Matsushima G K, Morell P
UNC Neuroscience Center, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, 27599, USA.
Brain Pathol. 2001 Jan;11(1):107-16. doi: 10.1111/j.1750-3639.2001.tb00385.x.
Myelin of the adult CNS is vulnerable to a variety of metabolic, toxic, and autoimmune insults. That remyelination can ensue, following demyelinating insult, has been well demonstrated. Details of the process of remyelination are, however difficult to ascertain since in most experimental models of demyelination/remyelination the severity, localization of lesion site, or time course of the pathophysiology is variable from animal to animal. In contrast, an experimental model in which massive demyelination can be reproducibly induced in large areas of mouse brain is exposure to the copper chelator, cuprizone, in the diet. We review work from several laboratories over the past 3 decades, with emphasis on our own recent studies, which suggest an overall picture of cellular events involved in demyelination/remyelination. When 8 week old C57BL/6 mice are fed 0.2% cuprizone in the diet, mature olidgodendroglia are specifically insulted (cannot fulfill the metabolic demand of support of vast amounts of myelin) and go through apoptosis. This is closely followed by recruitment of microglia and phagoctytosis of myelin. Studies of myelin gene expression, coordinated with morphological studies, indicate that even in the face of continued metabolic challenge, oligodendroglial progenitor cells proliferate and invade demyelinated areas. If the cuprizone challenge is terminated, an almost complete remyelination takes place in a matter of weeks. Communication between different cell types by soluble factors may be inferred. This material is presented in the context of a model compatible with present data -- and which can be tested more rigorously with the cuprizone model. The reproducibility of the model indicates that it may allow for testing of manipulations (e.g. available knockouts or transgenics on the common genetic background, or pharmacological treatments) which may accelerate or repress the process of demyelination and or remyelination.
成年中枢神经系统的髓磷脂易受多种代谢、毒性和自身免疫性损伤。脱髓鞘损伤后能够发生髓鞘再生，这一点已得到充分证实。然而，由于在大多数脱髓鞘/髓鞘再生的实验模型中，病理生理学的严重程度、损伤部位的定位或时间进程在动物之间存在差异，因此髓鞘再生过程的细节难以确定。相比之下，一种可在小鼠大脑大面积区域可重复诱导大量脱髓鞘的实验模型是在饮食中给予铜螯合剂双环己酮草酰二腙（cuprizone）。我们回顾了过去30年中几个实验室的工作，重点是我们自己最近的研究，这些研究揭示了脱髓鞘/髓鞘再生过程中细胞事件的整体情况。当给8周龄的C57BL/6小鼠喂食含0.2%双环己酮草酰二腙的饮食时，成熟的少突胶质细胞会受到特异性损伤（无法满足支持大量髓磷脂的代谢需求）并经历凋亡。紧接着是小胶质细胞的募集和髓磷脂的吞噬。与形态学研究相结合的髓磷脂基因表达研究表明，即使面对持续的代谢挑战，少突胶质前体细胞也会增殖并侵入脱髓鞘区域。如果终止双环己酮草酰二腙的刺激，在几周内几乎会发生完全的髓鞘再生。可以推断不同细胞类型之间通过可溶性因子进行通讯。本文是在一个与现有数据兼容的模型背景下呈现这些内容的，并且该模型可以用双环己酮草酰二腙模型进行更严格的测试。该模型的可重复性表明，它可能允许测试一些操作（例如在常见遗传背景下可用的基因敲除或转基因，或药物治疗），这些操作可能加速或抑制脱髓鞘和/或髓鞘再生过程。
