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目的探讨帕金森病(PD)长期左旋多巴治疗的运动并发症与纹状体神经元谷氨酸受体1的845位丝氨酸(GluR1Ser845)磷酸化的关系。方法通过6-羟基多巴立体定向注射至大鼠前脑内侧前脑束建立PD动物模型,然后左旋多巴甲酯腹腔注射治疗(25mg.kg-1.d-1,每天2次)22d,评估旋转时间、关期发生频率情况;采用免疫荧光与蛋白印迹法检测纹状体区谷氨酸受体1(GluR1)亚细胞分布及GluR1Ser845磷酸化的表达情况。结果PD大鼠长期应用左旋多巴处理后呈现旋转时间逐渐缩短、关期频率递增的趋势,与人类症状波动和开关现象具有相似特征。PD大鼠损伤侧纹状体细胞膜上GluR1和GluR1Ser845磷酸化的数量分别减少至73.0%±4.8%和42.0%±5.6%;长期左旋多巴处理后使损伤侧纹状体细胞膜上GluR1和GluR1Ser845磷酸化的数量分别增加至104.0%±5.5%和112.0%±3.4%;然而损伤侧纹状体GluR1总蛋白数量未发生明显变化。这些改变特异性发生在小清蛋白阳性的中间神经元上。结论长期左旋多巴治疗的运动并发症可能与小清蛋白阳性的神经元上GluR1的亚细胞分布及GluR1Ser845磷酸化的改变有关。
Objective To investigate the relationship between motor complications of long-term levodopa treatment of Parkinson’s disease (PD) and phosphorylation of serine 845 (GluR1Ser845) in glutamate receptor 1 of striatal neurons. Methods PD animal models were established by stereotactic injection of 6-hydroxydopamine into the medial forebrain bundle of rats and then treated with L-DOPA intraperitoneally (25mg.kg-1.d-1 twice a day for 22 days) The rotation time and the frequency of occurrence of off-cycle were evaluated. The subcellular distribution of glutamate receptor 1 (GluR1) and the phosphorylation of GluR1Ser845 in striatum were detected by immunofluorescence and Western blotting. Results After long-term administration of levodopa in PD rats, the rotation time was gradually shortened and the frequency of the off-cycle increased gradually, which was similar to the fluctuation and switching of human symptoms. The phosphorylation of GluR1 and GluR1Ser845 in PD rat striatum was reduced to 73.0% ± 4.8% and 42.0% ± 5.6%, respectively. After long-term administration of levodopa, the number of GluR1 and GluR1Ser845 phosphorylated While the number of GluR1 protein increased to 104.0% ± 5.5% and 112.0% ± 3.4% respectively. However, there was no significant change in the total GluR1 protein in injured lateral striatum. These changes occur specifically in small albumin-positive interneurons. Conclusions Long-term levodopa treatment may lead to complications related to subcellular distribution of GluR1 and phosphorylation of GluR1 Ser845 in small-albumin-positive neurons.