Chronic toxic demyelination in the central nervous system leads to axonal damage despite remyelination
Chronic toxic demyelination in the central nervous system leads to axonal damage despite remyelination
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DOI：
10.1016/j.neulet.2009.02.004
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发表时间：
2009-04-03
影响因子：
2.5
通讯作者：
Stangel, Martin
中科院分区：
文献类型：
--
作者：
Lindner, Maren;Fokuhl, Jantje;Stangel, Martin
大多数多发性硬化症病变在慢性脱髓鞘发作后无法进行髓鞘再生，导致神经功能障碍。在当前的研究中，通过使用铜宗模型（一种毒性脱髓鞘模型）研究慢性脱髓鞘。 C57BL/6 小鼠接受 0.2% 铜宗饮食长达 16 周，以诱导慢性脱髓鞘。为了进行比较，另一组仅维持 6 周的铜宗治疗以模拟急性脱髓鞘。分析两组在停止毒素后的髓鞘再生过程。根据 LFB 判断，慢性脱髓鞘后髓鞘蛋白的重新表达减少了两倍；和髓磷脂蛋白染色与髓鞘再生两周后的急性脱髓鞘相比。在慢性脱髓鞘过程中，与年龄匹配的对照相比，成熟的少突胶质细胞（Nogo-A 阳性细胞）严重减少了 90%。然而，停药后出现了广泛的髓鞘再生，并在 12 周后几乎完成。通过 APP 染色判断，仅存在最小的急性轴突损伤，APP 阳性轴突的过程与巨噬细胞/小胶质细胞的积累相关。 SMI-32阳性染色检测到的慢性轴突损伤仅在慢性脱髓鞘后可见，并且在整个髓鞘再生期间仍然可观察到。这些数据表明铜宗模型中发生两种模式的轴突损伤。 (C) 2009 Elsevier Ireland Ltd. 保留所有权利。
The majority of multiple sclerosis lesions fail to remyelinate after chronic demyelinating episodes resulting in neurologic disability. In the current study, chronic demyelination was investigated by using the cuprizone model, a toxic demyelination model. C57BL/6 mice were administered a 0.2% cuprizone diet up to 16 weeks to induce chronic demyelination. For comparison, another group was maintained only for 6 weeks on cuprizone to model acute demyelination. Both groups were analysed regarding the remyelination process after withdrawal of the toxin. Reexpression of myelin proteins after chronic demyelination was reduced by a factor of two as judged by LFB; and myelin protein stainings compared to acute demyelination after 2 weeks on remyelination. During chronic demyelination mature oligodendrocytes (Nogo-A positive cells) were severely depleted by 90% compared to age matched controls. Nevertheless, extensive remyelination occurred after withdrawal of cuprizone and was nearly complete after 12 weeks. There was only minimal acute axonal damage as judged by APP staining, with the course of APP positive axons correlating with macrophage/microglia accumulation. Chronic axonal damage detected by SMI-32 positive staining was only seen after chronic demyelination and was still observable during the whole remyelination period. These data suggest that two pattern of axonal injury occur in the cuprizone model. (C) 2009 Elsevier Ireland Ltd. All rights reserved.