Abstract：
Manganese (Mn) overexposure has been associated with the development of neurological damage reminiscent of Parkinson\'s disease, while the underlying mechanisms have yet to be fully characterized. This study aimed to investigate the mechanisms leading to injury in dopaminergic neurons induced by Mn and identify novel treatment approaches. In the in vivo and in vitro models, ICR mice and dopaminergic neuron-like PC12 cells were exposed to Mn, respectively. We treated them with anti-ferroptotic agents ferrostatin-1 (Fer-1), deferoxamine (DFO), HIF-1α activator dimethyloxalylglycine (DMOG) and inhibitor LW6. We also used p53-siRNA to verify the mechanism underlying Mn-induced neurotoxicity. Fe and Mn concentrations increased in ICR mice brains overexposed to Mn. Additionally, Mn-exposed mice exhibited movement impairment and encephalic pathological changes, with decreased HIF-1α, SLC7A11, and GPX4 proteins and increased p53 protein levels. Fer-1 exhibited protective effects against Mn-induced both behavioral and biochemical changes. Consistently, in vitro, Mn exposure caused ferroptosis-related changes and decreased HIF-1α levels, all ameliorated by Fer-1. Upregulation of HIF-1α by DMOG alleviated the Mn-associated ferroptosis, while LW6 exacerbated Mn-induced neurotoxicity through downregulating HIF-1α. p53 knock-down also rescued Mn-induced ferroptosis without altering HIF-1α protein expression. Mn overexposure resulted in ferroptosis in dopaminergic neurons, mediated through the HIF-1α/p53/SLC7A11 pathway.
摘要：
锰（Mn）的过度暴露与神经系统损伤的发展有关，这让人联想到帕金森病，而基本机制尚未得到充分表征。本研究旨在探讨锰诱导多巴胺能神经元损伤的机制，并寻找新的治疗方法。在体内和体外模型中，ICR小鼠和多巴胺能神经元样PC12细胞暴露于Mn，分别。我们用抗铁蛋白抑制剂-1(Fer-1)治疗它们，去铁胺（DFO），HIF-1α激活剂二甲氧合甘氨酸(DMOG)和抑制剂LW6。我们还使用p53-siRNA来验证Mn诱导的神经毒性的潜在机制。在过量暴露于Mn的ICR小鼠脑中Fe和Mn浓度增加。此外,锰暴露小鼠表现出运动障碍和脑病理变化，随着HIF-1α的减少，SLC7A11和GPX4蛋白和增加的p53蛋白水平。Fer-1对Mn诱导的行为和生化变化均具有保护作用。始终如一，在体外，锰暴露导致铁凋亡相关变化和降低HIF-1α水平，全部由Fer-1改善。DMOG对HIF-1α的上调减轻了Mn相关的铁性凋亡，而LW6通过下调HIF-1α加重Mn诱导的神经毒性。p53敲低也拯救了Mn诱导的铁死亡而不改变HIF-1α蛋白表达。锰过度暴露导致多巴胺能神经元铁死亡，通过HIF-1α/p53/SLC7A11通路介导。
