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首页> 外文期刊>The European Journal of Neuroscience >Nitric oxide-induced cell death in developing oligodendrocytes is associated with mitochondrial dysfunction and apoptosis-inducing factor translocation.
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Nitric oxide-induced cell death in developing oligodendrocytes is associated with mitochondrial dysfunction and apoptosis-inducing factor translocation.

机译：一氧化氮诱导的发育中少突胶质细胞死亡与线粒体功能障碍和凋亡诱导因子易位有关。

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Abstract Reactive nitrogen species are thought to be involved in both hypoxic-ischemic and cytokine-induced brain injury, including periventricular leukomalacia (PVL), the major pathological substrate of cerebral palsy in premature infants. PVL appears to be the result of perinatal inflammatory events and hypoxic-ischemic injury to the cerebral white matter. The chronic disturbance of myelination resulting from PVL suggests that developing oligodendrocytes (OLs) are involved in its pathogenesis. We hypothesized that nitric oxide (NO) could participate in the pathogenesis of PVL through a toxic effect on developing OLs. Using primary cultures of highly enriched OLs we found that NO is toxic to developing OLs (O4(+), O1(-), MBP(-)), with an EC(50) value of 236 +/- 125 micro m of DETANOnoate. Peroxynitrite formation does not appear to be involved in NO toxicity in developing OLs, as determined by the failure of peroxynitrite scavengers as well as superoxide dismutase overexpression to prevent NO-induced toxicity. Similarly, several pathways involving PARP, excitotoxicity, guanylyl cyclase and caspase activation were not related to NO toxicity to developing OLs. NO toxicity to OLs resulted in ATP depletion and loss of mitochondrial membrane potential (DeltaPsi) in developing OLs. Apoptosis-inducing factor (AIF) has been shown to be involved in caspase-independent cell death, and we found that AIF translocated from mitochondria into the nucleus upon NO exposure. In conclusion, we suggest that the vulnerability of developing OLs to NO involves mitochondrial dysfunction and translocation of AIF from mitochondria to nuclei.
机译：摘要活​​性氮物质被认为参与了缺氧缺血性脑损伤和细胞因子诱导的脑损伤，包括早产儿脑瘫的主要病理底物脑室白细胞软化（PVL）。 PVL似乎是围产期炎症事件和脑白质缺氧缺血性损伤的结果。由PVL引起的髓鞘形成的慢性紊乱表明发育中的少突胶质细胞（OLs）参与了其发病机理。我们假设一氧化氮（NO）可能通过对发育中的OLs产生毒性作用而参与PVL的发病机理。使用高浓度OL的原代培养物，我们发现NO对发育中的OL（O4（+），O1（-），MBP（-））有毒，EC（50）值为DETANOnoate的236 +/- 125微米。过氧化亚硝酸盐清除剂的失败以及超氧化物歧化酶过表达的失败阻止了过氧化亚硝酸盐清除剂的失败，从而阻止了发育中的OLs的过氧化亚硝酸盐的形成。同样，涉及PARP，兴奋性毒性，鸟苷酸环化酶和胱天蛋白酶激活的几种途径与NO对发育中的OL的毒性无关。 NO对OL的毒性导致发育中的OL导致ATP耗竭和线粒体膜电位（DeltaPsi）损失。凋亡诱导因子（AIF）已被证明与caspase无关的细胞死亡有关，并且我们发现AIF在暴露于NO后会从线粒体转移到细胞核中。总之，我们认为发展中的OLs对NO的脆弱性涉及线粒体功能障碍和AIF从线粒体到细胞核的易位。

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