CB1受体激动剂WIN55212-2改善帕金森病运动并发症的实验研究  

CB1 receptor agonist WIN55212-2 improves motor complications in Parkinson's disease

作　　者：马雅萍[1] 宋璐[1] 刘振国[1] 巴茂文[1] 卞雷斯[1] 

机构地区：[1]上海交通大学医学院附属新华医院神经内科,上海200092

出　　处：《中风与神经疾病杂志》2011年第10期914-917,共4页Journal of Apoplexy and Nervous Diseases

基　　金：上海市科委基础研究重点项目(No.09JC1411000);上海市教委科研创新重点项目(No.10ZZ72);上海市白玉兰科技人才基金项目(No.1009B097);国家自然科学基金(No.81071025;81171203)

摘　　要：目的探讨CB1受体激动剂WIN55212-2对左旋多巴诱发的运动并发症的行为学及细胞学作用。方法通过6-OHDA立体定向注射至大鼠右侧前脑内侧束建立PD动物模型,成功的PD大鼠模型分别接受左旋多巴/苄丝肼(50mg/kg加12.5mg/kg苄丝肼,每天2次)+溶剂、左旋多巴/苄丝肼+WIN55212-2(1mg/kg)腹腔注射,共持续21d。评估用药后大鼠的旋转反应时间、剂峰旋转圈数变化和关期发生率;采用Western blot方法检测纹状体信号转导蛋白DARPP-32(Thr75)和ERK1/2(Thr202/Tyr204)的磷酸化表达。结果长期联合应用WIN55212-2和左旋多巴,缓解了左旋多巴单独用药所致的PD大鼠旋转反应时间缩短、剂峰旋转圈数增加的趋势,并明显降低关期发生频率。WIN55212-2与左旋多巴合用显著降低了纹状体内DARPP-32(Thr75)的磷酸化;但未使ERK1/2磷酸化表达降低至对照组水平。结论激动CB1受体可能有益于预防帕金森病运动并发症。Objective To investigate cellular and behavioural effects of CB1 receptor agonist WIN55212-2 in a rat model of levodopa-induced motor complications.Methods The hemi-Parkinsonian rat model was produced by stereotaxically injecting 6-OHDA to right medial forebrain bundle（MFB）.Animals were intraperitoneally treated with levodopa/ benserazide（50mg/kg levodopa plus 12.5mg/kg benserazide） or WIN55212-2（1mg/kg）＋levodopa/benserazide twice a day for 21 days.Rotational duration,peak rotation and the frequency of failures to L-dopa were estimated.After sacrificed,the phosphorylation of dopamine and cAMP-regulated phosphoprotein of Mr 32,000（DARPP-32） at Thr75 site and extracellular signal-regulated kinase（ERK） at Thr202 and Tyr204 site was observed by Western blot.Results WIN55212-2 plus L-dopa treatment prolonged the duration of the motor response and reduced peak turning.WIN55212-2 plus L-dopa also decreased the frequency of failures to L-dopa.The long-term use of L-dopa reduced the phosphorylation of DARPP-32（Thr75） and co-administration with WIN55212-2 made this reduction more significant.Long-term use of L-dopa increased ERK（Thr202/Tyr204） phosphorylation significantly.Co-administration with WIN55212-2 with L-dopa could not make ERK（Thr202/Tyr204）phosphorylation back to normal and it was still higher than sham-operated group.Conclusion Pharmacologically stimulate CB1 receptors may be useful in the treatment and prevention of the motor complications in Parkinsonian patients.

关 键 词：帕金森病 运动并发症 大麻素CB1受体 磷酸化 WIN55212-2DARPP-32 ERK 

分 类 号：R742.5[医药卫生—神经病学与精神病学]