Cause and prevention of demyelination in a model multiple sclerosis lesion.
Cause and prevention of demyelination in a model multiple sclerosis lesion.
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在模型多发性硬化病变中的原因和预防。
DOI：
10.1002/ana.24607
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发表时间：
2016-04
影响因子：
11.2
通讯作者：
Smith KJ
中科院分区：
文献类型：
--
作者：
Desai RA;Davies AL;Tachrount M;Kasti M;Laulund F;Golay X;Smith KJ
脱髓鞘是多发性硬化的一个主要特征，但仍不清楚为什么会形成新的病变，以及它们是否可以预防。神经病理学证据表明，脱髓鞘可以发生在淋巴细胞相对缺乏，并与独特的特征提示组织能量不足。目的是检查早期多发性硬化病变的实验模型，并确定致病机制和治疗机会。用微量注射脂多糖诱导大鼠脊髓背柱脱髓鞘病变，并在不同发育阶段进行化学染色。评估了病变诱导后吸入氧气治疗2天的疗效。脱髓鞘病变并不集中在注射部位，而是在1周后在白质-灰质边界形成，优先包括腹侧背柱分水岭。病变形成之前，短暂的早期缺氧和增加生产的超氧化物和一氧化氮。在脱髓鞘之前，该部位的少突胶质细胞数量在不久之后减少。病变形成于固有的缺氧易感性部位，如幼稚动物暴露于缺氧环境所示。值得注意的是，在缺氧期间提高吸入氧（80%，常压）显著减少或防止脱髓鞘。至少一些早期多发性硬化病变的脱髓鞘特征可以在先天免疫机制激活后在血管分水岭处出现，所述先天免疫机制引起缺氧以及超氧化物和一氧化氮形成，所有这些都可以损害细胞能量充足。通过增加吸入氧以减轻短暂缺氧可减少或消除脱髓鞘。神经学年鉴2016;79：591-604
Demyelination is a cardinal feature of multiple sclerosis, but it remains unclear why new lesions form, and whether they can be prevented. Neuropathological evidence suggests that demyelination can occur in the relative absence of lymphocytes, and with distinctive characteristics suggestive of a tissue energy deficit. The objective was to examine an experimental model of the early multiple sclerosis lesion and identify pathogenic mechanisms and opportunities for therapy. Demyelinating lesions were induced in the rat spinal dorsal column by microinjection of lipopolysaccharide, and examined immunohistochemically at different stages of development. The efficacy of treatment with inspired oxygen for 2 days following lesion induction was evaluated. Demyelinating lesions were not centered on the injection site, but rather formed 1 week later at the white–gray matter border, preferentially including the ventral dorsal column watershed. Lesion formation was preceded by a transient early period of hypoxia and increased production of superoxide and nitric oxide. Oligodendrocyte numbers decreased at the site shortly afterward, prior to demyelination. Lesions formed at a site of inherent susceptibility to hypoxia, as revealed by exposure of naive animals to a hypoxic environment. Notably, raising the inspired oxygen (80%, normobaric) during the hypoxic period significantly reduced or prevented the demyelination. Demyelination characteristic of at least some early multiple sclerosis lesions can arise at a vascular watershed following activation of innate immune mechanisms that provoke hypoxia, and superoxide and nitric oxide formation, all of which can compromise cellular energy sufficiency. Demyelination can be reduced or eliminated by increasing inspired oxygen to alleviate the transient hypoxia. Ann Neurol 2016;79:591–604