stimulation of the HPA axis. I will focus on ACTH related peptides (i.e., ?-MSH and CORT). Although these peptides and the associated HPA axis are most commonly associated with stress and are usually thought of as being toxic, I will outline evidence that in fact activation of the HPA axis can also serve a critical neuroprotective function and that a better understanding of this function may lead to novel and important strategies for the treatment of PD Thus, the overall goal of the present proposal is to examine the impact of forced forelimb use on peptides whose release can be initiated through activation of the HPA axis and their role in forced limb use-induced protection. To achieve this goal I propose 2 specific aims: (1) determine the impact of forced limb use on CORT levels and whether there is a causal relationship between CORT levels, neurotrophic factor expression, and forced use-induced neuroprotection in a 6-OHDA rodent model of PD and (2) determine the relationship between forced limb use-induced neuroprotection and the increased expression of specific melanocortins. A better understanding of the mechanism by which exercise protects against 6-OHDA neurotoxicity holds great promise to provide insights into the development of such therapies, including offering a rational basis for physical therapy and targets of drug discovery.