Iron (Fe) overload triggers free radical production and lipid peroxidation processes that may lead to cell death (ferroptosis). The hypothesis of this work was that acute Fe-dextran treatment triggers Nrf2-mediated antioxidant regulation in rat brain involving glutathione (GSH) metabolism. Over the initial 8 h after Fe-dextran administration (single dose of 500 mg Fe-dextran/kg), total Fe, malondialdehyde (MDA) content, glutathione peroxidase (GPx), GPx-Se dependent (GPx-Se) and glutathione S-transferases (GST) activities were increased in rat whole brain. The content of GSH and the activity of glutathione reductase (GR) showed decreases (p < 0.05) after 6 and 8 h post injection in cortex. A significant increase in nuclear Nrf2 protein levels over control values was achieved after 6 h of Fe-dextran administration, while no significant differences were observed in the cytosolic fraction. Nuclear Nrf2/cytosolic Nrf2 ratios showed enhancement (p < 0.05) after 6 h of Fe overload, suggesting a greater translocation of the factor to the nucleus. No significant differences were observed in the expression of Keap1 in nuclear or cytosolic extracts. It is concluded that acute Fe overload induces oxidative stress in rat brain with the concomitant lipid peroxidation increase and GSH depletion, leading to the elevation of Nrf2-controlled GPx, GPx-Se and GST protein expression as a protective adaptive response. Further studies are required to fully comprehend the complex network of interrelated processes keeping the balance of GSH functions as chelator, antioxidant and redox buffer in the understanding of the ferroptotic and hormetic mechanisms triggered by Fe overload in brain.

铁 (Fe) 过载会引发自由基产生和脂质过氧化过程，从而导致细胞死亡（铁死亡）。这项工作的假设是急性 Fe-葡聚糖治疗触发了大鼠脑中 Nrf2 介导的抗氧化调节，涉及谷胱甘肽 (GSH) 代谢。在 Fe-葡聚糖给药后的最初 8 小时内（单剂量 500 mg Fe-葡聚糖/kg），总 Fe、丙二醛 (MDA) 含量、谷胱甘肽过氧化物酶 (GPx) 、在大鼠全脑中，GPx-Se 依赖性 (GPx-Se) 和谷胱甘肽 S-转移酶 (GST) 活性增加。注射后 6 小时和 8 小时，皮质中 GSH 的含量和谷胱甘肽还原酶 (GR) 的活性降低 (p < 0.05)。Fe-葡聚糖给药 6 小时后，核 Nrf2 蛋白水平比对照值显着增加，而在细胞溶质部分中没有观察到显着差异。铁过载 6 小时后，核 Nrf2/细胞溶质 Nrf2 比率显示增强 (p < 0.05)，表明该因子向细胞核的易位更大。Keap1 在核或细胞溶质提取物中的表达未观察到显着差异。得出的结论是，急性 Fe 超负荷会在大鼠脑中诱导氧化应激，并伴随脂质过氧化增加和 GSH 耗竭，导致 Nrf2 控制的 GPx、GPx-Se 和 GST 蛋白表达升高作为保护性适应性反应。需要进一步的研究来充分理解保持GSH作为螯合剂、抗氧化剂和氧化还原缓冲剂平衡的相互关联过程的复杂网络，以了解大脑中Fe超载引发的铁死亡和兴奋机制。