Glutamate NMDA receptor dysregulation in Parkinson's disease with dyskinesias
Glutamate NMDA receptor dysregulation in Parkinson's disease with dyskinesias
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DOI：
10.1093/brain/awr028
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发表时间：
2011-04-01
期刊：
影响因子：
14.5
通讯作者：
Brooks, David J.
中科院分区：
文献类型：
--
作者：
Ahmed, Imtiaz;Bose, Subrata K.;Brooks, David J.
左旋多巴引起的运动障碍是帕金森病长期治疗的常见并发症。尽管突触前和突触后机制似乎都与它们的发育有关，但这些致残性不随意运动的精确病理生理学仍有待充分阐明。谷氨酸传输异常（N-甲基-d-天冬氨酸受体的过度表达和磷酸化）与帕金森病动物模型中左旋多巴诱导的运动障碍的发生有关。然而，谷氨酸功能在帕金森病运动障碍患者中的作用尚不清楚。我们使用 C-11-CNS 5161 [N-甲基-3(硫代甲基苯基)氰酰胺]正电子发射断层扫描（激活的 N-甲基-d-天冬氨酸受体离子通道的标记物）来比较患有和不患有左旋多巴诱发的运动障碍的帕金森病患者的体内谷氨酸功能。在服用左旋多巴和停药后，每位患者均接受两次正电子发射断层扫描评估。使用感兴趣区域方法计算纹状体和皮质示踪剂的摄取。在停用左旋多巴的“关闭”状态下，运动障碍和非运动障碍患者的基底神经节和运动皮层示踪剂摄取水平相似。然而，当在“ON”状态下进行正电子发射断层扫描时，与无运动障碍的患者相比，运动障碍患者的尾状核、壳核和中央前回的 C-11-CNS 5161 摄取较高，这表明运动障碍患者在服用左旋多巴后运动区可能存在异常谷氨酸能传递。这些发现与动物模型研究的结果一致，表明谷氨酸能活性的增加与左旋多巴诱导的运动障碍的发生和维持有关。他们支持这样的假设：阻断谷氨酸传输可能在帕金森病致残性运动障碍的治疗中占有一席之地。
Levodopa-induced dyskinesias are a common complication of long-term therapy in Parkinson's disease. Although both pre- and post-synaptic mechanisms seem to be implicated in their development, the precise physiopathology of these disabling involuntary movements remains to be fully elucidated. Abnormalities in glutamate transmission (over expression and phosphorylation of N-methyl-d-aspartate receptors) have been associated with the development of levodopa-induced dyskinesias in animal models of Parkinsonism. The role of glutamate function in dyskinetic patients with Parkinson's disease, however, is unclear. We used C-11-CNS 5161 [N-methyl-3(thyomethylphenyl)cyanamide] positron emission tomography, a marker of activated N-methyl-d-aspartate receptor ion channels, to compare in vivo glutamate function in parkinsonian patients with and without levodopa-induced dyskinesias. Each patient was assessed with positron emission tomography twice, after taking and withdrawal from levodopa. Striatal and cortical tracer uptake was calculated using a region of interest approach. In the 'OFF' state withdrawn from levodopa, dyskinetic and non-dyskinetic patients had similar levels of tracer uptake in basal ganglia and motor cortex. However, when positron emission tomography was performed in the 'ON' condition, dyskinetic patients had higher C-11-CNS 5161 uptake in caudate, putamen and precentral gyrus compared to the patients without dyskinesias, suggesting that dyskinetic patients may have abnormal glutamatergic transmission in motor areas following levodopa administration. These findings are consistent with the results of animal model studies indicating that increased glutamatergic activity is implicated in the development and maintenance of levodopa-induced dyskinesias. They support the hypothesis that blockade of glutamate transmission may have a place in the management of disabling dyskinesias in Parkinson's disease.