Microglial/macrophage accumulation during cuprizone-induced demyelination in C57BL/6 mice

Hiremath, M.M.; Saito, Y.; Knapp, G.W.; Ting, J.P.-Y.; Suzuki, K.; Matsushima, G.K.

doi:10.1016/s0165-5728(98)00168-4

Cited by 412Neuroinflammation and Neurodegeneration MechanismsMultiple Sclerosis Research StudiesNeurological Disease Mechanisms and Treatments

Microglial/macrophage accumulation during cuprizone-induced demyelination in C57BL/6 mice

Hiremath, M.M., Saito, Y., Knapp, G.W., Ting, J.P.-Y., Suzuki, K., Matsushima, G.K.·1998·Journal of Neuroimmunology

DOI 10.1016/s0165-5728(98)00168-4

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Abstract

To study microglial/macrophage infiltration, a cuprizone-induced model for demyelination in C57BL/6 mice was established. Cuprizone is known to cause demyelination in Swiss mice, however, cuprizone-induced demyelination in C57BL/6 mice has not been previously described. Induction of demyelination in C57BL/6 mice enables examination of the function of microglia/macrophage through comparative analyses of syngeneic mice with various targeted genetic mutations. In this report, cuprizone-induced demyelination is easily inducible, localized, and predictable. Concurrent with the initiation of demyelination, we noted microglial/macrophage accumulation and changes in astrocyte morphology. Astrogliosis promptly followed microglia/macrophage recruitment. These observations suggested that microglia/macrophage actively contribute to the demyelination process.

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In the corpus callosum, cuprizone treatment induces apoptosis of oligodendrocytes together with recruitment of microglia/macrophages, astrocytes and OPCs.
“In the corpus callosum, apoptosis of oligodendrocytes is observed, together with recruitment of microglia/macrophages, astrocytes and oligodendrocyte progenitor cells (OPCs) [5, 6].”
From Strain differences in cuprizone induced demyelination (2017) · cites this paper as [6]
Cuprizone selectively affects oligodendrocytes.
“Nevertheless, a consensus seems to be that cuprizone selectively affects oligodendrocytes.”
From Strain differences in cuprizone induced demyelination (2017) · cites this paper as [6]
The cuprizone induced demyelination in the corpus callosum is best documented in the commonly used C57BL/6 strain and at a dosage of 0.2%.
“However, the cuprizone induced demyelination in the corpus callosum is best documented in the commonly used C57BL/6 strain and at a dosage of 0.2% [6, 15].”
From Strain differences in cuprizone induced demyelination (2017) · cites this paper as [6]
In our experiments, we observed a dramatic increase of microglia in C57BL/6 mice following 4 weeks of cuprizone exposure.
“In our experiments, we observed a dramatic increase of microglia in C57BL/6 mice following 4 weeks of cuprizone exposure, which is similar to previous reports [6].”
From Strain differences in cuprizone induced demyelination (2017) · cites this paper as [6]
In C57BL/6 mice, 0.2% cuprizone is optimal to induce full demyelination of the midline corpus callosum at week 5.
“In the C57BL/6 strain, initial studies indicated that a lower dose of 0.2% of cuprizone was optimal (23) to induce full demyelination of the midline corpus callosum at week 5.”
From SJL Mice Exposed to Cuprizone Intoxication Reveal Strain and Gender Pattern Differences in Demyelination (2009) · cites this paper as [23]

