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

Tanja Hochstrasser,Matthias Brendel,Florian Eckenweber,Uta Chrzanowski,Christian Sacher,Kai H Fabisch,Markus Kipp,Kerstin Hecher,Sebastian Rühling,Christoph Schmitz

doi:10.3390/cells8091024

Tanja Hochstrasser, Matthias Brendel + Show 8 more

Open Access

https://doi.org/10.3390/cells8091024

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Abstract

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.

Highlights

Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disease of the central nervous system
We firstly investigated the severity of acute cuprizone-induced injury in the different brain regions
Demyelination was most severe in the corpus callosum, followed by the cerebral cortex and the subcortical area

Summary

Introduction

Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disease of the central nervous system. The majority of MS patients experience two clinical phases reflecting distinct but inter-related pathologies. The first phase is characterized by recurrent episodes of immune-driven inflammation and demyelination, from which the patients can recover completely (relapsing–remitting (RR) MS). A continuous progression of clinical, permanent disability can be observed, while the relapse frequency decreases [1,2]. This secondary disease phase is called secondary progressive. MS (SPMS), and the findings of several imaging and pathological studies suggest that neuro-axonal damage plays a central role for the observed clinical disease progression [3,4,5]. Current therapeutic strategies for MS are beneficial during RRMS by modulating or suppressing immune function [6]

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