Cuprizone feed formulation influences the extent of demyelinating disease pathology

Lillian M Toomey,Alexander J Wright,Melissa Papini,Andrew Warnock,Chidozie Anyaegbu,Sarah C Hellewell,Carole A Bartlett,Melinda Fitzgerald,Terence Mcgonigle,Brittney Lins

doi:10.1038/s41598-021-01963-3

Lillian M Toomey, Alexander J Wright + Show 8 more

Open Access

https://doi.org/10.1038/s41598-021-01963-3

Copy DOI

Abstract

Cuprizone is a copper-chelating agent that induces pathology similar to that within some multiple sclerosis (MS) lesions. The reliability and reproducibility of cuprizone for inducing demyelinating disease pathology depends on the animals ingesting consistent doses of cuprizone. Cuprizone-containing pelleted feed is a convenient way of delivering cuprizone, but the efficacy of these pellets at inducing demyelination has been questioned. This study compared the degree of demyelinating disease pathology between mice fed cuprizone delivered in pellets to mice fed a powdered cuprizone formulation at an early 3 week demyelinating timepoint. Within rostral corpus callosum, cuprizone pellets were more effective than cuprizone powder at increasing astrogliosis, microglial activation, DNA damage, and decreasing the density of mature oligodendrocytes. However, cuprizone powder demonstrated greater protein nitration relative to controls. Furthermore, mice fed control powder had significantly fewer mature oligodendrocytes than those fed control pellets. In caudal corpus callosum, cuprizone pellets performed better than cuprizone powder relative to controls at increasing astrogliosis, microglial activation, protein nitration, DNA damage, tissue swelling, and reducing the density of mature oligodendrocytes. Importantly, only cuprizone pellets induced detectable demyelination compared to controls. The two feeds had similar effects on oligodendrocyte precursor cell (OPC) dynamics. Taken together, these data suggest that demyelinating disease pathology is modelled more effectively with cuprizone pellets than powder at 3 weeks. Combined with the added convenience, cuprizone pellets are a suitable choice for inducing early demyelinating disease pathology.

Highlights

A recent study has discovered that the copper chelating action of cuprizone produces dysregulation of iron homeostasis, leading to ferroptosis-mediated loss of oligodendrocytes and m yelin[19]
In this study we investigated the extent that cuprizone pathology is dependent on feed formulation at an early 3 week timepoint
Across most of the outcome measures analysed, cuprizone pellets were generally better than cuprizone powder at inducing early demyelinating disease pathology compared to their relative controls, in the caudal corpus callosum (Table 1)

Summary

Introduction

A recent study has discovered that the copper chelating action of cuprizone produces dysregulation of iron homeostasis, leading to ferroptosis-mediated loss of oligodendrocytes and m yelin[19]. Another study has directly compared the potency of cuprizone pellets and powder and demonstrated that cuprizone powder was more effective at inducing demyelinating pathology than pellets at an equivalent dose of cuprizone[27]. Information on the effects of pelleted cuprizone at the early 3 week timepoint during demyelination is lacking. We assessed the potency of pelleted and powdered cuprizone at an early demyelinating timepoint. 0.2% cuprizone was delivered in both powdered and pelleted form and outcomes were assessed following 3 weeks of cuprizone administration. Various cytochemical and immunohistochemical parameters, including oligodendroglial death, gliosis, oxidative stress and demyelination, were investigated to determine the extent to which powdered and pelleted cuprizone differ in their capacity to induce the hallmarks of cuprizone-intoxication in the CNS

Methods

Results

Conclusion