Regulation of glutathione and cell toxicity following exposure to neurotropic substances and human immunodeficiency virus-1 in vitro
Regulation of glutathione and cell toxicity following exposure to neurotropic substances and human immunodeficiency virus-1 in vitro
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DOI：
10.3109/13550289709030748
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发表时间：
1997-10-01
影响因子：
3.2
通讯作者：
Riederer, P
中科院分区：
文献类型：
--
作者：
Koutsilieri, E;Gotz, ME;Riederer, P
本研究的目的是评估滥用药物和其他神经药理学药物在艾滋病痴呆综合征（ADC）（艾滋病的神经系统并发症）发病机制中的毒性潜力。表达多巴胺转运蛋白的神经母细胞瘤和胶质母细胞瘤细胞系，以及暴露于人类免疫缺陷病毒-1（HIV-1）的原代巨噬细胞，用于研究此类物质的毒性模式和病毒暴露之间的任何协同效应的可能性。在我们的实验中使用的滥用药物是可卡因和吗啡，它们对多巴胺能系统发挥作用。效果与多巴胺本身和一种典型的多巴胺能药物司来吉兰治疗进行了比较。在巨噬细胞培养物中，谷胱甘肽（GSH）在用多巴胺、吗啡或司来吉兰处理后强烈上调，并且当细胞预先暴露于病毒时，这种作用增强。这种上调被讨论为氧化信号的补偿反应。用过氧化氢和硫酸铁作强氧化剂时，GSH浓度因细胞损伤而降低，但各处理组细胞数保持不变。相反，在神经母细胞瘤和胶质母细胞瘤细胞系中，亲神经性物质对GSH浓度的调节伴随着显著的细胞损失，而HIV-1预处理则加剧了这种情况。司来吉兰单独孵育时不改变细胞数量。然而，当用HIV-1处理后孵育时，细胞死亡非常显著。抗坏血酸（AA），包括作为抗氧化剂，完全恢复细胞损失与多巴胺处理的文化。然而，在AA与吗啡或司来吉兰的联合治疗中没有观察到效果。结果表明，由于亲神经物质和HIV-1的细胞毒性的协同作用，并建议神经药理学药物可能有助于ADC的发病机制。
The aim of the present study was to assess the toxic potential of drugs of abuse and other neuropharmacological agents in the pathogenesis of AIDS dementia complex (ADC), the neurological complication of AIDS. Neuroblastoma and glioblastoma cell lines expressing the dopamine transporter, as well as primacy macrophages exposed to human immunodeficiency virus-1 (HIV-1), were used to investigate the possibility of any synergistic effect between the mode of toxicity of such substances and virus exposure, The drugs of abuse used in our experiments were cocaine and morphine, which exert their action, among others, on the dopaminergic system. Effects were compared to treatment with dopamine itself and a typical dopaminergic drug used pharmaceutically, selegiline. In macrophage cultures, glutathione (GSH) was upregulated strongly after treatment with dopamine, morphine or selegiline, and this effect was enhanced when cells were pre-exposed to virus. This upregulation is discussed as a compensatory reaction to an oxidative signal. When hydrogen peroxide plus iron sulfate was used as a strong oxidant in macrophages, GSH concentrations decreased as a result of cell injury, Cell numbers remained constant in all treatment groups. In contrast, in both neuroblastoma and glioblastoma cell lines, the modulation of GSH concentrations by neurotropic substances was accompanied by significant cell loss, which was exacerbated by HIV-1 pretreatment. Selegiline did not change cell numbers when incubated alone. However, when incubated following treatment with HIV-1 cell death was highly significant. Ascorbic acid (AA), included as antioxidant, totally restored cell loss in cultures treated with dopamine. However, no effect was observed in combined treatment of AA and morphine or selegiline. The results demonstrate a synergistic role in cellular toxicity due to neurotropic substances and HIV-1, and suggest that neuropharmacological agents may contribute to the pathogenesis of ADC.