Cognitive disturbances in the cuprizone model of multiple sclerosis

Abstract

Cognitive problems frequently accompany neurological manifestations of multiple sclerosis (MS). However, during screening of preclinical candidates, assessments of behaviour in mouse models of MS typically focus on locomotor activity. In the present study, we analysed cognitive behaviour of 9 to 10‐week‐old female C57Bl/6J mice orally administered with the toxin cuprizone that induces demyelination, a characteristic feature of MS. Animals received 400 mg/kg cuprizone daily for 2 or 4 weeks, and their performance was compared with that of vehicle‐treated mice. Cuprizone‐treated animals showed multiple deficits in short touchscreen‐based operant tasks: they responded more slowly to visual stimuli, rewards and made more errors in a simple rule‐learning task. In contextual/cued fear conditioning experiments, cuprizone‐treated mice showed significantly lower levels of contextual freezing than vehicle‐treated mice. Diffusion tensor imaging showed treatment‐dependent changes in fractional anisotropy as well as in axial and mean diffusivities in different white matter areas. Lower values of fractional anisotropy and axial diffusivity in cuprizone‐treated mice indicated developing demyelination and/or axonal damage. Several diffusion tensor imaging measurements correlated with learning parameters. Our results show that translational touchscreen operant tests and fear conditioning paradigms can reliably detect cognitive consequences of cuprizone treatment. The suggested experimental approach enables screening novel MS drug candidates in longitudinal experiments for their ability to improve pathological changes in brain structure and reverse cognitive deficits.

Cuprizone feed formulation influences the extent of demyelinating disease pathology

“…Instead, the initial weight loss observed in mice fed the cuprizone powder despite reduced cuprizone pathology suggests that the weight loss was due to the mice not ingesting the powdered cuprizone feed. It is plausible that the addition of cuprizone to powdered chow changes the palatability of the feed 41 , but why this did not occur with the cuprizone pellets is currently unclear. Nevertheless, the current data suggest that reduced palatability and subsequent aversion to the powdered cuprizone by the mice may result in the animals initially not ingesting the powdered feed and thus having a reduced or perhaps a delayed effect of cuprizone at the 3 week timepoint.…”

An in vivo accelerated developmental myelination model for testing promyelinating therapeutics

“…Given that several weeks or more may be required in the standard preclinical models to induce demyelination before the promyelinating candidates may be administered, we sought to develop a faster assay, in which myelination-enhancing action could be detected on a shorter time scale. We used DTI, an MRI technique sensitive to the integrity of WM, which is routinely used for the assessment of myelination disorders in clinical [ 70 – 73 ] and preclinical studies [ 74 – 76 ]. We chose to use T4 as a powerful promyelinating compound and in this respect, it should be noted that DTI has been used to detect myelination differences due to altered thyroid status both in humans and in animal models [ 38 , 77 ].…”

Evaluation of Lithium chloride effects as a GSK3-β inhibitor on human Adipose Derived Stem cells differentiation into oligodendrocytes and re-myelination in animal model of multiple sclerosis

“…Cuprizone (Cup), as a toxic compound and a copper chelating agent, is able to cause demyelination in different areas of the brain (especially in the corpus callosum) by disrupting the metabolism of oligodendrocytes (Zhen et al 2017;Kopanitsa et al 2021). In addition, it has been reported that Cup can reduce the expression of myelin-related genes and proteins, such as myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) and proteolipid protein in carpus callosum (Han et al 2020).…”