The cuprizone animal model: new insights into an old story

Abstract

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease that affects the central nervous system and represents the most common neurological disorder in young adults in the Western hemisphere. There are several well-characterized experimental animal models that allow studying potential mechanisms of MS pathology. While experimental allergic encephalomyelitis is one of the most frequently used models to investigate MS pathology and therapeutic interventions, the cuprizone model reflects a toxic experimental model. Cuprizone-induced demyelination in animals is accepted for studying MS-related lesions and is characterized by degeneration of oligodendrocytes rather than by a direct attack on the myelin sheet. The present article reviews recent data concerning the cuprizone model and its relevance for MS. Particular focus is given to the concordance and difference between human MS patterns (types I-IV lesions) and cuprizone-induced histopathology, including a detailed description of the sensitive brain regions extending the observations to different white and grey matter structures. Similarities between pattern III lesions and cuprizone-induced demyelination and dissimilarities, such as inflamed blood vessels or the presence of CD3+ T cells, are outlined. We also aim to distinguish acute and chronic demyelination under cuprizone including processes such as spontaneous remyelination during acute demyelination. Finally, we point at strain and gender differences in this animal model and highlight the contribution of some growth factors and cytokines during and after cuprizone intoxication, including LIF, IGF-1, and PDGFalpha.

An initial top-down proteomic analysis of the standard cuprizone mouse model of multiple sclerosis

“…Thus, it is perhaps not unexpected that prolonged damage to oligodendrocytes may lead to an increase in energy demand of demyelinated axons in chronic cuprizone treatment; cuprizone is after all a copper chelator Figures given are mean±SEM Table 4 Deep imaging and LC/MS/MS analyses identified a select number of protein species determined to be consistently detectable or not detectable following cuprizone treatment (indicated in Fig. 3 All identified proteins were from Mus musculus + Detectable in cuprizone treatment − Not detectable in cuprizone treatment MP membrane protein fraction, SP soluble protein fraction, T total protein fraction, MW molecular weight and would be expected to have some effect on mitochondria [6,7,28]. This increased energy demand may lead to degeneration of the axons.…”

“…If a slowly progressing oligodendrocytosis is central to MS, then an animal model of this process would be critical to understanding the initiation and progression of the disease. In the cuprizone model, mice undergo oligodendrocyte cell death resulting in demyelination [6,7]. Furthermore, studies also implicate mitochondrial dysfunction in this model oligodendrocytosis, as in the aetiology of MS [6][7][8].…”

“…In the cuprizone model, mice undergo oligodendrocyte cell death resulting in demyelination [6,7]. Furthermore, studies also implicate mitochondrial dysfunction in this model oligodendrocytosis, as in the aetiology of MS [6][7][8]. However, the selectivity of the standard cuprizone treatment in terms of more extensively modelling MS is somewhat questionable as the drug also has effects on peripheral tissues [6,7].…”

“…Furthermore, studies also implicate mitochondrial dysfunction in this model oligodendrocytosis, as in the aetiology of MS [6][7][8]. However, the selectivity of the standard cuprizone treatment in terms of more extensively modelling MS is somewhat questionable as the drug also has effects on peripheral tissues [6,7]. To better characterise these effects of cuprizone, we have undertaken a broader initial top-down proteomic analysis of cortex, spleen, skeletal muscle and peripheral blood mononuclear cells (PBMCs).…”

Effects of green tea epigallocatechin-3-gallate on the proteolipid protein and oligodendrocyte transcription factor 1 messenger RNA gene expression in a mouse model of multiple sclerosis

“…Cuprizone induces reversible demyelination in several brain regions including the hippocampus, cerebellum, caudate putamen, corpus callosum and grey matter regions. It is still not clear whether the copper chelating nature of cuprizone is implicated in its neurotoxic properties [15]. Additional mechanisms such as inhibition of oligodendrocyte progenitor cell (OPC) differentiation [3] and secretion of pro-inflammatory cytokines from activated microglia/macrophages are also discussed [24].…”