Toxic exposures to heavy metals, such as iron (Fe) and manganese (Mn), can result in long-range neurological diseases and are therefore of significant environmental and medical concerns. We have previously reported that damage to neuroblastoma-derived dopaminergic cells (SH-SY5Y) by both Fe and Mn could be prevented by pre-treatment with nicotine. Moreover, butyrate, a short chain fatty acid (SCFA) provided protection against salsolinol, a selective dopaminergic toxin, in the same cell line. Here, we broadened the investigation to determine whether butyrate might also protect against Fe and/or Mn, and whether, if combined with nicotine, an additive or synergistic effect might be observed. Both butyrate and nicotine concentration-dependently blocked Fe and Mn toxicities. Ineffective concentrations of nicotine and butyrate, when combined, provided full protection against both Fe and Mn. Moreover, the effects of nicotine but not butyrate could be blocked by mecamylamine, a non-selective nicotinic antagonist. On the other hand, the effects of butyrate, but not nicotine, could be blocked by beta-hydroxy butyrate, a fatty acid-3 receptor antagonist. These results not only provide further support for neuroprotective effects of both nicotine and butyrate but also indicate distinct mechanisms of action for each one. Furthermore, potential utility of butyrate and nicotine combination against heavy metal toxicities is suggested.

有毒地接触铁 (Fe) 和锰 (Mn) 等重金属可能导致长期神经系统疾病，因此具有重大的环境和医疗问题。我们之前曾报道过，通过尼古丁预处理可以预防铁和锰对神经母细胞瘤来源的多巴胺能细胞（SH-SY5Y）的损害。此外，丁酸盐（一种短链脂肪酸（SCFA））在同一细胞系中提供针对猪油醇（一种选择性多巴胺能毒素）的保护。在这里，我们扩大了研究范围，以确定丁酸盐是否也可以预防铁和/或锰，以及如果与尼古丁结合，是否可以观察到相加或协同效应。丁酸盐和尼古丁浓度依赖性地阻断铁和锰的毒性。低浓度的尼古丁和丁酸盐结合在一起，可以提供对铁和锰的全面保护。此外，美加明（一种非选择性烟碱拮抗剂）可以阻断尼古丁而非丁酸盐的作用。另一方面，β-羟基丁酸盐（一种脂肪酸 3 受体拮抗剂）可以阻断丁酸盐的作用，但不能阻断尼古丁的作用。这些结果不仅为尼古丁和丁酸盐的神经保护作用提供了进一步的支持，而且还表明了每种物质不同的作用机制。此外，还提出了丁酸盐和尼古丁组合对抗重金属毒性的潜在用途。