Animal Weight Is an Important Variable for Reliable Cuprizone-Induced Demyelination

Leopold, Patrizia; Schmitz, Christoph; Kipp, Markus

doi:10.1007/s12031-019-01312-0

Cited by 12 publications

(11 citation statements)

References 29 publications

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“…To this end, animals were intoxicated with cuprizone for five weeks, and myelination (anti-PLP), microgliosis (anti-IBA1), and acute axonal damage (anti-APP) were compared to controls which were fed normal chow during the experimental period. In line with previous findings [23,34,36,43,44], immunohistochemical analyses revealed extensive demyelination of the medial corpus callosum, the cerebral cortex, and the subcortical area after five weeks of cuprizone intoxication (Figure 2A). Demyelination was most severe in the corpus callosum, followed by the cerebral cortex and the subcortical area.…”

Section: Resultssupporting

confidence: 92%

Stereological Investigation of Regional Brain Volumes after Acute and Chronic Cuprizone-Induced Demyelination

Hochstrasser

Rühling

Hecher

et al. 2019

Cells

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Brain volume measurement is one of the most frequently used biomarkers to establish neuroprotective effects during pre-clinical multiple sclerosis (MS) studies. Furthermore, whole-brain atrophy estimates in MS correlate more robustly with clinical disability than traditional, lesion-based metrics. However, the underlying mechanisms leading to brain atrophy are poorly understood, partly due to the lack of appropriate animal models to study this aspect of the disease. The purpose of this study was to assess brain volumes and neuro-axonal degeneration after acute and chronic cuprizone-induced demyelination. C57BL/6 male mice were intoxicated with cuprizone for up to 12 weeks. Brain volume, as well as total numbers and densities of neurons, were determined using design-based stereology. After five weeks of cuprizone intoxication, despite severe demyelination, brain volumes were not altered at this time point. After 12 weeks of cuprizone intoxication, a significant volume reduction was found in the corpus callosum and diverse subcortical areas, particularly the internal capsule and the thalamus. Thalamic volume loss was accompanied by glucose hypermetabolism, analyzed by [18F]-fluoro-2-deoxy-d-glucose (18F-FDG) positron-emission tomography. This study demonstrates region-specific brain atrophy of different subcortical brain regions after chronic cuprizone-induced demyelination. The chronic cuprizone demyelination model in male mice is, thus, a useful tool to study the underlying mechanisms of subcortical brain atrophy and to investigate the effectiveness of therapeutic interventions.

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Section: Resultssupporting

confidence: 92%

Stereological Investigation of Regional Brain Volumes after Acute and Chronic Cuprizone-Induced Demyelination

Hochstrasser

Rühling

Hecher

et al. 2019

Cells

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“…First, we analyzed myelin‐integrity loss, microglia activation, and acute axonal injury during the course of cuprizone‐induced demyelination. As demonstrated in Figure 1a,b, and in line with several previous studies (Gingele et al, 2020; Hiremath et al, 1998; Leopold, Schmitz, & Kipp, 2019), myelin disintegration started at week 3 (loss of staining intensity in LFB/PAS‐stained sections) and was severe at week 5 (loss of anti‐PLP staining intensity). Demyelination was paralleled by pronounced microglia activation and acute axonal injury, as demonstrated by anti‐IBA1 and anti‐APP immunohistochemistry, respectively ( Figure 1c,d).…”

Section: Resultssupporting

confidence: 90%

Cuprizone‐induced demyelination triggers a CD8‐pronounced T cell recruitment

Kaddatz

Joost

Nedelcu

et al. 2020

Glia

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The loss of myelinating oligodendrocytes is a key characteristic of many neurological diseases, including Multiple Sclerosis (MS). In progressive MS, where effective treatment options are limited, peripheral immune cells can be found at the site of demyelination and are suggested to play a functional role during disease progression. In this study, we hypothesize that metabolic oligodendrocyte injury, caused by feeding the copper chelator cuprizone, is a potent trigger for peripheral immune cell recruitment into the central nervous system (CNS). We used immunohistochemistry and flow cytometry to evaluate the composition, density, and activation status of infiltrating T lymphocytes in cuprizone‐intoxicated mice and post‐mortem progressive MS tissues. Our results demonstrate a predominance of CD8+ T cells along with high proliferation rates and cytotoxic granule expression, indicating an antigenic and pro‐inflammatory milieu in the CNS of cuprizone‐intoxicated mice. Numbers of recruited T cells and the composition of lymphocytic infiltrates in cuprizone‐intoxicated mice were found to be comparable to those found in progressive MS lesions. Finally, amelioration of the cuprizone‐induced pathology by treating mice with laquinimod significantly reduces the number of recruited T cells. Overall, this study provides strong evidence that toxic demyelination is a sufficient trigger for T cells to infiltrate the demyelinated CNS. Further investigation of the mode of action and functional consequence of T cell recruitment might offer promising new therapeutic approaches for progressive MS.

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“…While sex, genetic background, and age of the animals have been identified as important variables for the reproducibility and the extent of cuprizone-induced pathological changes [99][100][101], "weight" as a critical variable for reliable and consistent demyelination has just recently been systematically addressed. In a recent work, we have investigated this issue, and were able to show that animal weight is an important variable for reliable cuprizone-induced demyelination [102]. In our group, we obtain the most reliable results if we order male mice from the vendor at an age of 6-7 weeks with weights ranging from 18 to 20 g. Of note, the weight of the mice should be determined after 1 week of rest, because mice show considerable weight loss due to transport-induced stress.…”

Section: Animal Weightmentioning

confidence: 99%

The Cuprizone Model: Dos and Do Nots

Zhan

Mann

Joost

et al. 2020

Cells

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Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. Various pre-clinical models with different specific features of the disease are available to study MS pathogenesis and to develop new therapeutic options. During the last decade, the model of toxic demyelination induced by cuprizone has become more and more popular, and it has contributed substantially to our understanding of distinct yet important aspects of the MS pathology. Here, we aim to provide a practical guide on how to use the cuprizone model and which pitfalls should be avoided.

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Animal Weight Is an Important Variable for Reliable Cuprizone-Induced Demyelination

Cited by 12 publications

References 29 publications

Stereological Investigation of Regional Brain Volumes after Acute and Chronic Cuprizone-Induced Demyelination

Stereological Investigation of Regional Brain Volumes after Acute and Chronic Cuprizone-Induced Demyelination

Cuprizone‐induced demyelination triggers a CD8‐pronounced T cell recruitment

The Cuprizone Model: Dos and Do Nots

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