Hemoglobin and iron-evoked oxidative stress in the brain: protection by bile pigments, manganese and S-nitrosoglutathione.
Hemoglobin and iron-evoked oxidative stress in the brain: protection by bile pigments, manganese and S-nitrosoglutathione.
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血红蛋白和铁引起的大脑氧化应激：胆汁色素、锰和 S-亚硝基谷胱甘肽的保护。
DOI：
10.1080/10715769900301201
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发表时间：
1999
影响因子：
3.3
通讯作者：
Chiueh,CC
中科院分区：
文献类型：
--
作者：
VanBergen,P;Rauhala,P;Spooner,CM;Chiueh,CC
在目前的体外和体内研究中，我们研究了血红蛋白的促氧化作用，以及其代谢产物的抗氧化作用，在大脑中。将大鼠脑匀浆与血红蛋白（0-10 μM）孵育，但不与氯化血红素孵育，可诱导脂质过氧化反应长达24 h（EC 50 = 1.2 μM）。血红蛋白的作用类似于亚铁离子（EC 50 = 1.7 μM），可被螯合剂去铁胺（IC 50 = 0.5 μM）和释放一氧化氮的化合物S-亚硝基谷胱甘肽（IC 50 = 40 μM）阻断。然而，血红蛋白的代谢产物胆绿素和胆红素可抑制细胞破坏和血红蛋白诱导的脑脂质过氧化（胆绿素IC 50 = 12-30，胆红素IC 50 = 75-170 μM）。锰（2 μM）可进一步增强胆绿素在自发和铁诱发的脂质过氧化中的抗氧化作用，因为锰是一种抗氧化过渡金属，与胆色素结合。纹状体内输注血红蛋白（0-24 nmol）使纹状体多巴胺水平轻微但显著降低20-22%。而纹状体内注入柠檬酸亚铁（0-24 nmol）剂量依赖性地诱导纹状体多巴胺消耗66%以上，这之前是急性脂质过氧化反应的增加。总之，与体外实验结果相反，血红蛋白对大脑的神经毒性远小于亚铁离子。推测血红蛋白在脑内可能被血红素加氧酶和胆绿素还原酶部分解毒为其抗氧化代谢产物。然而，在头部创伤和中风中，大量出血可显著产生铁介导的氧化应激和神经变性，内源性抗氧化剂如胆绿素、胆红素、锰和S-亚硝基谷胱甘肽可最小化铁介导的氧化应激和神经变性。
In the presentin vitroandin vivostudy we investigated the pro-oxidant effects of hemoglobin, as well as the antioxidant effects of its metabolites, in the brain. Incubation of rat brain homogenates with hemoglobin (0–10 μM) but not hemin induced lipid peroxidation up to 24 h (EC50= 1.2 μM). Hemoglobin's effects were similar to ferrous ion (EC50= 1.7 μM) and were blocked by the chelating agent deferoxamine (IC50= 0.5 μM) and a nitric oxide-releasing compoundS-nitrosoglutathione (IC50= 40 μM). However, metabolites of hemoglobin — biliverdin and bilirubin — inhibited brain lipid peroxidation induced by cell disruption and hemoglobin (biliverdin IC50= 12–30 and bilirubin IC50= 75–170 μM). Biliverdin's antioxidative effects in spontaneous and iron-evoked lipid peroxidation were further augmented by maganese (2 μM) since manganese is an antioxidative transition metal and conjugates with bile pigments. Intrastriatal infusion of hemoglobin (0–24 nmol) produced slight, but significant 20–22% decreases in striatal dopamine levels. Whereas, intrastriatal infusion of ferrous citrate (0–24 nmol) dose-dependently induced a greater 66% depletion of striatal dopamine which was preceded by an acute increase of lipid peroxidation. In conclusion, contrary to thein vitroresults hemoglobin is far less neurotoxic than ferrous ions in the brain. It is speculated that hemoglobin may be partially detoxified by heme oxygenase and biliverdin reductase to its antioxidative metabolites in the brain. However, in head trauma and stroke, massive bleeding could significantly produce iron-mediated oxidative stress and neurodegeneration which could be minimized by endogenous antioxidants such as biliverdin, bilirubin, manganese andS-nitrosoglutathione.