Protective effects of exercise in an animal model of PD

描述（由申请方提供）：PD是一种病因不明的进行性神经退行性疾病，导致从黑质投射到纹状体的多巴胺神经元丢失。我和我的同事已经证明，如果在单侧6-OHDA输注之前或之后的前7天内将石膏放置在同侧肢体上，迫使依赖受损的对侧肢体，则行为和神经化学缺陷都会减少（Tillerson et al，2001; 2002; Cohen et al，2003）。强迫使用肢体的保护作用的机制尚不清楚。然而，我已经表明GDNF，一种有效的多巴胺营养因子，可以保护免受6-OHDA毒性（例如，Kearns和Gash，1995; Choi-Lundberg等人，1998），随着强迫肢体使用而增加，表明其可能参与强迫肢体使用对6-OHDA的保护作用（Cohen等人，2003）。虽然GDNF可能发挥其保护作用的机制也是未知的，但有证据表明GDNF部分通过Ras/ERK信号级联起作用（例如：Soler et al.，1999年）。该项目的具体目标是：目标1：确定6-OHDA后，先前强迫肢体使用对DA神经元解剖状态的影响。目的2：确定ERK信号级联是否参与强迫肢体使用诱导的GDNF增加和神经保护作用。目的3：确定纹状体中GDNF的增加与强迫肢体使用的神经保护作用之间的关系。

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.