Apotransferrin protects cortical neurons from hemoglobin toxicity.
Apotransferrin protects cortical neurons from hemoglobin toxicity.
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DOI：
10.1016/j.neuropharm.2010.10.015
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发表时间：
2011-02
影响因子：
4.7
通讯作者：
Regan, Raymond F.
中科院分区：
文献类型：
--
作者：
Chen-Roetling, Jing;Chen, Lifen;Regan, Raymond F.
铁螯合剂对脑出血实验模型的保护作用提示非血红素铁可能对血肿周围细胞的损伤有促进作用。高亲和力铁螯合剂的治疗受到其毒性的限制，其部分原因可能是金属在难以接近的络合物中被隔离。转铁蛋白在螯合铁方面具有很高的亲和力，同时通过受体介导的内吞作用将其输送到细胞中。然而，其对铁介导的神经元损伤的疗效从未被描述过，因此在本研究中使用已建立的血红蛋白神经毒性细胞培养模型进行了评估。在与CSF转铁蛋白相似的浓度下（50-100微克/毫升），铁饱和全转铁蛋白和转铁蛋白本身都是无毒的。在无血清培养基中暴露于3 μM纯化的人血红蛋白中过夜，通过乳酸脱氢酶释放试验测量，大约四分之三的神经元死亡。培养铁、丙二醛、蛋白羰基、铁蛋白和血红素加氧酶-1也显著增加。全转铁蛋白对这些参数没有影响，但在50 ~ 100微克/毫升转铁蛋白的作用下，这些参数都减弱了。载转铁蛋白的作用与去铁胺非常相似，其浓度提供了相同的铁结合能力，并且与全转铁蛋白同时治疗不会拮抗。转铁蛋白受体-1的表达局限于神经元，不受血红蛋白或转铁蛋白处理的影响。提示转铁蛋白可减轻脑出血后血红蛋白的神经毒性。增加其在血肿周围组织中的浓度可能是有益的。
The protective effect of iron chelators in experimental models of intracerebral hemorrhage suggests that nonheme iron may contribute to injury to perihematomal cells. Therapy with high affinity iron chelators is limited by their toxicity, which may be due in part to sequestration of metals in an inaccessible complex. Transferrin is unique in chelating iron with very high affinity while delivering it to cells as needed via receptor-mediated endocytosis. However, its efficacy against iron-mediated neuronal injury has never been described, and was therefore evaluated in this study using an established cell culture model of hemoglobin neurotoxicity. At concentrations similar to that of CSF transferrin (50–100 micrograms/ml), both iron-saturated holotransferrin and apotransferrin were nontoxic per se. Overnight exposure to 3 μM purified human hemoglobin in serum-free culture medium resulted in death, as measured by lactate dehydrogenase release assay, of about three-quarters of neurons. Significant increases in culture iron, malondialdehyde, protein carbonyls, ferritin and heme oxygenase-1 were also observed. Holotransferrin had no effect on these parameters, but all were attenuated by 50–100 micrograms/ml apotransferrin. The effect of apotransferrin was very similar to that of deferoxamine at a concentration that provided equivalent iron binding capacity, and was not antagonized by concomitant treatment with holotransferrin. Transferrin receptor-1 expression was localized to neurons and was not altered by hemoglobin or transferrin treatment. These results suggest that apotransferrin may mitigate the neurotoxicity of hemoglobin after intracerebral hemorrhage. Increasing its concentration in perihematomal tissue may be beneficial.
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影响因子：
4.2
作者：
CONNOR, JR;MENZIES, SL;MUFSON, EJ
通讯作者：
MUFSON, EJ
MEK/ERK途径的抑制剂减弱了血红素氧酶活性和血红蛋白神经毒性。
影响因子：
4.7
作者：
Chen-Roetling J;Li Z;Chen M;Awe OO;Regan RF
通讯作者：
Regan RF
影响因子：
4.1
作者：
Nakamura, T;Keep, RF;Xi, GH
通讯作者：
Xi, GH
DOI：
10.1016/s0169-328x(99)00011-x
发表时间：
1999-03-05
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Hansen, TM;Nielsen, H;Moos, T
通讯作者：
Moos, T
影响因子：
19.7
作者：
HARDY, PA;KUCHARCZYK, W;HENKELMAN, RM
通讯作者：
HENKELMAN, RM