蛋白酶体抑制剂诱导帕金森病大鼠模型行为学退行性改变的研究

目的观察蛋白酶体抑制剂诱导的帕金森病(PD)行为学退行性变化,探索其发病机制。方法将32只大鼠随机分成实验组和对照组,每组16只,将蛋白酶体抑制剂Lactacystin立体定向注射到实验组大鼠左侧黑质致密部,对照组注射等体积生理盐水。术后1、3、5、7、9、11、14、18和21d,追踪观察大鼠自主行为和阿扑吗啡诱导的旋转行为变化;开野实验观察大鼠自发运动行为改变。结果实验组给药后,随着时间推移大鼠开始出现渐进性自发性活动减少、动作缓慢、对外界刺激不自主竖毛、震颤;阿扑吗啡诱导的向健侧旋转运动逐渐增多。开野实验结果显示:实验组大鼠自发运动行为出现渐进性异常改变。结论蛋白酶体抑制剂Lactacystin单侧黑质致密部微量注射诱导的大鼠行为学呈渐进性发展,符合PD发病过程,说明蛋白酶体功能下降可能在PD发病机制起重要作用。

Retrograde changes of motor behavior in the rat models of Parkinson disease induced by Lactacystin

Objective To observe the retrograde changes of motor behavior in Parkinson disease (PD) induced by proteasome inhibitors, and investigate its pathogenesis. Methods Thirty-two rats were equally randomized into two groups: lactacystin group and control group. Lactacystin, a selective proteasome inhibitor, was injected stereotaxically into the left substantia nigral pars compacta (SNc) in experimental rats. Equal volume of saline was injected into the control rats. At different stages (1, 3, 5, 7, 9, 11, 14, 18 and 21 d after injection), the spontaneous behavioral abnormalities were observed. The changes in the contralateral rotations induced by apomorphine and the spontaneous behavior in the rats in the open-field tests were tracked. Results Compared with the control group, the rats in the lactacystin group began gradually to have some behavioral symptoms, for example, the spontaneous motors decreased progressively, tardive dyskinesia, piloerection, tremor, contralateral rotations induced by apomorphine increased gradually. Simultaneously, the retrogression of behavior in open-field tests was observed. Conclusion Lactacystin unilaterally injected stereotaxically into SNc of rats could induce time-dependent retrograde changes of behavior in rats after proteasome inhibition, which is just in accord with Parkinson symptoms, indicating that proteasome dysfunction may play a significant role in the pathogenesis of PD.