School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong.
Neurotox Res. 2012 Nov;22(4):345-54. doi: 10.1007/s12640-012-9319-6. Epub 2012 Mar 27.
Dopamine toxicity is an ongoing controversy surrounding the use of levadopa (L-Dopa) in the therapy of Parkinson's disease. The initial objective of this study was to investigate the potential of neuroprotective botanicals such as Z-ligustilide in reducing the cytotoxicity of dopamine. We surprisingly found that Z-ligustilide potentiated dopamine toxicity in a dopaminergic cell specific manner. Using rat dopaminergic cell line PC12 as a model, we demonstrated that dopamine and Z-ligustilide in combination profoundly induced cell death, although these drugs alone, to a lesser extent, affected the cell viability in a concentration-dependent manner. The synergistic cytotoxicity of dopamine and Z-ligustilide is likely mediated via apoptosis, characterized by DNA fragmentation and chromatin shrinking after 12 h incubation. By measuring the intracellular reactive oxygen species (ROS) and reduced glutathione (GSH), Z-ligustilide and dopamine in combination dramatically enhanced the ROS formation and further depleted reduced GSH, whereas these drugs alone showed much less activity. Importantly, the synergistic cytotoxicity of dopamine and Z-ligustilide could be largely prevented by thiol-containing antioxidant N-acetylcysteine and GSH other than vitamin C and Trolox. Since the cytotoxicity of Z-ligustilide was not reported previously, the results of this study should raise public concerns over the potential risk associated with the combined use of herbal medicines containing Z-ligustilide with L-Dopa in the therapy of Parkinson's disease.
多巴胺毒性是围绕左旋多巴（L-Dopa）在帕金森病治疗中的应用而持续存在的争议。本研究的最初目的是研究神经保护植物药，如 Z-藁本内酯，是否有可能降低多巴胺的细胞毒性。我们惊讶地发现，Z-藁本内酯以多巴胺能细胞特异性方式增强了多巴胺毒性。我们使用大鼠多巴胺能细胞系 PC12 作为模型，证明多巴胺和 Z-藁本内酯联合使用会强烈诱导细胞死亡，尽管这些药物单独使用在一定程度上以浓度依赖的方式影响细胞活力。多巴胺和 Z-藁本内酯的协同细胞毒性可能是通过细胞凋亡介导的，在孵育 12 小时后，特征是 DNA 片段化和染色质收缩。通过测量细胞内活性氧（ROS）和还原型谷胱甘肽（GSH），Z-藁本内酯和多巴胺联合使用可显著增强 ROS 的形成，并进一步耗尽还原型 GSH，而这些药物单独使用时活性要小得多。重要的是，含巯基的抗氧化剂 N-乙酰半胱氨酸和 GSH（而非维生素 C 和 Trolox）可大大预防多巴胺和 Z-藁本内酯的协同细胞毒性。由于先前未报道过 Z-藁本内酯的细胞毒性，因此本研究的结果应引起公众对含 Z-藁本内酯的草药与 L-Dopa 联合用于帕金森病治疗相关潜在风险的关注。
