The dietary consumption of cuprizone – a copper chelator – has long been known to induce demyelination of specific brain structures and is widely used as model of multiple sclerosis. Despite the extensive use of cuprizone, the mechanism by which it induces demyelination are still unknown. With this review we provide an updated understanding of this model, by showcasing two distinct yet overlapping modes of action for cuprizone-induced demyelination; 1) damage originating from within the oligodendrocyte, caused by mitochondrial dysfunction or reduced myelin protein synthesis. We term this mode of action ‘intrinsic cell damage’. And 2) damage to the oligodendrocyte exerted by inflammatory molecules, brain resident cells, such as oligodendrocytes, astrocytes, and microglia or peripheral immune cells – neutrophils or T-cells. We term this mode of action ‘extrinsic cellular damage’. Lastly, we summarize recent developments in research on different forms of cell death induced by cuprizone, which could add valuable insights into the mechanisms of cuprizone toxicity. With this review we hope to provide a modern understanding of cuprizone-induced demyelination to understand the causes behind the demyelination in MS.

中文翻译：

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铜宗模型中的少突胶质细胞死亡和髓鞘丢失：铜宗脱髓鞘的内在和外在原因的最新概述

长期以来，人们一直知道铜酮（一种铜螯合剂）的膳食消耗会诱导特定大脑结构的脱髓鞘，并被广泛用作多发性硬化症的模型。尽管铜宗广泛使用，但其诱导脱髓鞘的机制仍然未知。通过这篇综述，我们通过展示铜酮诱导的脱髓鞘的两种不同但重叠的作用模式，提供了对该模型的最新理解；1) 源自少突胶质细胞内部的损伤，由线粒体功能障碍或髓鞘蛋白合成减少引起。我们将这种作用方式称为“内在细胞损伤”。2) 炎症分子、大脑驻留细胞（如少突胶质细胞、星形胶质细胞和小胶质细胞或外周免疫细胞 - 中性粒细胞或 T 细胞）对少突胶质细胞造成的损害。我们将这种作用方式称为“外在细胞损伤”。最后，我们总结了铜宗诱导的不同形式细胞死亡的最新研究进展，这可以为铜宗毒性机制提供有价值的见解。通过这篇综述，我们希望提供对铜宗诱导的脱髓鞘的现代理解，以了解 MS 脱髓鞘背后的原因。