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At least 19 recordsLinked to original sources
PubMed1975

The failure of supplemental dietary copper to prevent cuprizone-induced alterations in mouse hepatocytes.

Weaning mice were fed a powdered complete diet containing either 0.5% cuprizone, 0.5% cuprizone + 0.01% copper sulfate, or 0.01% copper sulfate. With cuprizone as the sole additive, hepatic mitochondria became greatly enlarged. When the diet contained cuprizone + copper sulfate, giant mitochondria were still present, and, in addition, numerous lysosome-like structures became evident. When only copper sulfate was added to the normal diet, the mitochondria were of normal size, but the hepatocytes contained abundant lysosomes. Dietary supplementation with cuprizone or with cuprizone + copper sulfate resulted in considerably depressed (20-50%) rates of mitochondrial oxidation. Supplementation solely with copper sulfate produced virtually no changes in oxidative activity. It may be concluded that the subcellular effects of cuprizone are not based on its ability to produce copper deficiency by chelation of copper, but on other properties of this drug.

Animal Nutritional Physiological Phenomena↗
PubMed1988

Cuprizone neurotoxicity in the rat: morphologic observations.

Weanling male Wistar rats fed a diet containing 0.5-2% cuprizone developed intramyelinic edema of the cerebellar white matter, hilum of the dentate nucleus and superior cerebellar peduncle. Oligodendrocytes in these regions showed hyperchromatic nuclei and abnormally dense cytoplasm, with an increase in the number of free ribosomes and enlargement of mitochondria. Unlike the lesions produced by cuprizone in weanling mice, those in the rat did not lead to demyelination. Cuprizone caused a distal peripheral axonopathy, with degeneration of myelinated axons in the sciatic nerve but preservation of the spinal nerve roots, dorsal root ganglia, posterior spinal funiculi and anterior horn cells. Unmyelinated fibers were largely spared. Some axonal regeneration occurred despite the continued administration of cuprizone. The intramyelinic edema and the nuclear and cytoplasmic abnormalities of the oligodendrocytes disappeared after the resumption of a normal diet.

Animals↗
PubMed1983

Biochemical changes in Cuprizone-induced spongiform encephalopathy. I. Changes in the activities of 2',3'-cyclic nucleotide 3'-phosphohydrolase, oligodendroglial ceramide galactosyl transferase, and the hydrolysis of the alkenyl group of alkenyl, acyl-glycerophospholipids by plasmalogenase in different regions of the brain.

Cuprizone (biscyclohexanone oxaldihydrazone) which is known to produce a status spongiosus and demyelination in the CNS was administered in the diet of weanling male mice at a concentration of 0.4% by weight for a period of six weeks before returning animals to a normal diet. Changes in body weight but not brain weight were reversible. Based on the decline in CNP'ase activity and the concentration of galactocerebroside, the loss of myelin was around 70% in those sections of the cerebrum with a high content of white matter while the cerebellum was less affected. The activity of oligodendroglial HFA-ceramide galactosyl transferase was also reduced. These biochemical parameters of myelination were increased after withdrawal of Cuprizone. Remyelination in the cerebrum but not the cerebellum was incomplete. The activity of plasmalogenase hydrolysing the alkenyl group of alkenyl, acyl-phospholipids increased 2-fold in those sections in which myelin loss was most severe. The increase preceded the greatest loss of myelin components (3 to 6 weeks on Cuprizone). The origin of the increased phospholipase activity in demyelinating tissue is discussed. Following myelination, there was a deficit in plasmalogenase activity particularly in the frontal cortex of the cerebrum, where the plasmalogen concentration was higher than in controls.

2',3'-Cyclic Nucleotide 3'-Phosphodiesterase↗
PubMed1987

Blood-brain barrier permeability during Cuprizone-induced demyelination. Implications for the pathogenesis of immune-mediated demyelinating diseases.

Blood vessels in the superior cerebellar peduncles were studied in Cuprizone-fed mice for leakage of proteins into the parenchyma. The status of the blood-brain barrier was determined at various stages of demyelination both by tracer methods using horseradish peroxidase and immunochemically using antisera to extravasated serum proteins and was compared to three positive and negative control conditions. The results showed no evidence of significant protein leakage into the subendothelial basement membrane or extravascular space in Cuprizone mice, during the development of demyelination. The apparent lack of damage to the blood-brain barrier found in Cuprizone animals as compared to the blood-brain barrier alterations previously reported for immune-mediated demyelinating diseases, confirms the theory that these alterations are not a non-specific association of any demyelinating process, but are of primary pathogenetic importance in immune-mediated demyelination.

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↗
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↗
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↗
PubMed1987

Blood-brain barrier permeability to horseradish peroxidase in twitcher and cuprizone-intoxicated mice.

The status of blood-brain barrier (BBB) permeability was investigated in the twitcher, an authentic murine model of globoid cell leukodystrophy (GLD, Krabbe disease) and cuprizone-intoxicated mice. Although extensive demyelination was noted in the CNS of both mice and additionally, macrophage infiltration was pronounced in the twitcher, BBB remained intact to horseradish peroxidase. Thus, the change of microenvironment caused by demyelination is not necessarily a responsible factor for increased BBB permeability in the inflammatory demyelinating conditions.

Animals↗