Choi Hojin, Koh Seong-Ho
a Department of Neurology , Hanyang University College of Medicine , Seoul , South Korea.
Expert Opin Drug Metab Toxicol. 2018 Jan;14(1):83-90. doi: 10.1080/17425255.2018.1417387. Epub 2017 Dec 15.
Levodopa (L-DOPA) is the most commonly used drug for Parkinson's disease (PD), but its long-term use is associated with various complications, including L-DOPA-induced dyskinesia (LID). Many studies have suggested that L-DOPA neurotoxicity and LID are associated with glycogen synthase kinase-3 (GSK-3) activation. Areas covered: LID is caused by striatal dopamine (DA) denervation in PD and pulsatile L-DOPA treatment. These factors lead to dysregulated DA transmission, abnormal intracellular signaling and transcription factors in striatal neurons, and altered gene expression and plasticity at corticostriatal synapses. The mechanisms of L-DOPA toxicity involve oxidative stress, L-DOPA oxidation to quinone, mitochondrial dysfunction, and α-synuclein. GSK-3 has been suggested to play key roles in all the mechanisms associated of L-DOPA toxicity and LID in PD. Expert opinion: GSK-3 plays critical roles in L-DOPA-induced neurotoxicity, and the development of specific methods to inhibit GSK-3 function may help prevent L-DOPA neurotoxicity and LID in PD. However, balanced GSK-3 inhibition and less β-catenin degradation is essential for preventing LID, because too much GSK-3 inhibition increases β-catenin levels, which is related to cancers.
左旋多巴（L-DOPA）是治疗帕金森病（PD）最常用的药物，但其长期使用会引发各种并发症，包括左旋多巴诱导的异动症（LID）。许多研究表明，左旋多巴神经毒性和异动症与糖原合酶激酶-3（GSK-3）激活有关。涵盖领域：异动症是由帕金森病中的纹状体多巴胺（DA）去神经支配和脉冲式左旋多巴治疗引起的。这些因素导致纹状体神经元中多巴胺传递失调、细胞内信号传导和转录因子异常，以及皮质纹状体突触处的基因表达和可塑性改变。左旋多巴毒性机制包括氧化应激、左旋多巴氧化为醌、线粒体功能障碍和α-突触核蛋白。有人提出GSK-3在帕金森病中与左旋多巴毒性和异动症相关的所有机制中都起关键作用。专家观点：GSK-3在左旋多巴诱导的神经毒性中起关键作用，开发抑制GSK-3功能的特定方法可能有助于预防帕金森病中的左旋多巴神经毒性和异动症。然而，平衡的GSK-3抑制和较少的β-连环蛋白降解对于预防异动症至关重要，因为过多的GSK-3抑制会增加β-连环蛋白水平，这与癌症有关。
