Maladaptive striatal plasticity in L-DOPA-induced dyskinesia.
Maladaptive striatal plasticity in L-DOPA-induced dyskinesia.
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DOI：
10.1016/s0079-6123(10)83011-0
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发表时间：
2010
影响因子：
--
通讯作者：
Konradi, Christine
中科院分区：
文献类型：
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作者：
Cenci, M. Angela;Konradi, Christine
左旋多巴 (l-DOPA) 多巴胺 (DA) 替代疗法仍然是帕金森病最有效的治疗方法，但会导致绝大多数患者出现运动障碍（异常不自主运动）。 L-DOPA 引起的运动障碍 (LID) 的基本机制已成为集中研究纹状体神经化学和分子适应的对象。在这里，我们回顾了这些大量的文献，并强调了汇聚成统一的病理生理学解释的趋势。我们认为 LID 中纹状体神经元的核心分子改变在于无法降低 DA D1 受体下游的超敏感信号反应（其中超敏感主要是由 DA 去神经支配引起的）。每个剂量的左旋多巴诱导的细胞内信号通路的持续激活导致异常的细胞可塑性和高生物能消耗。治疗过程中信号通路和能量储备的过度利用会损害纹状体神经元动态控制皮质驱动的运动命令的能力。因此，LID 是一种疾病的例证，“太多”的分子可塑性导致纹状体可塑性失败。
Dopamine (DA) replacement therapy with l-DOPA remains the most effective treatment for Parkinson’s disease, but causes dyskinesia (abnormal involuntary movements) in the vast majority of the patients. The basic mechanisms of l-DOPA-induced dyskinesia (LID) have become the object of intense research focusing on neurochemical and molecular adaptations in the striatum. Here we review this vast literature and highlight trends that converge into a unifying pathophysiological interpretation. We propose that the core molecular alteration of striatal neurons in LID consists in an inability to turn down supersensitive signaling responses downstream of DA D1 receptors (where supersensitivity is primarily caused by DA denervation). The sustained activation of intracellular signaling pathways induced by each dose of l-DOPA leads to abnormal cellular plasticity and high bioenergetic expenditure. The over-exploitation of signaling pathways and energy reserves during treatment impairs the ability of striatal neurons to dynamically gate cortically driven motor commands. LID thus exemplifies a disorder where ‘too much’ molecular plasticity leads to plasticity failure in the striatum.