The Experts below are selected from a list of 3417 Experts worldwide ranked by ideXlab platform
Peter Ponsaerts - One of the best experts on this subject based on the ideXlab platform.
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longitudinal monitoring of metabolic alterations in Cuprizone mouse model of multiple sclerosis using 1h magnetic resonance spectroscopy
NeuroImage, 2015Co-Authors: Jasmien Orije, Jelle Praet, Caroline Guglielmetti, Peter Ponsaerts, Firat Kara, Annemie Van Der Linden, Marleen VerhoyeAbstract:Abstract Non-invasive measures of well-known pathological hallmarks of multiple sclerosis (MS) such as demyelination, inflammation and axonal injury would serve as useful markers to monitor disease progression and evaluate potential therapies. To this end, in vivo localized proton magnetic resonance spectroscopy (1H-MRS) provides a powerful means to monitor metabolic changes in the brain and may be sensitive to these pathological hallmarks. In our study, we used the Cuprizone mouse model to study pathological features of MS, such as inflammation, de- and remyelination, in a highly reproducible manner. C57BL/6J mice were challenged with a 0.2% Cuprizone diet for 6-weeks to induce demyelination, thereafter the mice were put on a Cuprizone free diet for another 6 weeks to induce spontaneous remyelination. We employed in vivo 1H-MRS to longitudinally monitor metabolic changes in the corpus callosum of Cuprizone-fed mice during the demyelination (weeks 4 and 6) and spontaneous remyelination (week 12) phases. The MRS spectra were quantified with LCModel and since the total creatine (tCr) levels did not change over time or between groups, metabolite concentrations were expressed as ratios relative to tCr. After 4 and 6 weeks of Cuprizone treatment a significant increase in taurine/tCr and a significant reduction in total N-acetylaspartate/tCr, total choline-containing compounds/tCr and glutamate/tCr could be observed compared to mice under normal diet. At week 12, when almost full remyelination was established, no statistically significant metabolic differences were present between the control and Cuprizone group. Our results suggest that these metabolic changes may represent sensitive markers for Cuprizone induced demyelination, axonal injury and inflammation. To the best of our knowledge, this is the first longitudinal in vivo 1H-MRS study that monitored biochemical changes in the corpus callosum of Cuprizone fed mice.
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Cuprizone‐induced demyelination and demyelination‐associated inflammation result in different proton magnetic resonance metabolite spectra
NMR in biomedicine, 2015Co-Authors: Jelle Praet, Caroline Guglielmetti, Zwi N Berneman, Jasmien Orije, Firat Kara, Marleen Verhoye, Eva Santermans, Jasmijn Daans, Niel Hens, Peter PonsaertsAbstract:Conventional MRI is frequently used during the diagnosis of multiple sclerosis but provides only little additional pathological information. Proton MRS (1H-MRS), however, provides biochemical information on the lesion pathology by visualization of a spectrum of metabolites. In this study we aimed to better understand the changes in metabolite concentrations following demyelination of the white matter. Therefore, we used the Cuprizone model, a well-established mouse model to mimic type III human multiple sclerosis demyelinating lesions. First, we identified CX3CL1/CX3CR1 signaling as a major regulator of microglial activity in the Cuprizone mouse model. Compared with control groups (heterozygous CX3CR1+/− C57BL/6 mice and wild type CX3CR1+/+ C57BL/6 mice), microgliosis, astrogliosis, oligodendrocyte cell death and demyelination were shown to be highly reduced or absent in CX3CR1−/− C57BL/6 mice. Second, we show that 1H-MRS metabolite spectra are different when comparing Cuprizone-treated CX3CR1−/− mice showing mild demyelination with Cuprizone-treated CX3CR1+/+ mice showing severe demyelination and demyelination-associated inflammation. Following Cuprizone treatment, CX3CR1+/+ mice show a decrease in the Glu, tCho and tNAA concentrations as well as an increased Tau concentration. In contrast, following Cuprizone treatment CX3CR1−/− mice only showed a decrease in tCho and tNAA concentrations. Therefore, 1H-MRS might possibly allow us to discriminate demyelination from demyelination-associated inflammation via changes in Tau and Glu concentration. In addition, the observed decrease in tCho concentration in Cuprizone-induced demyelinating lesions should be further explored as a possible diagnostic tool for the early identification of human MS type III lesions. Copyright © 2015 John Wiley & Sons, Ltd.
