Zhang Xiaoqian, Chen Wei, Wu Yi, Zeng Weiqi, Yuan Yuhao, Cheng Chi, Yang Xiaoman, Wang Jialing, Yang Xiaomei, Xu Yu, Lei Hao, Cao Xuebing, Xu Yan
Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Innovation Academy for Precision Measurement Science and Technology, National Center for Magnetic Resonance in Wuhan, Chinese Academy of Sciences, Wuhan, China.
Front Aging Neurosci. 2021 Oct 28;13:759934. doi: 10.3389/fnagi.2021.759934. eCollection 2021.
Long-term therapy with levodopa (L-DOPA) in patients with Parkinson's disease (PD) often triggers motor complications termed as L-DOPA-induced dyskinesia (LID). However, few studies have explored the pathogenesis of LID from the perspective of neuroanatomy. This study aimed to investigate macroscopic structural changes in a rat model of LID and the underlying histological mechanisms. First, we established the hemiparkinsonism rat model through stereotaxic injection of 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle, followed by administration of saline (PD) or L-DOPA to induce LID. Magnetic resonance imaging (MRI) and behavioral evaluations were performed at different time points. Histological analysis was conducted to assess the correlations between MRI signal changes and cellular contributors. Voxel-based morphometry (VBM) analysis revealed progressive bilateral volume reduction in the cortical and subcortical areas in PD rats compared with the sham rats. These changes were partially reversed by chronic L-DOPA administration; moreover, there was a significant volume increase mainly in the dorsolateral striatum, substantia nigra, and piriform cortex of the lesioned side compared with that of PD rats. At the striatal cellular level, glial fibrillary acidic protein-positive (GFAP+) astrocytes were significantly increased in the lesioned dorsolateral striatum of PD rats compared with the intact side and the sham group. Prolonged L-DOPA treatment further increased GFAP levels. Neither 6-OHDA damage nor L-DOPA treatment influenced the striatal expression of vascular endothelial growth factor (VEGF). Additionally, there was a considerable increase in synapse-associated proteins (SYP, PSD95, and SAP97) in the lesioned striatum of LID rats relative to the PD rats. Golgi-Cox staining analysis of the dendritic spine morphology revealed an increased density of dendritic spines after chronic L-DOPA treatment. Taken together, our findings suggest that striatal volume changes in LID rats involve astrocyte activation, enrichment of synaptic ultrastructure and signaling proteins in the ipsilateral striatum. Meanwhile, the data highlight the enormous potential of structural MRI, especially VBM analysis, in determining the morphological phenotype of rodent models of LID.
帕金森病（PD）患者长期使用左旋多巴（L-DOPA）治疗通常会引发称为L-DOPA诱导的异动症（LID）的运动并发症。然而，很少有研究从神经解剖学角度探讨LID的发病机制。本研究旨在调查LID大鼠模型的宏观结构变化及其潜在的组织学机制。首先，我们通过立体定向将6-羟基多巴胺（6-OHDA）注射到右侧内侧前脑束中建立偏侧帕金森病大鼠模型，随后给予生理盐水（PD组）或L-DOPA以诱导LID。在不同时间点进行磁共振成像（MRI）和行为评估。进行组织学分析以评估MRI信号变化与细胞成分之间的相关性。基于体素的形态学（VBM）分析显示，与假手术组大鼠相比，PD大鼠的皮质和皮质下区域出现渐进性双侧体积减小。长期给予L-DOPA可部分逆转这些变化；此外，与PD大鼠相比，主要在损伤侧的背外侧纹状体、黑质和梨状皮质有显著的体积增加。在纹状体细胞水平，与完整侧和假手术组相比，PD大鼠损伤的背外侧纹状体中胶质纤维酸性蛋白阳性（GFAP+）星形胶质细胞显著增加。长期L-DOPA治疗进一步提高了GFAP水平。6-OHDA损伤和L-DOPA治疗均未影响纹状体血管内皮生长因子（VEGF）的表达。此外，与PD大鼠相比，LID大鼠损伤纹状体中突触相关蛋白（SYP、PSD95和SAP97）有相当大的增加。对树突棘形态的高尔基-考克斯染色分析显示，长期L-DOPA治疗后树突棘密度增加。综上所述，我们的研究结果表明，LID大鼠的纹状体体积变化涉及星形胶质细胞激活、同侧纹状体中突触超微结构和信号蛋白的富集。同时，数据突出了结构MRI，尤其是VBM分析在确定LID啮齿动物模型形态表型方面的巨大潜力。
