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Cited by 188Multiple Sclerosis Research StudiesNeurological Disease Mechanisms and TreatmentsNeuroinflammation and Neurodegeneration Mechanisms

Five Decades of Cuprizone, an Updated Model to Replicate Demyelinating Diseases

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Vega-Riquer, Jose M., Mendez-Victoriano, Gerardo, Morales-Luckie, Raul A., Gonzalez-Perez, Oscar·2019·Current Neuropharmacology
DOI 10.2174/1570159x15666170717120343PMC PMC6343207
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Abstract

Introduction: Demyelinating diseases of the central nervous system (CNS) comprise a group of neurological disorders characterized by progressive (and eventually irreversible) loss of oligodendrocytes and myelin sheaths in the white matter tracts. Some of myelin disorders include: Multiple sclerosis, Guillain-Barré syndrome, peripheral nerve polyneuropathy and others. To date, the etiology of these disorders is not well known and no effective treatments are currently available against them. Therefore, further research is needed to gain a better understand and treat these patients. To accomplish this goal, it is necessary to have appropriate animal models that closely resemble the pathophysiology and clinical signs of these diseases. Herein, we describe the model of toxic demyelination induced by cuprizone (CPZ), a copper chelator that reduces the cytochrome and monoamine oxidase activity into the brain, produces mitochondrial stress and triggers the local immune response. These biochemical and cellular responses ultimately result in selective loss of oligodendrocytes and microglia accumulation, which conveys to extensive areas of demyelination and gliosis in corpus callosum, superior cerebellar peduncles and cerebral cortex. Remarkably, some aspects of the histological pattern induced by CPZ are similar to those found in multiple sclerosis. CPZ exposure provokes behavioral changes, impairs motor skills and affects mood as that observed in several demyelinating diseases. Upon CPZ removal, the pathological and histological changes gradually revert. Therefore, some authors have postulated that the CPZ model allows to partially mimic the disease relapses observed in some demyelinating diseases. Conclusion: for five decades, the model of CPZ-induced demyelination is a good experimental approach to study demyelinating diseases that has maintained its validity, and is a suitable pharmacological model for reproducing some key features of demyelinating diseases, including multiple sclerosis.

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  • Both microglia and astrocytes contribute to cuprizone-induced pathology and could influence oligodendrocyte regeneration.

    “Both microglia and astrocytes contribute to cuprizone‐induced pathology and could influence oligodendrocyte regeneration (Vega‐Riquer et al. 2019).”

    From Depletion of Microglia Increases Cortical Oligodendrocyte Density During Remyelination (2026) · cites this paper as Vega‐Riquer et al. 2019

    The ‘Immune System Influence in the CPZ Model’ section (page not provided) says that cytokines from microglia and astrocytes have cytotoxic roles in cuprizone-induced demyelination, supporting their contribution to pathology. It also links astrocytes to reduced myelin synthesis, but does not establish that both cell types influence oligodendrocyte regeneration. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Cuprizone is a copper chelator that, when fed to rodents, results in loss of oligodendrocytes and myelin in specific brain regions, with limited blood-brain barrier disturbance and infiltration of peripheral immune cells.

    “Cuprizone is a copper chelator that, when fed to rodents, results in a loss of oligodendrocytes and thus, myelin, in specific brain regions, with limited BBB disturbance and infiltration of peripheral immune cells.”

    From Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination (2022) · cites this paper as [20]

    The Introduction describes cuprizone as a copper chelator and says dietary exposure causes oligodendrocyte loss and demyelination in named brain regions. It also says inflamed blood vessels and CD3+ T cells have not been described in the model, supporting limited peripheral immune-cell infiltration. Our copy does not state that blood-brain barrier disturbance is limited; it mentions barrier permeability only in a reference title. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • In contrast to EAE, where lesion formation happens stochastically/sporadically in the spinal cord, cuprizone lesions are confined to certain topographical areas in the brain, increasing reproducibility.

    “In contrast to the EAE model where lesion formation happens stochastically/sporadically in the spinal cord, the lesions are confined to these certain topographical areas in the brain – increasing the reproducibility [189, 190].”

    From Insights and challenges on animal models for progressive multiple sclerosis (2026) · cites this paper as [190]

    The Introduction describes cuprizone-induced lesions in the brain, and the References list work on region-specific susceptibility to cuprizone lesions. Our copy does not say that EAE spinal-cord lesions form stochastically or that the location of cuprizone lesions increases reproducibility. (LLM, conf=0.73)

    Experimental — accuracy not yet measured

  • Variability in toxin models, dosing regimens, lesion localization, quantification methods and behavioral readouts limits cross-study comparability.

    “Variability in toxin models, dosing regimens, lesion localization, quantification methods and behavioral readouts limits cross-study comparability201,202.”

    From From insights to innovations: evaluating preclinical paradigms in demyelinating disease therapeutics (2026) · cites this paper as [202]

    The “Cuprizone as demyelination model” section describes differences among models, cuprizone doses, and lesion patterns. It does not say that variation in quantification methods or behavioral readouts limits cross-study comparability, so the broader claim is not fully supported. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • Exposure to a cuprizone-containing diet is a prototypical model of demyelination probably due to copper-chelating effects in oligodendrocytes.

    “Exposure to a cuprizone-containing diet is a prototypical model of demyelination probably due to the copper-chelating effects of the compound in oligodendrocytes (Vega-Riquer et al. 2019).”

    From Cuprizone-Dependent De/Remyelination Responses and Functional Correlates in Mouse Strains Adopted to Model Relapsing, Chronic and Progressive Experimental Autoimmune Encephalomyelitis (2021) · cites this paper as Vega-Riquer et al. 2019

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References 120 · Cited by 188

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Authors
Vega-Riquer, J. M., Mendez-Victoriano, G., Morales-Luckie, R. A., & Gonzalez-Perez, O.
Affiliations
  • Universidad de Colima (MX)
  • Laboratory of Neuroscience, School of Psychology, University of Colima, Mexico
  • Centro Conjunto de Investigación en Quimica Sustentable, Universidad Autonoma del Estado de Mexico, Mexico
ORCID
Vega-Riquer, Jose M.
Venue
Current Neuropharmacology
Publisher
Bentham Science Publishers Ltd.
Published
2019-01-07
Volume
17
Issue
2
Pages
129-141
ISSN
1570-159X (ISSN-L)
DOI
10.2174/1570159x15666170717120343
PMC
PMC6343207
OpenAlex
W2761098718
Cited by
188
References
120
Citations by year
2026: 21 · 2025: 31 · 2024: 24 · 2023: 28 · 2022: 33 · 2021: 24 · 2020: 16 · 2019: 9 · 2018: 2
FWCI
3.05
Type
journal article
Language
en
Open access
Locations
  • Current Neuropharmacology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Institutional Repository (Universidad Autónoma del Estado de México) (submittedVersion, cc-by-nc-nd)
Funders
  • CONACyT’s fellowship ((No.377084))
  • UAEM (3789/2014/CIA)
  • Consejo Nacional de Ciencia y Tecnologia (INFR- 268062, PN-2015-01-465)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
cuprizone, demyelinating disease, multiple sclerosis, oligodendrocyte loss, myelin damage, gliosis, copper chelation, mitochondrial stress, recurrence, behavioral impairment, corpus callosum
MeSH terms
Animals, Brain, Cuprizone, Demyelinating Diseases, Disease Models, Animal, Oligodendroglia, Reproducibility of Results

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