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Cuprizone‐induced demyelination and demyelination‐associated inflammation result in different proton magnetic resonance metabolite spectra
NMR in biomedicine, 2015Co-Authors: Jelle Praet, Caroline Guglielmetti, Zwi N Berneman, Jasmien Orije, Firat Kara, Marleen Verhoye, Eva Santermans, Jasmijn Daans, Niel Hens, Peter PonsaertsAbstract:Conventional MRI is frequently used during the diagnosis of multiple sclerosis but provides only little additional pathological information. Proton MRS ((1) H-MRS), however, provides biochemical information on the lesion pathology by visualization of a spectrum of metabolites. In this study we aimed to better understand the changes in metabolite concentrations following demyelination of the white matter. Therefore, we used the Cuprizone model, a well-established mouse model to mimic type III human multiple sclerosis demyelinating lesions. First, we identified CX3 CL1/CX3 CR1 signaling as a major regulator of microglial activity in the Cuprizone mouse model. Compared with control groups (heterozygous CX3 CR1(+/-) C57BL/6 mice and wild type CX3 CR1(+/+) C57BL/6 mice), microgliosis, astrogliosis, oligodendrocyte cell death and demyelination were shown to be highly reduced or absent in CX3 CR1(-/-) C57BL/6 mice. Second, we show that (1) H-MRS metabolite spectra are different when comparing Cuprizone-treated CX3 CR1(-/-) mice showing mild demyelination with Cuprizone-treated CX3 CR1(+/+) mice showing severe demyelination and demyelination-associated inflammation. Following Cuprizone treatment, CX3 CR1(+/+) mice show a decrease in the Glu, tCho and tNAA concentrations as well as an increased Tau concentration. In contrast, following Cuprizone treatment CX3 CR1(-/-) mice only showed a decrease in tCho and tNAA concentrations. Therefore, (1) H-MRS might possibly allow us to discriminate demyelination from demyelination-associated inflammation via changes in Tau and Glu concentration. In addition, the observed decrease in tCho concentration in Cuprizone-induced demyelinating lesions should be further explored as a possible diagnostic tool for the early identification of human MS type III lesions.
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cellular and molecular neuropathology of the Cuprizone mouse model clinical relevance for multiple sclerosis
Neuroscience & Biobehavioral Reviews, 2014Co-Authors: Jelle Praet, Caroline Guglielmetti, Zwi N Berneman, Annemarie Van Der Linden, Peter PonsaertsAbstract:The Cuprizone mouse model allows the investigation of the complex molecular mechanisms behind nonautoimmune-mediated demyelination and spontaneous remyelination. While it is generally accepted that oligodendrocytes are specifically vulnerable to Cuprizone intoxication due to their high metabolic demands, a comprehensive overview of the etiology of Cuprizone-induced pathology is still missing to date. In this review we extensively describe the physico-chemical mode of action of Cuprizone and discuss the molecular and enzymatic mechanisms by which Cuprizone induces metabolic stress, oligodendrocyte apoptosis, myelin degeneration and eventually axonal and neuronal pathology. In addition, we describe the dual effector function of the immune system which tightly controls demyelination by effective induction of oligodendrocyte apoptosis, but in contrast also paves the way for fast and efficient remyelination by the secretion of neurotrophic factors and the clearance of cellular and myelinic debris. Finally, we discuss the many clinical symptoms that can be observed following Cuprizone treatment, and how these strengthened the Cuprizone model as a useful tool to study human multiple sclerosis, schizophrenia and epilepsy.
Jelle Praet - One of the best experts on this subject based on the ideXlab platform.
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longitudinal monitoring of metabolic alterations in Cuprizone mouse model of multiple sclerosis using 1h magnetic resonance spectroscopy
NeuroImage, 2015Co-Authors: Jasmien Orije, Jelle Praet, Caroline Guglielmetti, Peter Ponsaerts, Firat Kara, Annemie Van Der Linden, Marleen VerhoyeAbstract:Abstract Non-invasive measures of well-known pathological hallmarks of multiple sclerosis (MS) such as demyelination, inflammation and axonal injury would serve as useful markers to monitor disease progression and evaluate potential therapies. To this end, in vivo localized proton magnetic resonance spectroscopy (1H-MRS) provides a powerful means to monitor metabolic changes in the brain and may be sensitive to these pathological hallmarks. In our study, we used the Cuprizone mouse model to study pathological features of MS, such as inflammation, de- and remyelination, in a highly reproducible manner. C57BL/6J mice were challenged with a 0.2% Cuprizone diet for 6-weeks to induce demyelination, thereafter the mice were put on a Cuprizone free diet for another 6 weeks to induce spontaneous remyelination. We employed in vivo 1H-MRS to longitudinally monitor metabolic changes in the corpus callosum of Cuprizone-fed mice during the demyelination (weeks 4 and 6) and spontaneous remyelination (week 12) phases. The MRS spectra were quantified with LCModel and since the total creatine (tCr) levels did not change over time or between groups, metabolite concentrations were expressed as ratios relative to tCr. After 4 and 6 weeks of Cuprizone treatment a significant increase in taurine/tCr and a significant reduction in total N-acetylaspartate/tCr, total choline-containing compounds/tCr and glutamate/tCr could be observed compared to mice under normal diet. At week 12, when almost full remyelination was established, no statistically significant metabolic differences were present between the control and Cuprizone group. Our results suggest that these metabolic changes may represent sensitive markers for Cuprizone induced demyelination, axonal injury and inflammation. To the best of our knowledge, this is the first longitudinal in vivo 1H-MRS study that monitored biochemical changes in the corpus callosum of Cuprizone fed mice.
