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PubMed2006

Age increases axon loss associated with primary demyelination in cuprizone-induced demyelination in C57BL/6 mice.

Axon loss is recognised as a significant contributor to the progression of the disability associated with multiple sclerosis. Although evidence of axon damage is found in areas of chronic demyelination it is more frequently seen in association with acute demyelination. This study compares the incidence of axon degeneration associated with the areas undergoing demyelination in young adult (8-10 weeks) and aged (6-7 months) C57BL/6 mice in cuprizone intoxication; a widely used model of demyelination. The incidence of axon transection, as indicated by the presence of SMI 32 positive axonal spheroids, and evidence of axon loss in the medial corpus callosum, were significantly greater in aged mice, as was the magnitude of the macrophage and astrocyte response to demyelination. Aged C57BL/6 mice are thus more prone to axon degeneration in association with demyelination than young adult mice. A retrospective study indicated that the incidence of axon degeneration was much higher in C57BL/6 mice than in the Swiss albino mice used in the early cuprizone intoxication studies which were fed much higher doses of cuprizone. These results indicate both a genetic and age susceptibility to demyelination-associated axon transection.

Aging↗

PubMed2001

Cuprizone and piperonyl butoxide, proposed inhibitors of T-cell function, attenuate experimental allergic encephalomyelitis in SJL mice.

Multiple sclerosis (MS) and its animal model, experimental allergic encephalomyelitis (EAE), are autoimmune demyelinating diseases with autoreactive T-cells acting as important mediators of pathogenesis. Cuprizone, a copper chelator, and piperonyl butoxide (PBO), a pesticide synergist, are implicated to inhibit T-cell activation and function. The purpose of this study was to assess whether either of these agents would suppress PLP-peptide-induced EAE in the SJL mouse. Indeed, treatment with cuprizone beginning 1 week prior to disease induction, and PBO administration from days 1 to 9 of EAE, significantly attenuated EAE clinical severity. Furthermore, both agents decreased blood CD4+/CD8+ ratios, and reduced signs of chronic graft vs. host disease (GVHD) indicating attenuation of an immune T-cell response. These results suggest that cuprizone and PBO suppress EAE and use of these agents will provide insights into the mechanisms of T-cell mediated diseases.

Animals↗

PubMed2001

Cerebroside synthesis as a measure of the rate of remyelination following cuprizone-induced demyelination in brain.

We studied markers of myelin content and of the rate of myelination in brains of mice between 8 and 20 weeks of age. During the 12-week time-course, control animals showed slight increases in the content of oligodendroglial-specific cerebroside, as well as cholesterol (enriched in, but not specific to, myelin). In contrast, synthesis of these lipids, as assayed by in vivo incorporation of (3)H(2)O, was substantial, indicating turnover of 0.4% and 0.7% of total brain cerebroside and cholesterol, respectively, each day. We also studied mice exposed to a diet containing 0.2% of the copper chelator, cuprizone. After 6 weeks 20%, and by 12 weeks, over 30% of brain cerebroside was gone. Demyelination was accompanied by down-regulation of mRNA expression for enzymes controlling myelin lipid synthesis (ceramide galactosyl transferase for cerebroside; hydroxymethylglutaryl-CoA reductase for cholesterol), and for myelin basic protein. Synthesis of myelin lipids was also greatly depressed. The 20% cerebroside deficit consequent to 6 weeks of cuprizone exposure was restored 6 weeks after return to a control diet. During remyelination, expression of myelin-related mRNA species, as well as cerebroside and cholesterol synthesis were restored to normal. However, in contrast to the steady state metabolic turnover in the control situation, all the cerebroside and cholesterol made were accumulated. To the extent that accumulating cerebroside is targeted for eventual inclusion in myelin (discussed) the rate of its synthesis is proportional to remyelination. With our assay, in vivo rates of cerebroside synthesis can be determined for a time window of the order of hours. This offers greater temporal resolution and accuracy relative to classical methods assaying accumulation of myelin components at time intervals of several days. We propose this experimental design, and the reproducible cuprizone model, as appropriate for studies of how to promote remyelination.

Animals↗

PubMed2005

p75NTR independent oligodendrocyte death in cuprizone-induced demyelination in C57BL/6 mice.

