Department of Neurology and Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, PA, United States of America.
Department of Neurosurgery, The Pennsylvania State University College of Medicine, Hershey, PA, United States of America.
Neurobiol Dis. 2021 Nov;159:105491. doi: 10.1016/j.nbd.2021.105491. Epub 2021 Aug 27.
Parkinson's disease (PD) is a neurodegenerative movement disorder that is routinely treated with levodopa. Unfortunately, long-term dopamine replacement therapy using levodopa leads to levodopa-induced dyskinesias (LID), a significant and disabling side-effect. Clinical findings indicate that LID typically only occurs following the progression of PD motor symptoms from the unilateral (Hoehn and Yahr (HY) Stage I) to the bilateral stage (HY Stage II). This suggests the presence of some compensatory interhemispheric mechanisms that delay the occurrence of LID. We therefore investigated the role of interhemispheric connections of the nigrostriatal pathway on LID expression in a rat model of PD. The striatum of one hemisphere of rats was first injected with a retrograde tracer to label the ipsi- and cross-hemispheric nigrostriatal pathways. Rats were then split into groups and unilaterally lesioned in the striatum or medial forebrain bundle of the tracer-injected hemisphere to induce varying levels of hemiparkinsonism. Finally, rats were treated with levodopa and tested for the expression of LID. Distinct subsets emerged from rats that underwent the same lesioning paradigm based on LID. Strikingly, non-dyskinetic rats had significant sparing of their cross-hemispheric nigrostriatal pathway projecting from the unlesioned hemisphere. In contrast, dyskinetic rats only had a small proportion of this cross-hemispheric nigrostriatal pathway survive lesioning. Crucially, both non-dyskinetic and dyskinetic rats had nearly identical levels of ipsi-hemispheric nigrostriatal pathway survival and parkinsonian motor deficits. Our data suggest that the survival of the cross-hemispheric nigrostriatal pathway plays a crucial role in preventing the expression of LID and represents a potentially novel target to halt the progression of this devastating side-effect of a common anti-PD therapeutic.
帕金森病（PD）是一种神经退行性运动障碍，通常用左旋多巴治疗。不幸的是，长期使用左旋多巴进行多巴胺替代治疗会导致左旋多巴诱导的运动障碍（LID），这是一种严重且致残的副作用。临床发现表明，LID 通常仅在 PD 运动症状从单侧（Hoehn 和 Yahr（HY）阶段 I）进展到双侧阶段（HY 阶段 II）后才会出现。这表明存在一些补偿性的大脑半球间机制，延迟了 LID 的发生。因此，我们在 PD 大鼠模型中研究了黑质纹状体通路的大脑半球间连接对 LID 表达的作用。首先将逆行示踪剂注射到大鼠一侧的纹状体中，以标记同侧和对侧黑质纹状体通路。然后将大鼠分为几组，在示踪剂注射侧的纹状体或内侧前脑束中单侧损伤，以诱导不同程度的偏侧帕金森病。最后，用左旋多巴治疗大鼠，并测试 LID 的表达。根据 LID，接受相同损伤范式的大鼠出现了不同的亚群。引人注目的是，无运动障碍的大鼠对未损伤侧半球投射的交叉黑质纹状体通路有明显的保留。相比之下，运动障碍大鼠只有一小部分交叉黑质纹状体通路在损伤后存活。至关重要的是，无运动障碍和运动障碍大鼠的同侧黑质纹状体通路存活率和帕金森病运动缺陷几乎相同。我们的数据表明，交叉黑质纹状体通路的存活在防止 LID 的表达中起着至关重要的作用，并且代表了一种潜在的新靶点，可以阻止这种常见抗 PD 治疗的破坏性副作用的进展。
