Abstract
Suitable in vivo and in vitro models are instrumental for the development of new drugs aimed at improving symptoms or progression of multiple sclerosis (MS). The cuprizone (CPZ)-induced murine model has gained momentum in recent decades, aiming to address the demyelination component of the disease. This work aims at assessing the differential cytotoxicity of CPZ in cells of different types and from different species: human oligodendroglial (HOG), human neuroblastoma (SH-SY5Y), human glioblastoma (T-98), and mouse microglial (N-9) cell lines. Moreover, the effect of CPZ was investigated in primary rat brain cells. Cell viability was assayed by oxygen rate consumption and by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-based (MTT) method. Our results demonstrated that CPZ did not cause death in any of the assayed cell models but affected mitochondrial function and aerobic cell respiration, thus compromising cell metabolism in neural cells and neuron-glia co-cultures. In this sense, we found differential vulnerability between glial cells and neurons as is the case of the CPZ-induced mouse model of MS. In addition, our findings demonstrated that reduced viability was spontaneous reverted in a time-dependent manner by treatment discontinuation. This reversible cell-based model may help to further investigate the role of mitochondria in the disease, and study the molecular intricacies underlying the pathophysiology of the MS and other demyelinating diseases.
Highlights
Cell viability was approached by the MTT reduction assay, which is mainly based on reduced activity of mitochondrial enzymes and electron carriers, i.e., is not, as often considered, a marker for cell death but of altered energy production
Our findings suggest that CPZ affects cell metabolism but that cells recover once the treatment is discontinued
Our findings show that CPZ caused a concentration-dependent decrease in oxygen consumption in both cell lines (Figure 9)
Summary
Multiple sclerosis (MS) is a neurodegenerative, demyelinating, and inflammatory disease of the central nervous system (CNS) that affects more than 2 million people worldwide, with a prevalence two to three times higher in women than in men [1]. This disabling pathology is characterized by the progressive focal loss of oligodendrocytes (OLG) and myelin membranes around axons, which compromises axonal transport and signal transduction, leading to progressive worsening of symptoms (reviewed in [2,3]). Some are promising in early stages of disease, their long-term effects remain uncertain [4,5,11,12,13,14,15]
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