Feeding C57Bl/6 J mice the copper chelator cuprizone leads to selective apoptosis of mature oligodendrocytes and concomitant demyelination predominantly in the corpus callosum. The process of oligodendrocyte apoptosis in this animal model for multiple sclerosis (MS) involves early microglial activation, but no infiltration of T-lymphocytes. Therefore, this model could mimic early stages of oligodendrocyte degeneration Affected oligodendrocytes express the common neurotrophin receptor, p75(NTR), a 'stress-receptor' which under certain circumstances can induce apoptosis. Only affected oligodendrocytes in MS lesions and MS animal models express this receptor. In order to study the significance of p75(NTR) in the fate of oligodendrocytes, we have exposed wild-type as well as p75(NTR)-knockout mice to a 0.2% (w/w) cuprizone diet and performed a comparative immunohistochemical analysis of the corpus callosum at various time points. Surprisingly, our results show that the absence of p75(NTR) did not alter cuprizone-induced oligodendrocyte death (and subsequent de- or remyelination). Apparently, intracellular apoptosis pathways in adult oligodendrocytes do not require p75(NTR) activated signal transduction in the absence of T-lymphocytes and T-lymphocyte derived cytokines.

Animals↗

PubMed1984

Membrane fusion in mitochondria. II. An ultrastructural interpretation of cristae-enriched megamitochondria induced by cuprizone.

Ultrastructure of megamitochondria in mouse hepatocytes induced by cuprizone was analyzed in the light of the fusion of inner mitochondrial membranes. Hepatic parenchymal cells of mice fed with a 0.5% cuprizone-diet for 7-8 days were characterized by megamitochondria with numerous cristae including disoriented, shorter ones than those of the control and those in vesicular configuration. After feeding the animals with cuprizone for 15-16 days, megamitochondria increased their sizes further and the number of cristae decreased drastically. Numbers of cristae based on a unit-mitochondrial area were 41.3 +/- 10.8 for the former type of cristae-enriched megamitochondria and 3.8 +/- 1.8 for the latter type of megamitochondria with the value of 23.9 +/- 6.2 for the control. Considering the content of cytochromes in megamitochondria previously reported, these results might suggest that the fusion and defusion of inner mitochondrial membrane take place along with the fusion of outer membranes during the megamitochondrial formation.

Animals↗

PubMed1975

Mechanism of the formation of megamitochondria induced by copper-chelating agents. II. Isolation and some properties of megamitochondria from the cuprizone-treated mouse liver.

Megamitochondria have been isolated from the liver of the cuprizone-fed mouse with the aid of bovine serum albumin. Phosphorylating capacities of megamitochondria, specified above, in terms of respiratory control ratios and ADP/O ratios have revealed that they are not uncoupled completely. Biochemical properties of megamitochondria which are related to the metabolism of copper have shown that copper-chelating action of cuprizone may not be directly related to the formation of megamitochondria in vivo. Namely, cytochrome contents, activities of cytochrome oxidase and monoamine oxidase and contents of copper of megamitochondria were unchanged compared with those of the control. However, contents of divalent metals such as Ca-++ and Mg-++, especially that of the former, in megamitochondria decreased significantly. It is suggested that cuprizone may alter Mg-++/Ca-++ ratios when it is administered in vivo, and that changes in the ratio might play a key role in the formation of megamitochondria.

Animals↗

PubMed1980

Induction of megamitochondria by cuprizone(biscyclohexanone oxaldihydrazone). Evidence for an inhibition of the mitochondrial division process.

1. Feeding weanling mice a diet containing 0.5% (w/w) cuprizone (biscyclohexanone oxaldihydrazone) induced megamitochondria of a different type of that previously described (Suzuki, K., Science 163, 81-82 (1969). 2. As in the normal controls, a single population of mitochondria with a narrow size distribution, was detected by analytical differential centrifugation of liver homogenates from mice fed a cuprizone-diet. However, their average S-value increased 2.4fold, i.e. from 11 500 S to 27 500 S. The marked increase in the mitochondrial size (megamitochondria) were also detected by morphometric analysis of hepatocytes and isolated mitochondrial fractions, and the 1.6fold increase in the average mitochondrial diameter (as determined by scanning electron microscopy) was as expected from the increase in the S-value. On the other hand, the relative volume density or volume fraction of the mitochondria was unchanged. 3. The megamitochondria revealed a normal content of respiratory chain pigments, normal specific respiratory rates with succinate and NADH-linked substrates as well as normal energy coupling. 4. Removal of cuprizone from the diet normalized the size distribution of mitochondria in hepatocytes. The transition followed first-order kinetics with a half-life of about 30 h. During the period dividing mitochondria were frequently observed, and the division process appeared to follow both a transverse-partition and an elongation-constriction mechanism.

Animals↗

PubMed2002

Peripheral macrophage recruitment in cuprizone-induced CNS demyelination despite an intact blood-brain barrier.

