Alterations of striatal NMDA receptor subunits associated with the development of dyskinesia in the MPTP-lesioned primate model of Parkinson's disease
Alterations of striatal NMDA receptor subunits associated with the development of dyskinesia in the MPTP-lesioned primate model of Parkinson's disease
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DOI：
10.1016/j.neuropharm.2004.11.008
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发表时间：
2005-03-01
影响因子：
4.7
通讯作者：
Standaert, DG
中科院分区：
文献类型：
--
作者：
Hallett, PJ;Dunah, AW;Standaert, DG
运动障碍和其他运动并发症的发展极大地限制了左旋多巴治疗帕金森病(PD)的使用。对帕金森病啮齿动物模型的研究表明，纹状体NMDA受体功能的改变是导致左旋多巴相关运动并发症发生的一个重要机制。我们在MPTP损毁的帕金森病灵长类动物模型中检测了纹状体NMDA受体。用定量免疫印迹法检测MPTP损毁(帕金森病)和MPTP损毁左旋多巴(运动障碍)猕猴纹状体内NR1、NR2A和NR2B亚基的亚细胞丰度。帕金森病猕猴突触体膜上NR1和NR2B亚基的表达水平分别降至未损伤水平的66+/-11%和51.2+/-5%，而NR2A的丰度无明显变化。左旋多巴治疗引起运动障碍，使NR1和NR2B恢复正常，并使NR2A亚单位增加到未损害水平的150+/-12%。受体亚单位酪氨酸磷酸化未见改变。这些结果表明，在帕金森病的灵长类动物模型和啮齿动物模型中，NMDA受体的突触丰度发生了变化，同时NR2A的丰度也相对增加，而在猕猴模型中，NR2A亚单位的丰度在运动障碍中进一步增加。这些数据支持纹状体NMDA受体系统的改变是帕金森病患者对多巴胺耗竭和替代的适应性和适应不良反应的原因，并强调了亚型选择性NMDA拮抗剂作为帕金森病新的治疗方法的价值。(C)2004爱思唯尔有限公司。保留所有权利。
The development of dyskinesias and other motor complications greatly limits the use of levodopa therapy in Parkinson's disease (PD). Studies in rodent models of PD suggest that an important mechanism underlying the development of levodopa-related motor complications is alterations in striatal NMDA receptor function. We examined striatal NMDA receptors in the MPTP-lesioned primate model of PD. Quantitative immunoblotting was used to determine the subcellular abundance of NR1, NR2A and NR2B subunits in striata from unlesioned, MPTP-lesioned (parkinsonian) and MPTP-lesioned, levodopa-treated (dyskinetic) macaques. In parkinsonian macaques, NR1 and NR2B subunits in synaptosomal membranes were decreased to 66 +/- 11% and 51.2 +/- 5 % of unlesioned levels respectively, while the abundance of NR2A was unaltered. Levodopa treatment eliciting dyskinesia normalized NR1 and NR2B and increased NR2A subunits to 150 +/- 12% of unlesioned levels. No alterations in receptor subunit tyrosine phosphorylation were detected. These results demonstrate that altered synaptic abundance of NMDA receptors with relative enhancement in the abundance of NR2A occurs in primate as well as rodent models of parkinsonism, and that in the macaque model, NR2A subunit abundance is further increased in dyskinesia. These data support the view that alterations in striatal NMDA receptor systems are responsible for adaptive and maladaptive responses to dopamine depletion and replacement in parkinsonism, and highlight the value of subtype selective NMDA antagonists as novel therapeutic approaches for PD. (c) 2004 Elsevier Ltd. All rights reserved.