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.
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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左旋多巴/苄丝肼负载微球通过防止帕金森病大鼠模型中 D1R/Shp-2/ERK1/2 信号通路的过度表达来缓解左旋多巴引起的运动障碍
DOI：
10.3389/fnagi.2017.00331
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发表时间：
2017
影响因子：
4.8
通讯作者：
Gan J
中科院分区：
文献类型：
--
作者：
Wan Y;Wu N;Song L;Wang X;Liu Z;Yuan W;Gan J
背景：长期间歇性刺激左旋多巴(Leodopa，L)可导致纹状体中棘神经元D1R介导的细胞外信号调节蛋白1/2(ERK1/2)异常激活，从而导致L多巴诱发的运动障碍(DID)。最近，一种新的信号通路D1R/SHP-2/ERK1/2被认为与LID的发生有关。在本研究中，我们设计了两种不同的L-多巴递送方法[连续多巴胺刺激和间歇性多巴胺刺激]，以进一步确定：(1)D1R/SHP-2/ERK1/2信号通路在LID发生中的作用；(2)CDS是否通过阻止D1R/SHP-2/ERK1/2信号通路的过度表达来缓解LID。方法：将6-羟基多巴胺(6-OHDA)所致帕金森病(PD)大鼠模型随机分为两组，分别给予L-多巴(L-多巴/苯丝肼标准体组，LS组)和CDS(L-多巴/苯丝肼微球，LBM组)刺激21d。通过AIMS评定和圆柱体试验比较两组患者的运动障碍和抗帕金森病疗效。Western blotting比较两组D1R/SHP-2/ERK1/2信号通路中关键蛋白的变化。结果：L多巴间歇给药可使6-羟基多巴胺所致大鼠出现严重的运动障碍，其抗帕金森病作用随运动障碍的出现而逐渐减弱。间歇给予L多巴可增强纹状体D1R的表达，并诱导纹状体SHP-2、Src、DARPP-32和ERK1/2的磷酸化增强。相反，CDS发挥了剂量依赖的抗帕金森病作用，而不会引起这种明显的运动障碍。此外，CDS没有引起6-OHDA损伤的纹状体D1R表达或SHP-2、Src、DARPP-32和ERK1/2磷酸化的改变。结论：D1R/SHP-2复合体的异常激活是D1R介导ERK1/2磷酸化和LID发生所必需的。CDS有效地抑制了D1R/SHP-2/ERK1/2信号通路的过度表达，导致6-OHDA损毁帕金森病大鼠LID减少。
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.
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影响因子：
3
作者：
Feyder M;Bonito-Oliva A;Fisone G
通讯作者：
Fisone G
影响因子：
2.9
作者：
Oh, JD;Vaughan, CL;Chase, TN
通讯作者：
Chase, TN
影响因子：
4.7
作者：
Fiorentini, Chiara;Mattanza, Cinzia;Missale, Cristina
通讯作者：
Missale, Cristina
影响因子：
8.6
作者：
Fiorentini, Chiara;Savoia, Paola;Missale, Cristina
通讯作者：
Missale, Cristina
影响因子：
6.1
作者：
Fiorentini, Chiara;Savoia, Paola;Missale, Cristina
通讯作者：
Missale, Cristina