Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary.
Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Mol Neurobiol. 2019 Jul;56(7):5111-5121. doi: 10.1007/s12035-018-1433-x. Epub 2018 Nov 27.
Chronic administration of L-DOPA, the first-line treatment of dystonic symptoms in childhood or in Parkinson's disease, often leads to the development of abnormal involuntary movements (AIMs), which represent an important clinical problem. Although it is known that Riluzole attenuates L-DOPA-induced AIMs, the molecular mechanisms underlying this effect are not understood. Therefore, we studied the behavior and performed RNA sequencing of the striatum in three groups of rats that all received a unilateral lesion with 6-hydroxydopamine in their medial forebrain bundle, followed by the administration of saline, L-DOPA, or L-DOPA combined with Riluzole. First, we provide evidence that Riluzole attenuates AIMs in this rat model. Subsequently, analysis of the transcriptomics data revealed that Riluzole is predicted to reduce the activity of CREB1, a transcription factor that regulates the expression of multiple proteins that interact in a molecular landscape involved in apoptosis. Although this mechanism underlying the beneficial effect of Riluzole on AIMs needs to be confirmed, it provides clues towards novel or existing compounds for the treatment of AIMs that modulate the activity of CREB1 and, hence, its downstream targets.
L-DOPA 的慢性给药，即儿童或帕金森病中治疗肌张力障碍症状的一线治疗方法，常常导致异常不自主运动（AIMs）的发展，这是一个重要的临床问题。虽然已知利鲁唑可减轻 L-DOPA 诱导的 AIMs，但这种作用的分子机制尚不清楚。因此，我们在三组接受内侧前脑束单侧 6-羟多巴胺损伤的大鼠中进行了行为和纹状体 RNA 测序研究，然后分别给予生理盐水、L-DOPA 或 L-DOPA 联合利鲁唑。首先，我们提供了证据表明利鲁唑可减轻该大鼠模型中的 AIMs。随后，转录组学数据分析表明，利鲁唑有望降低 CREB1 的活性，CREB1 是一种转录因子，可调节参与细胞凋亡的分子景观中相互作用的多种蛋白质的表达。尽管需要证实利鲁唑对 AIMs 的有益作用的这种机制，但它为治疗 AIMs 提供了线索，这些治疗方法可调节 CREB1 的活性及其下游靶标，从而提供了新的或现有的化合物。
