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首页> 外文期刊>Frontiers in Aging Neuroscience >Levodopa/Benserazide Loaded Microspheres Alleviate L-dopa Induced Dyskinesia through Preventing the Over-Expression of D1R/Shp-2/ERK1/2 Signaling Pathway in a Rat Model of Parkinson's Disease
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Levodopa/Benserazide Loaded Microspheres Alleviate L-dopa Induced Dyskinesia through Preventing the Over-Expression of D1R/Shp-2/ERK1/2 Signaling Pathway in a Rat Model of Parkinson's Disease

机译：左旋多巴/苄丝肼微球通过预防帕金森氏病大鼠模型中D1R / Shp-2 / ERK1 / 2信号通路的过表达来减轻左旋多巴诱发的运动障碍

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Background: The long-term intermittent Levodopa (L-dopa) stimulation contributes to an aberrant activation of D1 receptor (D1R) mediated extracellular signal-regulated kinases1/2 (ERK1/2) in the striatal medium spiny neurons, resulting in the occurrence of L-dopa induced dyskinesia (LID). Recently, a novel signaling pathway, D1R/Shp-2/ERK1/2, was proposed to be required for the occurrence of LID. Here we designed the study in which two different methods of L-dopa delivery [continuous dopamine stimulation (CDS) vs. intermittent dopamine stimulation] were used to further identify: (1) the role of D1R/Shp-2/ERK1/2 signaling pathway in the occurrence of LID; (2) whether CDS alleviated LID though preventing the over-expression of the D1R/Shp-2/ERK1/2 signaling pathway. Methods: 6-OHDA-lesioned rat models of Parkinson's disease (PD) were randomly divided into two groups to receive intermittent L-dopa stimulation (L-dopa/benserazide standard group, LS group) or CDS (L-dopa/benserazide loaded microspheres, LBM group) for 21 days. Dyskinesia and anti-parkinsonian effect were compared between the two groups through the AIMs assessment and cylinder test. The critical protein changes in the D1R/Shp-2/ERK1/2 signaling pathway were compared between the two groups through Western blotting. Results: Intermittent L-dopa administration induced serious dyskinetic movements in the 6-OHDA-lesioned rats, and the anti-parkinsonian effect of L-dopa was gradually counteracted by the occurrence of dyskinesia. Intermittent L-dopa administration enhanced the expression of membrane D1R, and induced a robust increase of phosphorylation of Shp-2, Src, DARPP-32, and ERK1/2 in the 6-OHDA-lesioned striatum. In contrast, CDS played a dose-dependent anti-parkinsonian role, without inducing such apparent dyskinetic movements. Moreover, CDS induced no change of membrane D1R expression or phosphorylation of Shp-2, Src, DARPP-32, and ERK1/2 in the 6-OHDA-lesioned striatum. Conclusion: The aberrant activation of D1R/Shp-2 complex was evidenced to be required for the D1R mediating ERK1/2 phosphorylation and the occurrence of LID. CDS effectively prevented the overexpression of D1R/Shp-2/ERK1/2 signaling pathway, resulting in the reduction of LID in 6-OHDA-lesioned rats model of PD.
机译：背景：长期间歇性左旋多巴（L-dopa）刺激导致纹状体中棘神经元中D1受体（D1R）介导的细胞外信号调节激酶1/2（ERK1 / 2）异常激活。 L-多巴引起的运动障碍（LID）。最近，提出了一种新的信号传导途径，D1R / Shp-2 / ERK1 / 2，是发生LID所必需的。在这里，我们设计了一项研究，其中使用两种不同的左旋多巴递送方法[连续多巴胺刺激（CDS）与间歇性多巴胺刺激]进一步确定：（1）D1R / Shp-2 / ERK1 / 2信号传导的作用LID发生的途径; （2）CDS是否通过阻止D1R / Shp-2 / ERK1 / 2信号通路的过表达来减轻LID。方法：将6-OHDA损伤的帕金森氏病（PD）大鼠模型随机分为两组，分别接受间歇性L-多巴刺激（L-多巴/苄丝肼标准组，LS组）或CDS（L-多巴/苄丝肼微球） ，LBM组）持续21天。通过AIM评估和气瓶测试比较两组运动障碍和抗帕金森病的作用。通过蛋白质印迹比较了两组之间D1R / Shp-2 / ERK1 / 2信号通路中的关键蛋白质变化。结果：间歇性给予左旋多巴可引起6-OHDA损伤大鼠严重的运动障碍，运动障碍的发生逐渐抵消了左旋多巴的抗帕金森病作用。间歇性左旋多巴的给药增强了膜D1R的表达，并诱导了6-OHDA损伤的纹状体中Shp-2，Src，DARPP-32和ERK1 / 2的磷酸化的强劲增加。相反，CDS发挥剂量依赖性的抗帕金森病作用，而不会引起这种明显的运动障碍运动。此外，CDS不会引起6-OHDA损伤的纹状体中膜D1R表达的改变或Shp-2，Src，DARPP-32和ERK1 / 2的磷酸化。结论：D1R / Shp-2复合物的异常激活被证明是D1R介导ERK1 / 2磷酸化和LID发生所必需的。 CDS有效地阻止了D1R / Shp-2 / ERK1 / 2信号通路的过表达，从而导致6-OHDA损伤的PD大鼠模型中的LID降低。

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