Colistin is increasingly used as the last-line therapy for infections caused by Gram-negative 'superbugs'. Although colistin neurotoxicity was reported in the literature, there has no data on its mechanism. In the present study, we examined the effect of colistin on primary chick neuron cells, which were treated with 0.83, 4.15 and 8.3μg/mL colistin for 6, 12 and 24h. Cell viability was evaluated with 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assays after exposure to colistin. Formation of reactive oxygen species (ROS), nuclear morphology, caspase-3 activity and internucleosomal DNA fragmentation were examined. The results showed that, compared with the control, no significant change was observed in cell viability, ROS formation and caspase-3 activity in cells treated for 6, 12 and 24h with 0.83μg/mL colistin. However, in the 4.15 and 8.3μg/mL colistin-treated groups, the viability of chick primary neurons significantly decreased at 12 and 24h, respectively; caspase-3 activities were significantly increased to 5.1 and 7.4 fold at 6h, more earlier than the changes of ROS, which was significant increased to 124.5% and 143.5% (P<0.01) of control at 12h, respectively. The apoptosis of neuron cells was revealed by both nuclear morphological observations and internucleosomal DNA fragmentation in the 4.15 and 8.3μg/mL colistin-treated groups at 6, 12 and 24h. Our data demonstrated that colistin can induce apoptosis in primary chick cortex neurons through caspase-3 activation, which may be contributed with ROS-dependent and independent mechanism.

译文

粘菌素越来越多地被用作革兰氏阴性 “超级细菌” 引起的感染的最后一种治疗方法。尽管文献中报道了粘菌素的神经毒性,但尚无有关其机制的数据。在本研究中,我们检查了粘菌素对原代雏鸡神经元细胞的作用,将其用0.83,4.15和8.3 μ g/mL粘菌素处理6、12和24小时。暴露于粘菌素后,用3-[4,5-二甲基噻唑-2-基]-2,5-二苯基溴化四唑鎓 (MTT) 测定法评估细胞活力。检查了活性氧 (ROS) 的形成,核形态,caspase-3活性和核小体间DNA片段化。结果表明,与对照相比,用0.83 μ g/mL粘菌素处理6、12和24h的细胞活力,ROS形成和caspase-3活性均未观察到显着变化。然而,在4.15和8.3 μ g/mL粘菌素处理组中,雏鸡原代神经元的活力分别在12和24h显着降低; caspase-3活性在6h显着增加到5.1和7.4倍,比ROS的变化更早。在12h分别显着增加到对照的124.5% 和143.5% (P<0.01)。在6、12和24小时,4.15和8.3 μ g/mL粘菌素处理的组中,通过核形态学观察和核小体间DNA片段化揭示了神经元细胞的凋亡。我们的数据表明,粘菌素可以通过caspase-3激活诱导初级雏鸡皮质神经元凋亡,这可能与ROS依赖性和独立机制有关。

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