Protective effects of exercise in an animal model of PD

运动对帕金森病动物模型的保护作用

• 批准号: 6885096
• 负责人: Ann D. Cohen
• 金额: $ 4.36万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6885096
• 关键词: 6 hydroxydopamine; Parkinson' s disease; apoptosis; biological signal transduction; corpus striatum; exercise; guanine nucleotide binding protein; laboratory rat; mitogen activated protein kinase; neural degeneration; neuroprotectants; neurotoxins; neurotrophic factors; predoctoral investigator; substantia nigra

DESCRIPTION (provided by applicant): PD is a progressive neurodegenerative disorder of unknown etiology that results in the loss of dopamine neurons projecting from substantia nigra to striatum. My colleagues and I have shown that if a cast is placed on the ipsilateral limb during the first 7 days prior to or following unilateral 6-OHDA infusion, forcing reliance on the impaired contralateral limb, both the behavioral and neurochemical deficits are reduced (Tillerson et al, 2001; 2002; Cohen et al, 2003). The mechanism underlying the protective effect of forced limb use is unknown. However I have shown that GDNF, a potent dopaminotrophic factor that protects against 6-OHDA toxicity (e.g., Kearns and Gash, 1995; Choi-Lundberg et al, 1998), is increased with forced limb use, indicating that it may be involved in the protective effects of forced limb use against 6-OHDA (Cohen et al, 2003). Although the mechanism by which GDNF might exert its protective effects is also unknown, evidence suggests that GDNF acts in part through the Ras/ERK signaling cascade (eg: Soler et al., 1999). The specific aims for this project are: Aim 1: Determine the impact of prior forced limb use on the anatomical state of DA neurons after 6-OHDA. Aim 2: Determine if the ERK signaling cascade is involved in forced-limb use-induced increases in GDNF and resulting neuroprotection. Aim 3: Determine the relationship between increases in GDNF in the striatum and the neuroprotective effects of forced limb use.

描述（由申请人提供）：PD是一种渐进的病因神经退行性疾病，导致从黑质Nigra到纹状体投射的多巴胺神经元的丧失。我和我的同事已经表明，如果在单侧6-OHDA输注之前或之后的前7天将演员放在同侧肢体上，迫使对对侧肢体受损的依赖，则行为和神经化学缺陷均减少（Tillerson等人，2001; 2002; Cohen et al，2003; Cohen et al，2003; Cohen et al，2003; Cohen et al，2003;强制肢体使用的保护作用的基础机制尚不清楚。但是，我已经证明，GDNF是一种有效的多巴胺营养因子，可预防6-OHDA毒性（例如Kearns和Gash，1995; Choi-Lundberg等，1998）随着强制性使用而增加，表明它可能参与了limbed Limb使用的保护作用，这可能与6-hohda（Coybhda and Al aff inlimb affice affice affice affice affice affical affice效应）（2003年）（2003），2003年）。尽管GDNF可能发挥其保护作用的机制也未知，但有证据表明，GDNF部分通过RAS/ERK信号级联反应起作用（例如：Soler等，1999）。该项目的具体目的是：目标1：确定在6-OHDA后，强迫肢体使用对DA神经元解剖状态的影响。 AIM 2：确定ERK信号级联是否参与强制使用诱导的GDNF的增加并导致神经保护作用。目标3：确定纹状体中GDNF的增加与强制肢体使用的神经保护作用之间的关系。