A neuropathological approach for pathogenesis of onion-bulb formation after acute axonal degeneration in an animal model.

动物模型急性轴突变性后洋葱球形成发病机制的神经病理学方法。

• 批准号: 11670624
• 负责人: YOSHIKAWA Hiroo
• 金额: $ 1.98万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670624/
• 关键词: MSR-A; oxidized phosphatidylcholine; onion-bulb formation; axonal degeneration; compression; isoniazid intoxication; onion-bulb; 酸化phosphatidyl-choline; 挫滅; 髄鞘再生

To investigate the role of the MSR in myelin phagocytosis in vivo, (1) we produced a single compression lesion to sciatic nerves of both wild-type and MSR class A (MSR-A) knockout (ko) mice, (2) we intoxicated ko mice with isoniazid (INH), and examined the nerves 21 days after compression or intoxication. A morphometric study showed that the average densities of remaining myelinated fibers in wild-type mice and MSR-A ko mice were reduced from about 22000/mm^22 without compression to 7500-10000/mm^2 after compression, with no significant difference between the wild-type and ko mice. The most prominent pathological feature at the compression site was formation of many small onion-bulbs (OBs) in the MSR-A ko mice, whereas the wild-type mice showed only few. With an antibody against oxidized phosphatidylcholine, myelin and its debris in and around compressed nerve fibers were more densely stained in the ko mice than in the wild-type mice, although non-compressed nerve fibers were not stained at all. Foamy cells were identified more in the ko mouse as compared to the wild-type mouse. After INH intoxication, some of the ko mice showed similar changes in their sciatic nerves as in the compression, although immunohistochemical staining with anti-oxidized phosphatidylcholine antibody showed more diffusely stained endoneurium. From these results, we conclude that 1) oxidized phospholipids was generated from the myelin sheath after a nerve compression and INH intoxication, 2) the MSR might have played an important role in scavenging damaged cell membranes including the myelin aheath, and 3) dysfunction of the MSR was responsible for OB formation.

为了探讨MSR在体内髓鞘吞噬中的作用，(1)对野生型和MSR A类基因敲除(KO)小鼠的坐骨神经造成单次压迫损伤，(2)用异烟肼(INH)染毒KO小鼠，并在压迫或中毒21d后对神经进行检查。形态计量学研究表明，野生型和Msr-A KO小鼠的有髓神经纤维平均密度从压缩前的约22000个/mm^22减少到压缩后的7,500-10000个/mm^2，野生型和KO小鼠之间无显著差异。受压部位最显著的病理特征是MSR-A KO小鼠形成许多小洋葱鳞茎(OBS)，而野生型小鼠只有很少的洋葱鳞茎。使用氧化型磷脂酰胆碱抗体，KO组小鼠受压神经纤维及其周围的髓鞘及其碎片比野生型小鼠染色更浓，尽管非受压神经纤维根本不染色。与野生型小鼠相比，KO小鼠体内发现了更多的泡沫细胞。异烟肼中毒后，部分KO小鼠的坐骨神经表现出与压迫时相似的变化，但抗氧化型磷脂酰胆碱抗体免疫组织化学染色显示内神经细胞弥漫性染色。根据这些结果，我们认为1)神经压迫和异烟肼中毒后髓鞘产生氧化磷脂，2)MSR可能在清除包括髓鞘在内的受损细胞膜中起重要作用，3)MSR功能障碍是OB形成的原因。