Iron inhibits neurotoxicity induced by trace copper and biological reductants.
Iron inhibits neurotoxicity induced by trace copper and biological reductants.
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铁可抑制微量铜和生物还原剂引起的神经毒性。
DOI：
10.1007/s00775-004-0521-8
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Cappai,Roberto
中科院分区：
文献类型：
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作者：
White,AnthonyR;Barnham,KevinJ;Huang,Xudong;Voltakis,Irene;Beyreuther,Konrad;Masters,ColinL;Cherny,RobertA;Bush,AshleyI;Cappai,Roberto
脑的细胞外微环境含有许多生物氧化还原剂，包括抗坏血酸盐、谷胱甘肽、半胱氨酸和同型半胱氨酸。在缺血/再灌注、衰老或神经系统疾病期间，由于体内平衡失调，细胞外还原剂水平可显著增加。细胞外浓度的过渡金属，如铜和铁，也大大提高在老化过程中，在一些神经退行性疾病。细胞外氧化还原能力的增加可能会从Cu（II）或Fe（III）的还原中产生神经毒性自由基，导致神经元细胞死亡。为了在体外研究这一点，细胞外还原剂（抗坏血酸，谷胱甘肽，半胱氨酸，同型半胱氨酸或蛋氨酸）对原代皮层神经元的影响进行了检查。所有氧化还原剂，除了蛋氨酸诱导广泛的神经元氧化应激和随后的细胞死亡发生在正常条件下或在神经损伤的浓度。这种神经毒性完全依赖于培养基中已存在的微量Cu（≥ 0.4 μ M），不需要添加外源性Cu。毒性涉及生成的Cu（I）和H2O2，而其他微量金属不诱导毒性。令人惊讶的是，给予Fe（II）或Fe（III）（≥ 2.5 μ M）完全消除了还原酶介导的神经毒性。铁的有效保护活性与铁抑制还原介导的Cu（I）和H2O2的产生在无细胞测定和减少细胞的神经元铜的摄取。这证明了铁在高还原环境中阻断铜介导的神经毒性的新作用。这些现象的一个可能的致病后果是通过在将培养物预先暴露于阿尔茨海默氏淀粉样蛋白β肽（A β）后消除Fe神经保护来证明的。人A β 1 - 42处理后，Fe神经保护作用对还原剂毒性的损失大于人A β 1 - 40或啮齿动物A β 1 - 42，这与A β 1 - 42在阿尔茨海默病中的核心作用一致。这些发现对阿尔茨海默病和老年痴呆症等神经退行性疾病期间的痕量生物金属相互作用和自由基介导的损伤具有重要意义。
The extracellular microenvironment of the brain contains numerous biological redox agents, including ascorbate, glutathione, cysteine and homocysteine. During ischemia/reperfusion, aging or neurological disease, extracellular levels of reductants can increase dramatically owing to dysregulated homeostasis. The extracellular concentrations of transition metals such as copper and iron are also substantially elevated during aging and in some neurodegenerative disorders. Increases in the extracellular redox capacity can potentially generate neurotoxic free radicals from reduction of Cu(II) or Fe(III), resulting in neuronal cell death. To investigate this in vitro, the effects of extracellular reductants (ascorbate, glutathione, cysteine, homocysteine or methionine) on primary cortical neurons was examined. All redox agents except methionine induced widespread neuronal oxidative stress and subsequent cell death at concentrations occurring in normal conditions or during neurological insults. This neurotoxicity was totally dependent on trace Cu (≥0.4 μM) already present in the culture medium and did not require addition of exogenous Cu. Toxicity involved generation of Cu(I) and H2O2, while other trace metals did not induce toxicity. Surprisingly, administration of Fe(II) or Fe(III) (≥2.5 μM) completely abrogated reductant-mediated neurotoxicity. The potent protective activity of Fe correlated with Fe inhibiting reductant-mediated Cu(I) and H2O2generation in cell-free assays and reduced cellular Cu uptake by neurons. This demonstrates a novel role for Fe in blocking Cu-mediated neurotoxicity in a high reducing environment. A possible pathogenic consequence for these phenomena was demonstrated by abrogation of Fe neuroprotection after pre-exposure of cultures to the Alzheimer’s amyloid beta peptide (Aβ). The loss of Fe neuroprotection against reductant toxicity was greater after treatment with human Aβ1–42 than with human Aβ1–40 or rodent Aβ1–42, consistent with the central role of Aβ1–42 in Alzheimer’s disease. These findings have important implications for trace biometal interactions and free radical-mediated damage during neurodegenerative illnesses such as Alzheimer’s disease and old-age dementia.