Increased striatal injury and behavioral deficits after intracerebral hemorrhage in hemopexin knockout mice.
Increased striatal injury and behavioral deficits after intracerebral hemorrhage in hemopexin knockout mice.
复制标题
脑癌敲除小鼠中脑出血后纹状体损伤和行为缺陷增加。
DOI：
10.3171/2010.10.jns10861
复制
发表时间：
2011-04
影响因子：
4.1
通讯作者：
Regan RF
中科院分区：
文献类型：
--
作者：
Chen L;Zhang X;Chen-Roetling J;Regan RF
血红素毒性可能参与脑出血的发病机制。针对细胞外血红素的主要防御由血红素结合素提供，血红素结合素是一种血清和神经元糖蛋白，其以非常高的亲和力结合血红素并减轻其促氧化作用。在本研究中，我们检验了血红素结合蛋白基因敲除小鼠在实验性脑出血后比野生型小鼠遭受更多损伤的假设。立体定向注射细菌胶原酶或自体血诱导纹状体脑出血。三天后，通过羰基测定评估纹状体蛋白质氧化。使用甲基噻唑基二苯基-溴化四唑（MTT）测定在8-9天时定量细胞活力。通过对6小时笼舍录像和标准测试的高分辨率数字分析检测行为缺陷。与对侧纹状体相比，野生型胶原酶注射纹状体中血肿周围蛋白氧化增加约2.1倍，而敲除纹状体中增加约3倍。通过注射胶原酶，野生型小鼠的纹状体细胞活力降低至对侧纹状体细胞活力的52.9±6.5%，敲除小鼠的纹状体细胞活力降低至31.1%±3.7%;血液注射后获得了相似的结果。对家庭笼舍录像的数字分析表明，两种模型的活动缺陷在敲除后8天显著加剧。通过血红素结合蛋白敲除，在血液注射后9天纹状体血红素含量增加约2.7倍。这些结果表明，血红素结合蛋白对出血性CNS损伤具有保护作用。通常与镰状细胞病相关的血红素结合蛋白缺乏可能使脑出血后的预后恶化。
Heme toxicity may contribute to the pathogenesis of intracerebral hemorrhage. The primary defense against extracellular heme is provided by hemopexin, a serum and neuronal glycoprotein that binds it with very high affinity and mitigates its pro-oxidant effect. In the present study, we tested the hypothesis that hemopexin knockout mice would sustain more injury after experimental intracerebral hemorrhage than their wild-type counterparts. Striatal intracerebral hemorrhage was induced by stereotactic injection of bacterial collagenase or autologous blood. Three days later, striatal protein oxidation was assessed by carbonyl assay. Cell viability was quantified at 8-9 days using the methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. Behavioral deficits were detected by high resolution digital analysis of six hour home cage video recordings and standard testing. Perihematomal protein oxidation was increased in wild-type collagenase-injected striata by approximately 2.1-fold compared with contralateral striata vs. 3-fold in knockouts. Striatal cell viability was reduced in wild-type mice to 52.9±6.5% of that in contralateral striata by collagenase injection, and to 31.1%±3.7% in knockouts; similar results were obtained after blood injection. Digital analysis of home cage video recordings demonstrated an activity deficit in both models that was significantly exacerbated at 8 days in knockouts. Striatal heme content 9 days after blood injection was increased approximately 2.7-fold by hemopexin knockout. These results suggest that hemopexin has a protective effect against hemorrhagic CNS injuries. Hemopexin deficiency, which is often associated with sickle cell disease, may worsen outcome after intracerebral hemorrhage.