title: Z-ligustilide potentiates the cytotoxicity of dopamine in rat dopaminergic PC12 cells.
abstract: 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.
authors.affiliation: School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong.
authors.forename: Hongyi
authors.initials: H
authors.lastname: Qi
authors.forename: Jia
authors.initials: J
authors.lastname: Zhao
authors.forename: Yifan
authors.initials: Y
authors.lastname: Han
authors.forename: Allan S Y
authors.initials: AS
authors.lastname: Lau
authors.forename: Jianhui
authors.initials: J
authors.lastname: Rong
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000633:toxicity; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D006690:Bisbenzimidazole; D002452:Cell Count; D053938:DNA Fragmentation / Q000187:drug effects; D004298:Dopamine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005434:Flow Cytometry; D005978:Glutathione / Q000378:metabolism; D007980:Levodopa / Q000633:toxicity; D018696:Neuroprotective Agents / Q000494:pharmacology; D016716:PC12 Cells; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors
chemical_list: D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; C027820:ligustilide; D007980:Levodopa; D005978:Glutathione; D006690:Bisbenzimidazole; D015107:4-Butyrolactone; D004298:Dopamine; D000111:Acetylcysteine