Disease relevance of Cuprizone

• Here we used mice lacking tumor necrosis factor-alpha (TNF alpha) and its associated receptors to study a model of demyelination and remyelination in which these events could be carefully controlled using a toxin, cuprizone [1].
• Limiting the dose of cuprizone to 0.2% overcame significant mouse morbidity and weight loss seen with a 0.4% dose, but the distribution of cuprizone-induced demyelination was anatomically variable [2].
• In the present study, we used a murine model of cuprizone-induced demyelination to broaden the application of PBR as a marker of brain injury and to validate the relationship between PBR levels and glial cell types [3].
• Upon cuprizone treatment, mice developed a pronounced astrocytosis, with brain oedema and spongiosis characterised by vacuolisations of the neuropil predominantly in the white matter [4].
• Cuprizone-induced demyelination is a mouse model of multiple sclerosis (MS) as cuprizone-fed mice exhibit neuroinflammation and demyelination in the brain [5].

Psychiatry related information on Cuprizone

• Effects of commissural de- and remyelination on motor skill behaviour in the cuprizone mouse model of multiple sclerosis [6].

High impact information on Cuprizone

• The membrane potentials of giant mitochondria from cuprizone-fed mice were found to be independent of metabolic state [7].
• The membrane potentials and resistances of giant mitochondria from mice fed cuprizone have been studied [8].
• Moreover, these SOCS3-deficient mice were protected against cuprizone-induced oligodendrocyte loss relative to wild-type animals [9].
• In cuprizone-treated mice, high levels of both IGF-I mRNA and peptide were expressed by astrocytes in areas of myelin breakdown [10].
• To investigate insulin-like growth factor I (IGF-I) and IGF-I receptor gene expression during experimental demyelination and myelin regeneration, young mice were fed cuprizone (( bis(cyclohexanone) oxaldihydrazone )) [10].

Chemical compound and disease context of Cuprizone

• Cerebroside synthesis as a measure of the rate of remyelination following cuprizone-induced demyelination in brain [11].
• On the basis of these results the inhibition of adenylate cyclase produced by TET in brain homogenates in vitro would not appear to be involved in the development of nervous changes associated with acute TET toxicity, or in the production of progressive brain oedema caused by TET, HCP and cuprizone [12].

Biological context of Cuprizone

• When 8 week old C57BL/6 mice are fed 0.2% cuprizone in the diet, mature olidgodendroglia are specifically insulted (cannot fulfill the metabolic demand of support of vast amounts of myelin) and go through apoptosis [13].
• We therefore investigated histology and ultrastructure during the early oligodendrocyte differentiation phase of remyelination in mice given cuprizone and allowed to recover for 2 weeks [2].
• In addition, cuprizone treatment severely altered copper and zinc homeostasis in the central nervous system (CNS) as well as in all other tissues examined, with increasing metal ion concentrations particularly in the CNS [4].
• This upregulation is brain-specific, as p8 is not elevated in the liver, lung, kidney, spleen, and heart of cuprizone-treated mice [5].
• We also localized the cellular source of p8 during cuprizone treatment, and further found elevated expression during embryogenesis but not in normal adult brain [5].

Anatomical context of Cuprizone

• Demyelination was observed within the corpus callosum in both wild-type and IGF-1 tg mice 3 weeks after exposure to cuprizone [14].
• The demyelinating toxin cuprizone is used increasingly in mouse studies of central nervous system remyelination [2].
• Here, we describe the role of macrophage inflammatory protein-1alpha (MIP-1alpha) during cuprizone intoxication, a model where demyelination of the CNS features a large accumulation of microglia/macrophage without T cell involvement or blood-brain barrier disruption [15].
• The role of lateral diffusion in mitochondrial electron transport has been investigated by measuring the diffusion coefficients for lipid, cytochrome c, and cytochrome oxidase in membranes of giant mitoplasts from cuprizone-fed mice using the technique of fluorescence redistribution after photobleaching (FRAP) [16].
• In addition, MHC class II-bearing macrophages were observed in cuprizone-induced inflammatory and demyelinating brain lesions of CIITA KO mice [17].

Associations of Cuprizone with other chemical compounds

• To acquire new information on copper metabolism/homeostasis, we utilized cuprizone, a very sensitive and selective copper-chelating agent with well-known neurotoxic properties, as a relevant chemical model in mice [4].
• 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 [18].
• Soluble benzylamine oxidase (BzAO) from cell homogenates and the conditioned culture medium of porcine aortic smooth muscle cells was purified by anionic HPLC methods and characterized with regard to enzyme kinetics and inhibition by semicarbazide, phenelzine, cuprizone, diethyldithiocarbamate (DDC), and p-chloromercuriphenylsuphonate (PCMPS) [19].
• The effect of triethyltin (TET), triphenyltin (TPT), hexachlorophene (HCP) and cuprizone on adenosine cyclic 3',5'-monophosphate (cyclic AMP) production in rat brain was examined both in vitro and in vivo [12].
• Dietary supplementation with cuprizone or with cuprizone + copper sulfate resulted in considerably depressed (20-50%) rates of mitochondrial oxidation [20].

Gene context of Cuprizone

• Indeed, RNase protection assays revealed increased expression of several chemokine transcripts in both untreated and cuprizone-treated MIP-1alpha(-/-) mice [15].
• Finally we found that OPC-targeted Notch1 ablation in cuprizone-treated Plp-creER Notch1(lox/lox) transgenic mice yielded no significant differences in remyelination parameters between knock-out and control mice [21].
• Interferon-gamma protects against cuprizone-induced demyelination [22].
• Wild-type and FGF2 mice exhibited similar demyelination during chronic cuprizone treatment [23].
• Here we show that the FcRgamma/Fyn signaling cascade is critically involved in cuprizone-induced demyelination/remyelination, with no lymphocytic response [24].

Analytical, diagnostic and therapeutic context of Cuprizone

• The proliferation and origin remyelinating oligodendrocytes was studied by light and electron miscrosopic autoradiography in the superior cerebellar peduncles of mice demyelinated by Cuprizone [25].
• To discover whether increasing PDGF expression increases the number of OPCs following demyelination and whether this enhances the efficiency of remyelination, we induced demyelination in GFAP-PDGF-A transgenic mice by intraspinal injection of lysolecithin or dietary administration of cuprizone [26].
• This motor test thus expands the usability of the cuprizone model to a functional level and might also be applicable to other animal models of human CNS diseases associated with subtle motor deficits of central origin [6].
• Flow cytometry of brain cells isolated from cuprizone-treated mice revealed an increase in the percentage of Mac-1(+)/CD45(hi) peripheral macrophage [27].
• Patch clamp techniques were applied to outer mitochondrial membranes of giant mitochondria from mice kept on a cuprizone diet or to vesicles produced by fusing membranes derived from the outer membrane of Neurospora mitochondria [28].

References