Transcription factors involved in the pathogenesis of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease
Transcription factors involved in the pathogenesis of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease
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DOI：
10.1007/s00726-001-0116-4
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发表时间：
2002-01-01
期刊：
影响因子：
3.5
通讯作者：
Cenci, MA
中科院分区：
文献类型：
--
作者：
Cenci, MA
左旋多巴诱导的运动障碍（异常不自主运动）是帕金森病慢性左旋多巴药物治疗的最严重并发症之一。一般认为，运动障碍是由于大脑中的多巴胺受体受到脉冲式刺激，导致下游基因和蛋白质发生变化而引起的。我们对这种变化的理解的进展严重依赖于合适的动物模型的可用性。我们已经介绍了一种新的方法来分类和6-羟基多巴胺（6-OHDA）损伤大鼠L-DOPA诱导的异常不自主运动（AIM）。这种方法使我们能够解剖的分子相关的运动障碍运动反应左旋多巴在这个物种。在大鼠中运动障碍发展的最显著的分子变化之一包括由L-DOPA引起的前强啡肽基因表达的纹状体诱导。这种作用是由FosB相关的32-37 kDa的转录因子介导的，这些转录因子与“直接途径”的纹状体神经元中的强啡肽原共同诱导。AIM的发展和相关的上调前强啡肽mRNA的左旋多巴显着抑制fosB反义纹状体内输注。然而，反义介导的CREB（环AMP反应元件结合蛋白）敲低没有效果。我们的研究结果确定fosB作为一个潜在的目标，连续抗帕金森病治疗。
L-DOPA-induced dyskinesia (abnormal involuntary movements) is one of the most debilitating complications of chronic L-DOPA pharmacotherapy in Parkinson's disease. It is generally agreed that dyskinesia arises as a consequence of pulsatile dopamine-receptor stimulation in the brain, causing downstream changes in genes and proteins. Advance in our understanding of such changes is critically dependent on the availability of suitable animal models. We have introduced a new method to classify and rate L-DOPA-induced abnormal involuntary movements (AIMs) in 6-hydroxydopamine (6-OHDA) lesioned rats. This method allows us to dissect the molecular correlates of a dyskinetic motor response to L-DOPA in this species. One of the most prominent molecular changes underlying the development of dyskinesia in the rat consists in the striatal induction of prodynorphin gene expression by L-DOPA. This effect is mediated by FosB-related transcription factors of 32-37 kDa, which are co-induced with prodynophin in striatal neurons of the "direct pathway". Both AIM development and the associated upregulation of prodynorphin mRNA by L-DOPA are significantly inhibited by the intrastriatal infusion of fosB antisense. Antisense-mediated knockdown of CREB (cyclic AMP response-element binding proteins) has however no effect. Our results identify fosB as a potential target for adjunctive antiparkinsonian therapies.