Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY 14214, United States.
Neurotoxicology. 2013 Mar;35:121-8. doi: 10.1016/j.neuro.2013.01.002. Epub 2013 Jan 11.
Chronic exposure to Mn results in the development of a neurological disorder known as manganism characterized by neurological deficits resembling that seen in Parkinsonism. Although dopaminergic neurons within the nigrostriatal pathway appear intact, Mn-induced irregularities in DA transmission have been observed including decreased amphetamine-induced DA release and loss of the dopamine transporter (DAT). Results of studies to evaluate the effect of Mn and DA on cell viability in control and DAT-transfected HEK cells reveal that Mn is equally toxic to both cell lines whereas DA was only toxic to cells containing DAT. DA toxicity was saturable suggesting that transport may be rate limiting. When Mn and DA were added simultaneously to the media, cell toxicity was similar to that produced by Mn alone suggesting that Mn may suppress DA uptake in the DAT containing cells. Preincubation of DA prior to the addition of Mn resulted in cell death which was essentially additive with that produced independently by the two agents. Mn was also shown to decrease DA uptake and amphetamine-induced DA efflux in DAT containing cells. Time-lapsed confocal microscopy indicates that Mn can promote trafficking of cell surface DAT into intracellular compartments which may account for the decrease in DA uptake and DA efflux in these cells. Mn-induced internalization of DAT may provide an explanation for disruption in DA transmission previously reported in the striatum.
慢性暴露于锰会导致一种神经系统疾病的发生，这种疾病被称为锰中毒，其特征是神经功能缺损类似于帕金森病。尽管黑质纹状体通路中的多巴胺能神经元似乎完好无损，但已经观察到锰诱导的 DA 传递异常，包括减少安非他命诱导的 DA 释放和多巴胺转运体（DAT）的丢失。评估锰和 DA 对对照和 DAT 转染的 HEK 细胞活力的影响的研究结果表明，锰对这两种细胞系同样有毒，而 DA 仅对含有 DAT 的细胞有毒。DA 的毒性是饱和的，表明转运可能是限速的。当 Mn 和 DA 同时添加到培养基中时，细胞毒性与单独添加 Mn 产生的毒性相似，这表明 Mn 可能抑制含有 DAT 的细胞中 DA 的摄取。在添加 Mn 之前预孵育 DA 会导致细胞死亡，这与两种药物单独产生的细胞死亡基本相加。Mn 还显示出降低含有 DAT 的细胞中的 DA 摄取和安非他命诱导的 DA 外排。时程对比共聚焦显微镜表明，Mn 可以促进细胞表面 DAT 向细胞内隔室的转运，这可能是这些细胞中 DA 摄取和 DA 外排减少的原因。DAT 的锰诱导内化可能为先前报道的纹状体中 DA 传递中断提供了解释。