SJL mice die or are lethargic at 0.3% cuprizone, and higher doses of 0.4, 0.5 and 0.6% resulted in death within the first couple of weeks.
“Similar to C57BL/6 mice (23), SJL mice die or are lethargic at 0.3%, and higher doses of 0.4, 0.5 and 0.6% resulted in death within the first couple of weeks.”
From SJL Mice Exposed to Cuprizone Intoxication Reveal Strain and Gender Pattern Differences in Demyelination (2009) · cites this paper as [23]
SJL mice demyelinate partially at midline, whereas C57BL/6 mice show robust demyelination, particularly at week 5.
“We found SJL mice demyelinate partially at midline (Figure 2A), whereas C57BL/6 mice show robust demyelination, particularly at week 5 2, 23, 35.”
From SJL Mice Exposed to Cuprizone Intoxication Reveal Strain and Gender Pattern Differences in Demyelination (2009) · cites this paper as [23]
Unlike microglia and astrocytes in C57BL/6 mice that respond vigorously to demyelination, these cell types in SJL mice have a guarded response at midline and in the lateral region, which correlates with subdued demyelination.
“Thus, unlike microglia and astrocytes in C57BL/6 mice that respond vigorously to demyelination 2, 23, 39, these cell types in SJL mice have a guarded response at midline and in the lateral region, which correlates with subdued demyelination.”
From SJL Mice Exposed to Cuprizone Intoxication Reveal Strain and Gender Pattern Differences in Demyelination (2009) · cites this paper as [23]
In the cuprizone model, oligodendrocyte degeneration in the brain is followed by a robust microglial response consisting of activation, proliferation and clearance of myelin debris.
“In this model, oligodendrocyte degeneration in the brain is followed by a robust microglial response consisting of activation, proliferation and clearance of myelin debris [17].”
From TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis (2020) · cites this paper as [17]
Cuprizone administration triggers activation of microglia, the resident immune cells of the central nervous system.
“Cuprizone administration triggers activation of microglia, the resident immune cells of the central nervous system [7].”
From Multifaceted response of microglia in the cuprizone model of demyelination (2026) · cites this paper as [7]
In the cuprizone model, myelin destabilization and loss begin at 2-3 weeks of cuprizone administration and peak at week 4-5, and myelin levels stay low until at least week 12 with continuous cuprizone feeding.
“In this model, myelin destabilization and loss begin at 2–3 weeks of cuprizone administration and peaks at week 4–5 [42], myelin levels stay low until at least week 12 [55] with continuous cuprizone feeding.”
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 [42]
The first signs of oligodendrocyte death are seen 2 days after initiation of cuprizone treatment, which is several weeks earlier than the accumulation of other cell types at the site of injury.
“In fact, the first signs of oligodendrocyte death are seen 2 days after initiation of cuprizone treatment [100, 101], which is several weeks earlier than the accumulation of other cell types at the site of injury [42].”
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 [42]
The histopathological hallmark of the cuprizone model as standardized by Hiremath is oligodendrocyte death and subsequent demyelination in the corpus callosum, superior cerebellar peduncles, hippocampus, and several other areas of the mouse brain.
“The histopathological hallmark of the cuprizone model as standardized by Hiremath is oligodendrocyte death and subsequent demyelination in the corpus callosum, superior cerebellar peduncles, hippocampus [42, 46–54] and several other areas of the mouse brain (reviewed in [20]).”
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 [42]
Astrocyte reactivity is associated with increased activity of oxidative enzymes, which may contribute to ROS mediated toxicity.
“Astrocyte reactivity is associated with increased activity of oxidative enzymes (glutamate dehydrogenase, lactate dehydrogenase, NAD(P)H dehydrogenase, NADH dehydrogenase) [42, 178, 179] which may contribute to ROS mediated toxicity.”
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 [42]
By week 3 of cuprizone administration, there is a roughly twofold increase in astrocyte numbers, which is likely a critical modulator of inflammation given that the number of reactive astrocytes is concomitant with the severity of demyelination.
“By week 3 of cuprizone administration, there is a roughly twofold increase in astrocyte numbers [42, 54] (Fig. 1), which is likely a critical modulator of inflammation given that the number of reactive astrocytes is concomitant with the severity of demyelination [42, 48].”
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 [42]
Microglia expand their numbers into the peak of demyelination observed after 3-5 weeks on a cuprizone diet, though microglia numbers decline afterward despite continuing cuprizone diet.
“In addition to expressing markers indicative of their reactivity, microglia also expand their numbers into the peak of demyelination observed after 3–5 weeks on a cuprizone diet [42], though, for unknown reasons, microglia numbers decline afterward despite continuing cuprizone diet [55, 56] (Fig. 1B).”
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 [42]
0.2% (w/w) cuprizone was established to induce highly reproducible and extensive demyelination without detrimental systemic effects in 8-10 weeks old mice.
“Thus, 0.2% (w/w) cuprizone was established to induce highly reproducible and extensive demyelination without detrimental systemic effects in 8–10 weeks old mice.”
From Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned (2014) · cites this paper as Hiremath et al., 1998
Demyelination peaks between 4.5 and 5 weeks of cuprizone exposure in the corpus callosum and between 5 and 6 weeks in the cortex and hippocampus.
“Demyelination peaks between 4.5 and 5 weeks of cuprizone exposure in the CC and between 5 and 6 weeks in the cortex and hippocampus (Hiremath et al., 1998; Matsushima and Morell, 2001; Skripuletz et al., 2008; Gudi et al., 2009; Koutsoudaki et al., 2009).”
From Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned (2014) · cites this paper as Hiremath et al., 1998
In the acute cuprizone model, activated microglia appear already at the first 2 weeks even before demyelination can be detected by histology and immunohistochemistry.
“In the acute cuprizone model activated microglia appear already at the first 2 weeks even before demyelination can be detected by histology and immunohistochemistry (Hiremath et al., 1998) (Figure 2).”
From Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned (2014) · cites this paper as Hiremath et al., 1998
Astrocytes display signs of proliferation during the course of acute demyelination.
“Concomitantly, astrocytes display signs of proliferation during the course of acute demyelination (Hiremath et al., 1998; Gudi et al., 2009).”
From Glial response during cuprizone-induced de- and remyelination in the CNS: lessons learned (2014) · cites this paper as Hiremath et al., 1998

