Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination

Abstract

Background 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.

Cuprizone-induced Demyelination in Mouse Brain is not due to Depletion of Copper

“…The protective effect of D-Pen supplementation in the CPZ diet could therefore also be interpreted as high-affinity chelation of astrocyte-derived copper. For an extensive review on the numerous potential downstream effects of CPZ:Cu toxicity, whether via direct action on oligodendrocytes or via toxification of CNS innate immune cells, we refer to Zirngibl et al, 2022 .…”

“…Despite its use in the study of white matter injury and repair for over 50 years, the mechanism of CPZ-induced demyelination is still incompletely understood (reviewed by Kipp et al, 2009 ; Praet et al, 2014 ; Zirngibl et al, 2022 ). Since CPZ chelates Cu, it is widely presumed that CNS damage is a result of Cu dyshomeostasis, as is observed in Menkes and Wilson’s disease, and acquired Cu deficiency in the human ( Prodan et al, 2002 ; Kumar, 2006 ).…”

Antiretroviral treatment reveals a novel role for lysosomes in oligodendrocyte maturation

“…While recent studies from rodent and large animal models suggest that oligodendrocytes that survive myelin breakdown can generate new sheaths and contribute to myelin pattern preservation following demyelination, the primary contributor to remyelination appears to be the migration, proliferation, and differentiation of OPCs (Bacmeister et al, 2020; Orthmann-Murphy et al, 2020). Therefore, animal models used to induce demyelination, such as cuprizone-feeding, can also provide insight on the mechanisms modulating OPC differentiation and maturation (Zirngibl et al, 2022). Since our previous work implicated another ARV drug, elvitegravir, in disruption of remyelination following cuprizone-mediated demyelination, we aimed to examine whether this was true for BIC.…”

Potential Utility of Natural Products against Oxidative Stress in Animal Models of Multiple Sclerosis

“…After 3 weeks of CPZ treatment, the mitochondria within oligodendrocytes swelled and elongated, and giant mitochondria appeared, leading to insufficient energy production. Subsequently, this led to the destruction of mitochondria, resulting in the generation of large amounts of free radicals [ 104 ] within the CNS. During this period, the level of GSH, an antioxidant, was significantly reduced, whereas the expression level of the oxidised form of GSH, GSSG, increased several-fold.…”