L-DOPA-Induced Dyskinesia and Abnormal Signaling in Striatal Medium Spiny Neurons: Focus on Dopamine D1 Receptor-Mediated Transmission.
L-DOPA-Induced Dyskinesia and Abnormal Signaling in Striatal Medium Spiny Neurons: Focus on Dopamine D1 Receptor-Mediated Transmission.
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DOI：
10.3389/fnbeh.2011.00071
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发表时间：
2011
影响因子：
3
通讯作者：
Fisone G
中科院分区：
文献类型：
--
作者：
Feyder M;Bonito-Oliva A;Fisone G
运动障碍是一种严重的运动并发症所造成的长期管理左旋多巴的患者受帕金森氏病。越来越多的证据表明，左旋多巴诱导的运动障碍（LID）主要是由纹状体中棘神经元（MSN）中致敏多巴胺D1受体（D1 R）传递的发展引起的。这种现象，与长期施用l-多巴相结合，导致cAMP信号级联的持续性和间歇性超活化。cAMP信号传导的激活导致cAMP依赖性蛋白激酶（PKA）和32 kDa的多巴胺和cAMP依赖性磷蛋白（DARPP-32）的活性增加，其调节涉及纹状体MSNs兴奋性控制的几个下游效应靶。运动障碍还伴随细胞外信号调节激酶（ERK）和雷帕霉素复合物1的哺乳动物靶蛋白（mTORC 1）的活性增强，其参与转录和翻译效率的控制。旨在减少这些不同细胞内级联水平的异常信号转导的药理学或遗传干预已显示在不同动物模型中减弱LID。例如，在DARPP-32缺陷的小鼠中或在PKA抑制后，LID降低。通过基因或使用特异性抑制剂阻断ERK也能够减弱啮齿动物和非人灵长类动物的运动障碍行为。最后，给予雷帕霉素（一种阻断mTORC 1的药物）导致LID的强烈降低。这篇评论的重点是影响D1 R表达MSN的信号异常及其与新型抗运动障碍疗法设计的潜在相关性。
Dyskinesia is a serious motor complication caused by prolonged administration of l-DOPA to patients affected by Parkinson’s disease. Accumulating evidence indicates that l-DOPA-induced dyskinesia (LID) is primarily caused by the development of sensitized dopamine D1 receptor (D1R) transmission in the medium spiny neurons (MSNs) of the striatum. This phenomenon, combined with chronic administration of l-DOPA, leads to persistent and intermittent hyper-activation of the cAMP signaling cascade. Activation of cAMP signaling results in increased activity of the cAMP-dependent protein kinase (PKA) and of the dopamine- and cAMP-dependent phosphoprotein of 32 kDa (DARPP-32), which regulate several downstream effector targets implicated in the control of the excitability of striatal MSNs. Dyskinesia is also accompanied by augmented activity of the extracellular signal-regulated kinases (ERK) and the mammalian target of rapamycin complex 1 (mTORC1), which are involved in the control of transcriptional and translational efficiency. Pharmacological or genetic interventions aimed at reducing abnormal signal transduction at the level of these various intracellular cascades have been shown to attenuate LID in different animal models. For instance, LID is reduced in mice deficient for DARPP-32, or following inhibition of PKA. Blockade of ERK obtained genetically or using specific inhibitors is also able to attenuate dyskinetic behavior in rodents and non-human primates. Finally, administration of rapamycin, a drug which blocks mTORC1, results in a strong reduction of LID. This review focuses on the abnormalities in signaling affecting the D1R-expressing MSNs and on their potential relevance for the design of novel anti-dyskinetic therapies.
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影响因子：
8.2
作者：
Borgkvist, Anders;Fisone, Gilberto
通讯作者：
Fisone, Gilberto
影响因子：
82.9
作者：
Bézard, E;Ferry, S;Sokoloff, P
通讯作者：
Sokoloff, P
DOI：
10.1073/pnas.1009874107
发表时间：
2010-08-17
影响因子：
11.1
作者：
Bateup, Helen S.;Santini, Emanuela;Greengard, Paul
通讯作者：
Greengard, Paul
影响因子：
5.3
作者：
Brami-Cherrier, K;Valjent, E;Caboche, J
通讯作者：
Caboche, J
影响因子：
6.1
作者：
Andersson, M;Hilbertson, A;Cenci, MA
通讯作者：
Cenci, MA