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Result
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Authors: Hiremath, M. M., Saito, Y., Knapp, G. W., Ting, J. P.-Y., Suzuki, K., & Matsushima, G. K.
Affiliations: University of North Carolina at Chapel Hill (US)
Corresponding author: Matsushima, G.K.
ORCID: Ting, J.P.-Y.
Suzuki, K.
Venue: Journal of Neuroimmunology
Publisher: Elsevier BV
Published: 1998-12
Volume: 92
Issue: 1-2
Pages: 38-49
ISSN: 0165-5728 (ISSN-L)
DOI: 10.1016/s0165-5728(98)00168-4
OpenAlex: W2007438030
Semantic Scholar: b9fc9c4e93a7cf3f82446bc83f828186cdd2e1c1
Cited by: 412
References: 46
Citations by year: 2026: 10 · 2025: 16 · 2024: 18 · 2023: 23 · 2022: 27 · 2021: 24 · 2020: 26 · 2019: 26 · 2018: 26 · 2017: 22 · 2016: 17 · 2015: 19 · 2014: 13 · 2013: 11 · 2012: 11
FWCI: 2.82
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Journal of Neuroimmunology (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of Neurological Disorders and Stroke (R01-NS-24453, NS34190, R29NS35372)
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords: cuprizone, demyelination, microglia, macrophages, astrocyte morphology, astrocyte activation, C57BL/6 mice, neuroinflammation, demyelinating disease model
MeSH terms: Animals, Astrocytes, Body Weight, Brain, Cell Count, Chelating Agents, Copper, Corpus Callosum, Cuprizone, Demyelinating Diseases, Dose-Response Relationship, Drug, Liver, Macrophages, Male, Mice, Inbred C57BL, Myelin Sheath, Time Factors, Microglia, Mice

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Microglial/macrophage accumulation during cuprizone-induced demyelination in C57BL/6 mice

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