Developmental up-regulation of MnSOD in rat oligodendrocytes confers protection against oxidative injury
Developmental up-regulation of MnSOD in rat oligodendrocytes confers protection against oxidative injury
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DOI：
10.1111/j.0953-816x.2004.03451.x
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发表时间：
2004-07-01
影响因子：
3.4
通讯作者：
Rosenberg, PA
中科院分区：
文献类型：
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作者：
Baud, O;Haynes, RF;Rosenberg, PA
脑室周围白质软化是早产儿脑瘫的主要病理改变，被认为是脑白色物质缺氧缺血性损伤的结果。受损的主要细胞类型是发育中的少突胶质细胞（OL），其已被证明比成熟OL对兴奋毒性和氧化损伤机制更敏感。以前在培养中已经证明了OL对胱氨酸剥夺诱导的谷胱甘肽耗尽的脆弱性的成熟依赖性。我们推测，线粒体可能参与这种毒性产生超氧化物和增加超氧化物歧化酶（SOD）活性在成熟的OL可能占其更大的阻力。发现胱氨酸剥夺毒性与发育中OL的线粒体功能障碍和细胞内超氧化物积累有关。CuZnSOD蛋白表达和酶活性沿着OL谱系是相似的。相反，MnSOD在成熟的OLs中上调，表现为其表达增加了53%，其活性增加了4倍。MnSOD在发展中的OLs与线粒体膜电位的保护作用，减少轻度胱氨酸剥夺诱导的细胞死亡。更大的挑战提出的总胱氨酸剥夺是耐MnSOD过表达，似乎与过氧化氢毒性。这些数据表明，主要参与的超氧化物谷胱甘肽耗竭毒性发展中的OL，并建议MnSOD在成熟OL中观察到的电阻的重要作用。
Periventricular leukomalacia, the predominant pathological lesion underlying cerebral palsy in premature infants, is thought to be the result of hypoxic-ischemic injury to the cerebral white matter. The main cell type injured is the developing oligodendrocyte (OL), which has been shown to be more sensitive than mature OLs to both excitotoxic and oxidative mechanisms of injury. A maturation dependence of OL vulnerability to cystine deprivation-induced glutathione depletion has been previously demonstrated in culture. We hypothesized that mitochondria could be involved in this toxicity by generating superoxide and that increased superoxide dismutase (SOD) activity in mature OLs may account for their greater resistance. Cystine deprivation toxicity was found to be associated with mitochondrial dysfunction and intracellular superoxide accumulation in developing OLs. CuZnSOD protein expression and enzyme activity was similar along the OL lineage. In contrast, MnSOD was up-regulated in mature OLs, as manifested by a 53% increase in its expression and a four-fold increase in its activity. Overexpressing MnSOD in developing OLs was associated with a protective effect on mitochondrial membrane potential and a decrease in cell death induced by mild cystine deprivation. The greater challenge presented by total cystine deprivation was resistant to MnSOD overexpression and appeared to be related to hydrogen peroxide toxicity. These data suggest a primary involvement of superoxide in glutathione depletion toxicity in developing OLs, and suggest an important role for MnSOD in the resistance observed in mature OLs.