Cuprizone Treatment Induces Distinct Demyelination, Astrocytosis, and Microglia Cell Invasion or Proliferation in the Mouse Cerebellum

Abstract

Demyelination of the cerebellum is a well-known phenomenon in human multiple sclerosis (MS). Concordantly, patients with MS frequently developed symptoms deriving from cerebellar lesions, i.e., dysmetria leading to hand dexterity impairment. Important advances in MS research have been made as a direct or indirect consequence of the establishment of adequate animal models. In this study, we used the cuprizone mouse model to investigate cerebellar demyelination in young adult male mice. The myelin status was analyzed by immunohistochemistry for proteolipoprotein and electron microscopy. The expression and presence of oligodendrocyte, astroglial, and microglia markers were supplementary studied. Cuprizone intoxication induced an almost complete demyelination of cerebellar nuclei. Cerebellar cortex regions were not (cortical gray matter) or only marginally (cortical white matter) affected. In addition, the affected areas displayed hypertrophic and hyperplastic astrocytosis accompanied by microglia or macrophage invasion. We conclude that cuprizone-induced demyelination pictures cerebellar deep gray matter involvement but not cerebellar cortex pathology as described for human MS. Behavioral changes after cuprizone described for this animal model may not only result from effects on commissural fiber tracts but also can arise from cerebellar demyelination.

CXCL10 Triggers Early Microglial Activation in the Cuprizone Model

“…Preparation of tissues was performed, as previously described (34)(35)(36). For histological and immunohistochemical (IHC) studies, mice were transcardially perfused with 2% paraformaldehyde.…”

“…Genes upregulated in the 2-d cuprizone-treated group versus the control group were identified according to the following criteria: expression of genes in cuprizonetreated sample is at least 2-fold higher compared with control samples, and the adjusted p value for changes in expression is ,0.05. Gene expression levels were further determined using the qRT-PCR technology (Bio-Rad), SensiMix SYBR Green (Bioline), and a standardized protocol, as described previously (34,48,50). Primer sequences and respective annealing temperatures are given in Table III.…”

Protective role of coenzyme Q 10 against high cholesterol dietinduced histological and biochemical changes in cerebellar cortex of adult albino rats

“…The astrocytes repair damage by filling spaces left by the degeneration of parts of nerve fibers and neurons and phagocytose some degenerating myelin. Amyloid plaques, a pathologic hallmark of AD, are associated with GFAP positive activated astrocytes [46]. Astrocytes and Microglia and may be consumers of amyloid plaques rather than producers [47].…”

“…Previous researches clarify that long term high cholesterol diet induced mild changes the gene expression in the mouse brain. Some of the altered genes were earlier shown to be involved in neurodegenerative disorderes especially in AD [46].…”

Animal Models of Human Cerebellar Ataxias: a Cornerstone for the Therapies of the Twenty-First Century

“…Most of these mechanisms have been unraveled thanks to animal studies based on ethanol exposure, in addition to cell cultures [216,217]. One model of cerebellotoxicity addresses the acute demyelination induced by cuprizone [218]. The model of cuprizone-induced toxicity reproduces several features of cerebellar deep gray matter observed in demyelinating disorders like multiple sclerosis (MS), a common disorder which affects the cerebellum frequently.…”