The contribution of peripheral macrophage was assessed in cuprizone intoxication, a model of demyelination and remyelination in which the blood-brain barrier remains intact. Flow cytometry of brain cells isolated from cuprizone-treated mice revealed an increase in the percentage of Mac-1(+)/CD45(hi) peripheral macrophage. To confirm these results in situ, C57BL/6 mice were lethally irradiated, transplanted with bone marrow from GFP-transgenic mice, and exposed to cuprizone. GFP(+) peripheral macrophages were seen in the CNS after 2 weeks of treatment, and infiltration continued through 6 weeks. While the peripheral macrophages were far outnumbered by the resident microglia, their recruitment across the blood-brain barrier alludes to a potentially important role.

Animals↗

PubMed1990

A characterization of cuprizone-induced giant mouse liver mitochondria.

Cuprizone affects the liver of treated mice in a random manner, causing no appreciable change in some cases and inducing the formation of megamitochondria with altered properties in others. Lack of a full appreciation of this variability may be at the origin of some discrepancies in published work dealing with the properties of cuprizone mouse liver mitochondria (CMLM). CMLM from fully affected livers were remarkably labile and difficult to isolate in a coupled state by homogenization and centrifugation techniques. The integral respiratory chain proteins of CMLM were functionally normal, with the exception of succinic dehydrogenase which showed considerable inhibition. Coupled morphological and functional analysis provided evidence that these properties were independent of CMLM size, a matter which had remained doubtful thus far and bears on the validity of literature reports.

Animals↗

PubMed1987

Decrease in oligodendrocyte carbonic anhydrase activity preceding myelin degeneration in cuprizone induced demyelination.

Both immunohistochemical and biochemical evidence is presented to show for the first time that carbonic anhydrase II (CA II) activity falls in the brain of mice in cuprizone (bis(cyclohexanone)oxalyldihydrazone) induced demyelination well before demyelination develops. This fall began during the first week, whereas the first signs of myelin degeneration induced by cuprizone did not appear until 3 weeks and demyelination in the superior cerebellar peduncle in the mouse took 6-8 weeks to develop. The findings suggest that oligodendrocyte CA II activity is essential either for the survival of oligodendrocytes or for the maintenance of central myelin.

Animals↗

PubMed2004

Remyelination assessment by MRI texture analysis in a cuprizone mouse model.

The purpose of this study was to perform serial texture analysis of brain MRI of cuprizone-treated mice for the assessment of regional demyelination and remyelination. Cuprizone-fed mice undergo a brain demyelination process. This process was followed over 56 days by MRI in the olfactory bulbs, cerebellum, putamen and brain stem. The texture of T2-weighted images has been analyzed at two levels: (1) with the average intensity as first order parameter and (2) with several higher order parameters for the best differentiation between myelinated (controls) and demyelinated brains. The most pertinent of these parameters, called horizontal gray level nonuniformity (HGLNU), has been selected by stepwise discriminant analysis. The time evolution of the average value of HGLNU not only confirmed the overall demyelination tendency followed by the average intensity, but also more precisely characterized a transitory remyelination on day 41 in the olfactory bulbs and cerebellum, in agreement with already published immunohistochemical destructive studies.

Animals↗

PubMed1975

Mechanism of the formation of megamitochondria induced by copper-chelating agents. I. On the formation process of megamitochondria in cuprizone-treated mouse liver.

Processes of the formation of cuprizone-induced megamitochondria in mouse liver have been studied in detail by electron microscopy. The earliest change observed was the presence of large intramitochondrial granules. The next stage was the formation of myelin figures by which mitochondria were apparently connected. The third stage was characterized by megamitochondria connected with each other by their outer membranes. Continuity of mitochondria were further examined by serial sections, and megamitochondria were proved to be connected to each other far more frequentlythan expected on one plane of section. A model for the mechanism of megamitochondrial formation is proposed based on electron microscopic evidences, involving the fusion of mitochondrial membranes. Possibility is also discussed that cuprizone-induced megamitochondria may fuse to one single branching mitochondrion.

Adrenal Glands↗

PubMed1978

Mechanism of the formation of megamitochondria by copper-chelating agents. IV. Role of fusion phenomenon in the cuprizone-induced megamitochondrial formation.

Megamitochondria were induced within 36-40 hours in mouse hepatocytes by injecting cuprizone into the peritoneal cavity. Induction of megamitochondria was dependent upon the amount and the time intervals of the injection of cuprizone: 200 mg of cuprizone/kg of body weight-injected every 12 hours or 400 mg of cuprizone/kg of body weight-injected every 24 hours. When the latter amount of the noxious reagent was administered to the animal every 12 hours, fatty changes of the liver was observed. Involvement of the fusion phenomenon in the mechanism of megamitochondrial formation is discussed in the light of turnover rates for various components of the mitochondrion.

