Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned

Abstract

Although astrogliosis and microglia activation are characteristic features of multiple sclerosis (MS) and other central nervous system (CNS) lesions the exact functions of these events are not fully understood. Animal models help to understand the complex interplay between the different cell types of the CNS and uncover general mechanisms of damage and repair of myelin sheaths. The so called cuprizone model is a toxic model of demyelination in the CNS white and gray matter, which lacks an autoimmune component. Cuprizone induces apoptosis of mature oligodendrocytes that leads to a robust demyelination and profound activation of both astrocytes and microglia with regional heterogeneity between different white and gray matter regions. Although not suitable to study autoimmune mediated demyelination, this model is extremely helpful to elucidate basic cellular and molecular mechanisms during de- and particularly remyelination independently of interactions with peripheral immune cells. Phagocytosis and removal of damaged myelin seems to be one of the major roles of microglia in this model and it is well known that removal of myelin debris is a prerequisite of successful remyelination. Furthermore, microglia provide several signals that support remyelination. The role of astrocytes during de- and remyelination is not well defined. Both supportive and destructive functions have been suggested. Using the cuprizone model we could demonstrate that there is an important crosstalk between astrocytes and microglia. In this review we focus on the role of glial reactions and interaction in the cuprizone model. Advantages and limitations of as well as its potential therapeutic relevance for the human disease MS are critically discussed in comparison to other animal models.

Differential local tissue permissiveness influences the final fate of GPR17‐expressing oligodendrocyte precursors in two distinct models of demyelination

“…Based on the above evidence, on the strikingly different contribution of inflammation to EAE‐ and cuprizone‐induced demyelination (Denic et al, 2011; Gudi et al, 2014), and based on the different capability of GPR17 + OPCs to undergo maturation in these two rodent models (the present results), we speculate that the proinflammatory local environment associated to EAE induction is responsible for persistent GPR17 overexpression in OPCs, leading to their blockade at immature stages.…”

“…This specific timing of tamoxifen administration was chosen to properly monitor the final fate of the OPCs that were expressing GPR17 at the beginning of the OPC proliferation wave (Gudi et al, 2014). At W8, mice were sacrificed and the maturation stage of the reacting GPR17 + cells was assessed by double labeling for both GFP and, either NG2 (a marker of oligodendrocyte precursors) or GSTπ (a marker of mature oligodendrocytes).…”

“…We indeed postulate that, in the EAE model, the inability of WM GFP + cells to maturate can be due, at least in part, to the presence of a strong chronic proinflammatory environment blocking cells at immature stages and preventing their terminal maturation. To further support this hypothesis, cuprizone‐induced demyelination mainly evolves as a toxic insult with much less involvement of immune cells leading to less inflammation, likely resulting in a more permissive local environment for OPC maturation (Gudi et al, 2014). …”

Cyclin-dependent kinase inhibitor flavopiridol promotes remyelination in a cuprizone induced demyelination model

“…When given to young adult C57BL/6 mice (0.2 % in the diet), CPZ induces apoptosis of mature oligodendrocytes and demyelination accompanied by spatial working memory impairment in mice. [3][4][5][6] Obvious demyelination was observed in the corpus callosum and the prefrontal cortex (PFC), external capsule, and hippocampus. 7 The PFC and hippocampus are important brain regions for a large range of cognitive functions such as working memory.…”

“…It is accepted that oxidative stress involves in the oligodendrocyte degeneration and myelin breakdown induced by CPZ, as evidenced by mitochondrial dysfunction parameters, such as mitochondrial swelling, production of ROS (reactive oxygen species), and collapse of the mitochondrial membrane potential, in CPZ-treated mice. [3][4][5]8 Moreover, certain antioxidants such as melatonin, 9 quetiapine, 10 and resveratrol, 11 showed protective effects on the CPZ-induced oligodendrocyte loss and myelin breakdown in recent animal studies. Interestingly, oligodendrocyte loss and myelin breakdown were accompanied by increase in the number of OPCs labeled as NG2 C (chondroitin sulfate proteoglycan) and PDGFRa C (platelet-derived growth factor a) cells in CPZexposed mice, [12][13][14] suggesting the existence of an aberrant cell cycle regulation following CPZ administration.…”