Longitudinal monitoring of metabolic alterations in cuprizone mouse model of multiple sclerosis using 1H-magnetic resonance spectroscopy

Abstract

Non-invasive measures of well-known pathological hallmarks of multiple sclerosis (MS) such as demyelination, inflammation and axonal injury would serve as useful markers to monitor disease progression and evaluate potential therapies. To this end, in vivo localized proton magnetic resonance spectroscopy ((1)H-MRS) provides a powerful means to monitor metabolic changes in the brain and may be sensitive to these pathological hallmarks. In our study, we used the cuprizone mouse model to study pathological features of MS, such as inflammation, de- and remyelination, in a highly reproducible manner. C57BL/6J mice were challenged with a 0.2% cuprizone diet for 6-weeks to induce demyelination, thereafter the mice were put on a cuprizone free diet for another 6weeks to induce spontaneous remyelination. We employed in vivo (1)H-MRS to longitudinally monitor metabolic changes in the corpus callosum of cuprizone-fed mice during the demyelination (weeks 4 and 6) and spontaneous remyelination (week 12) phases. The MRS spectra were quantified with LCModel and since the total creatine (tCr) levels did not change over time or between groups, metabolite concentrations were expressed as ratios relative to tCr. After 4 and 6weeks of cuprizone treatment a significant increase in taurine/tCr and a significant reduction in total N-acetylaspartate/tCr, total choline-containing compounds/tCr and glutamate/tCr could be observed compared to mice under normal diet. At week 12, when almost full remyelination was established, no statistically significant metabolic differences were present between the control and cuprizone group. Our results suggest that these metabolic changes may represent sensitive markers for cuprizone induced demyelination, axonal injury and inflammation. To the best of our knowledge, this is the first longitudinal in vivo (1)H-MRS study that monitored biochemical changes in the corpus callosum of cuprizone fed mice.

Hyperpolarized 13 C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model

“…In the initial part of this study our goal was twofold. First, we wanted to confirm that, in our hands, the CPZ mouse model was behaving as previously described in terms of spatial and temporal distribution of lesions (37,(39)(40)(41)(42). Next, we evaluated the potential of T 2 -weighted MRI at high field strength (14.1 T) to detect cerebral lesions in CPZ mice.…”

Intracerebral transplantation of interleukin 13-producing mesenchymal stem cells limits microgliosis, oligodendrocyte loss and demyelination in the cuprizone mouse model

“…Likewise, given the intrinsic toxic nature of CPZ to oligodendrocyte metabolism [17], it remains to be elucidated whether the observed myelin is fully functional on the structural and functional level. For this, electron microscopy [37, 38] and more advanced MRI studies [26, 27, 39] are planned in our future experiments. Nevertheless, as the field of CNS immunomodulation is highly complex and continuously evolving, a highly complex interplay between both proposed mechanisms may not be not unlikely.…”

“…For induction of CNS inflammation and demyelination, mice received standard rodent chow mixed with 0.2 % w / w CPZ (Sigma-Aldrich) for 4 weeks between the ages of 8 and 12 weeks, as previously described [14, 25–27]. …”

Diffusion kurtosis imaging probes cortical alterations and white matter pathology following cuprizone induced demyelination and spontaneous remyelination

“…Histological analyses were performed according to previously optimized procedures (Guglielmetti et al , 2014; Orije et al , 2015). Mice were deeply anesthetized via an intraperitoneal injection pentobarbital (60 mg/kg, Nembutal, Ceva Sante Animale) and transcardially perfused with ice cold PBS and perfused-fixed with 4% paraformaldehyde in 0.1 M PBS (pH 7.4).…”