Animals↗

PubMed1991

A comparison of spongiosis induced in the brain by hexachlorophene, cuprizone and triethyl tin in the Sprague-Dawley rat.

The effect of hexachlorophene (HCP; 2,2'-methylenebis(3,4,6-trichlorophenol), cuprizone (CPZ; bicyclohexone oxaldihydrazone) and triethyl tin (TET; triethyl tin sulphate) in producing vacuoles in the brain of the Sprague-Dawley rat has been quantified by image analysis of the extent of the spongy change in the white matter. The state of the astrocytes was assessed by immunocytochemical staining for glial fibrillary acidic protein (GFAP). HCP and TET caused a dose-related spongiosis, but cuprizone had no significant effect on the brain. With chronic HCP treatment, the spongiosis was accompanied by astrocyte hypertrophy and proliferation, and the extent of the gliotic reaction was related to the dose of HCP. The results demonstrate that HCP can produce and maintain astrocyte proliferation in the rat brain. Such an agent was required for use in an investigation of a putative tumour promoter in the rat.

Animals↗

PubMed1985

Differences in the in vivo effects of cuprizone on superoxide dismutase activity in rat liver cytosol and mitochondrial intermembrane space.

Through aerobic NBT2+ photoreduction in the absence or in the presence of 10(-4) M EDTA and through o-dianisidine photooxidation superoxide dismutase (SOD) activity was differentiated as enzymatic and nonenzymatic. SOD activity in cytosol and mitochondrial matrix was enzymatic, while 50% of the SOD activity in the intermembrane space was nonenzymatic. Cuprizone inhibited by 40% the cytosolic SOD activity and by more than 50% the nonenzymatic SOD activity in intermembrane space without, however, changing the enzymatic SOD activity in the latter fraction. Single copper injection increased enzymatic SOD activity: the cuprizone-inhibited cytosolic dismutase activity restored to normal and the unaltered dismutase activity in the intermembrane space exceeded that in the controls.

Animals↗

PubMed1982

Changes in the mitochondrial surface potential during cuprizone-induced formation of megamitochondria.

The formation of megamitochondria upon treatment of mice with cuprizone was studied in relation to the surface potential of mitochondria. The latter was monitored by binding of 8-anilino-1-naphthalene sulphonate to membranes, by kinetics of monoamine oxidase and by free-flow electrophoresis of the particles. It was found that the surface potential of megamitochondria was by about 20 mV less negative than that of normal mitochondria whereas no change of the surface potential upon cuprizone treatment was observed in microsomes. It is suggested that a partial neutralization of the negative surface charge of mitochondrial membranes may promote fusion or inhibit division of mitochondria, thus resulting in formation of giant structures.

Animals↗

PubMed1978

Central nervous system demyelination and remyelination in the mouse: an ultrastructural study of cuprizone toxicity.

Male weanling mice (Biobreeding Laboratories) exposed to the drug Cuprizone (biscyclohexanone, oxaldihydrazone) in the diet for periods of 6 weeks and longer, consistently showed almost complete demyelination of the superior cerebellar peduncle. The demyelination was primary and followed degeneration of oligodendrocytes and their processes, whereas axons remained intact. After formation of myelinic vacuoles and removal of myelin by macrophages and astrocytes, the axons became invested with astroglial processes. As part of the glial response to demyelination, numerous reactive or immature cells appeared, some of which were identified as being either astrocytic or oligodendrocytic in nature. Some mature oligodendrocytes survived. When allowed to recover on a normal diet, remyelination began within a week, and progressed until all axons were myelinated. The mechanism of remyelination appeared similar to the spiral wrapping mechanism seen in normal development. The myelinating cell in all cases was the mature oligodendrocyte. Sources for these oligodendrocytes include residual surviving oligodendrocytes, differentiation of immature forms, and possibly the perineuronal satellite cell. The sheaths eventually reached a thickness approximately half that of normal development, with a disturbed relationship between myelin thickness and axon diameter. A visual impression of shortened internodal length was obtained. It is concluded that the Cuprizone model is an excellent situation in which to study the cellular mechanisms of demyelination and remyelination.

Animals↗

PubMed1969

Giant hepatic mitochondria: production in mice fed with cuprizone.

Giant mitochondria in hepatocytes that have the average size of nuclei can be consistently produced in the liver of weanling mice by feeding them cuprizone (bis-cyclohexanone oxaldihydrazone). The simplicity of the procedure and the consistency of the results make the feeding of cuprizone a new and useful experimental tool for the study of mitochondrial metabolism.

Animals↗