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Cuprizone Model Overview

The cuprizone multiple sclerosis mouse model of demyelination and remyelination is induced by feeding mice the copper-chelating cuprizone toxin. Cuprizone administration in mice models several aspects of human multiple sclerosis (MS), including central nervous system (CNS) loss of myelin, spontaneous remyelination, oligodendrocyte precursor cell (OPC) proliferation & maturation to myelinating oligodendrocytes, astrogliosis, and microgliosis. The myelin pathology and associated neuroinflammation observed in the cuprizone model in mice is most prominent the corpus callosum with highly predictable pathology that mimics MS lesions.

Unlike EAE, the cuprizone model of multiple sclerosis is not autoimmune mediated and the cuprizone induced white matter demyelination and remyelination are not confounded by a peripheral immune response. EAE and cuprizone mice model different aspects of MS pathology, and therapeutic studies are often performed in parallel.

Cuprizone Model Generation

  • C57BL/6 mice are fed 0.2-0.3% cuprizone via diet (powdered chow or food pellets) or oral gavage to induce toxicity to mature oligodendrocytes and damage to the myelin sheath
  • A more severe, chronic, mouse demyelination model can be generated by injecting rapamycin (i.p. 5 days per week)
  • In our experience, the powdered chow diet route of administration provides the most reproducible results

Our Validated Cuprizone Mouse Model Measures

  • Body weight
  • Myelin-sensitive, in vivo magnetic resonance imaging (MRI)
  • Immunohistochemistry & multiplex immunofluorescence for myelin and multiple cell types in the corpus callosum
Two brain cross-sections stained for Myelin Basic Protein (MBP), used in studying demyelination in a cuprizone mouse model of Multiple Sclerosis (MS), with varying levels of myelin indicated by the staining intensity

Myelin Basic Protein (MBP) immunohistochemistry staining of the corpus callosum in control mice (top) and mice after 5 weeks of cuprizone diet treatment (bottom).

Learn more about our characterization of this model, our validated measures, and our Preclinical Neuroscience CRO services.

Discover more of our Multiple Sclerosis Models


What are the advantages of in vivo MRI for the cuprizone mouse model?

We use the Magnetization Transfer Ratio (MTR) to assess demyelination and remyelination this mouse model.

Two MRI brain scans in false color from a cuprizone mouse model, used to study demyelination related to Multiple Sclerosis (MS), highlighting areas of varying signal intensity that may represent tissue changes due to demyelination

Key advantages include:

  • Clinically translational measure that is widely used in MS clinical trials
  • Longitudinal assessment of alterations of myelin integrity in the same animal
  • In-life readout for faster go/no-go decision-making

What is the typical time course of demyelination and remyelination in the cuprizone model in mice?

Here is an illustration of a typical time course, showing loss and recovery of myelin and myelinating oligodendrocytes, as well as migration and maturation of oligodendrocyte precursor cells (OPCs) in this demyelination model:

Cuprizone myelin time course Graph

Is inflammation observed in the cuprizone mouse model?

The cuprizone multiple sclerosis model is an excellent model of neuroinflammation (microgliosis and astrogliosis). Here is a typical time course:

Cuprizone inflammation time course timeline

Two bar graphs indicating that a cuprizone diet significantly increases the activity or quantity of astrocytes and microglia compared to a normal diet, relevant in the study of demyelination in Multiple Sclerosis models

Unlike the EAE mouse model, it does not show significant peripheral inflammatory infiltrates, such as T cells.

Can cuprizone and EAE studies be performed in parallel?

Yes. Since cuprizone and EAE model different aspects of human MS, they can be run as parallel studies for a comprehensive assessment of therapeutic agents on demyelination, remyelination, neuroinflammation, peripheral inflammation, axonal damage, etc.

What is the cuprizone-rapamycin mouse model?

By adding rapamycin (typically i.p. administration 5 days per week) to cuprizone fed mice, there is a high degree of toxicity to mature oligodendrocytes and a more severe model can be generated. The option to include rapamycin in the model generation depends on your therapeutic agent and the questions that you are trying to answer. Our MS model scientists would be happy to discuss the pros and cons of this mouse model with you.

More Information

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