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Cuprizone‐induced demyelination and demyelination‐associated inflammation result in different proton magnetic resonance metabolite spectra
NMR in biomedicine, 2015Co-Authors: Jelle Praet, Caroline Guglielmetti, Zwi N Berneman, Jasmien Orije, Firat Kara, Marleen Verhoye, Eva Santermans, Jasmijn Daans, Niel Hens, Peter PonsaertsAbstract:Conventional MRI is frequently used during the diagnosis of multiple sclerosis but provides only little additional pathological information. Proton MRS (1H-MRS), however, provides biochemical information on the lesion pathology by visualization of a spectrum of metabolites. In this study we aimed to better understand the changes in metabolite concentrations following demyelination of the white matter. Therefore, we used the Cuprizone model, a well-established mouse model to mimic type III human multiple sclerosis demyelinating lesions. First, we identified CX3CL1/CX3CR1 signaling as a major regulator of microglial activity in the Cuprizone mouse model. Compared with control groups (heterozygous CX3CR1+/− C57BL/6 mice and wild type CX3CR1+/+ C57BL/6 mice), microgliosis, astrogliosis, oligodendrocyte cell death and demyelination were shown to be highly reduced or absent in CX3CR1−/− C57BL/6 mice. Second, we show that 1H-MRS metabolite spectra are different when comparing Cuprizone-treated CX3CR1−/− mice showing mild demyelination with Cuprizone-treated CX3CR1+/+ mice showing severe demyelination and demyelination-associated inflammation. Following Cuprizone treatment, CX3CR1+/+ mice show a decrease in the Glu, tCho and tNAA concentrations as well as an increased Tau concentration. In contrast, following Cuprizone treatment CX3CR1−/− mice only showed a decrease in tCho and tNAA concentrations. Therefore, 1H-MRS might possibly allow us to discriminate demyelination from demyelination-associated inflammation via changes in Tau and Glu concentration. In addition, the observed decrease in tCho concentration in Cuprizone-induced demyelinating lesions should be further explored as a possible diagnostic tool for the early identification of human MS type III lesions. Copyright © 2015 John Wiley & Sons, Ltd.
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Cuprizone‐induced demyelination and demyelination‐associated inflammation result in different proton magnetic resonance metabolite spectra
NMR in biomedicine, 2015Co-Authors: Jelle Praet, Caroline Guglielmetti, Zwi N Berneman, Jasmien Orije, Firat Kara, Marleen Verhoye, Eva Santermans, Jasmijn Daans, Niel Hens, Peter PonsaertsAbstract:Conventional MRI is frequently used during the diagnosis of multiple sclerosis but provides only little additional pathological information. Proton MRS ((1) H-MRS), however, provides biochemical information on the lesion pathology by visualization of a spectrum of metabolites. In this study we aimed to better understand the changes in metabolite concentrations following demyelination of the white matter. Therefore, we used the Cuprizone model, a well-established mouse model to mimic type III human multiple sclerosis demyelinating lesions. First, we identified CX3 CL1/CX3 CR1 signaling as a major regulator of microglial activity in the Cuprizone mouse model. Compared with control groups (heterozygous CX3 CR1(+/-) C57BL/6 mice and wild type CX3 CR1(+/+) C57BL/6 mice), microgliosis, astrogliosis, oligodendrocyte cell death and demyelination were shown to be highly reduced or absent in CX3 CR1(-/-) C57BL/6 mice. Second, we show that (1) H-MRS metabolite spectra are different when comparing Cuprizone-treated CX3 CR1(-/-) mice showing mild demyelination with Cuprizone-treated CX3 CR1(+/+) mice showing severe demyelination and demyelination-associated inflammation. Following Cuprizone treatment, CX3 CR1(+/+) mice show a decrease in the Glu, tCho and tNAA concentrations as well as an increased Tau concentration. In contrast, following Cuprizone treatment CX3 CR1(-/-) mice only showed a decrease in tCho and tNAA concentrations. Therefore, (1) H-MRS might possibly allow us to discriminate demyelination from demyelination-associated inflammation via changes in Tau and Glu concentration. In addition, the observed decrease in tCho concentration in Cuprizone-induced demyelinating lesions should be further explored as a possible diagnostic tool for the early identification of human MS type III lesions.
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cellular and molecular neuropathology of the Cuprizone mouse model clinical relevance for multiple sclerosis
Neuroscience & Biobehavioral Reviews, 2014Co-Authors: Jelle Praet, Caroline Guglielmetti, Zwi N Berneman, Annemarie Van Der Linden, Peter PonsaertsAbstract:The Cuprizone mouse model allows the investigation of the complex molecular mechanisms behind nonautoimmune-mediated demyelination and spontaneous remyelination. While it is generally accepted that oligodendrocytes are specifically vulnerable to Cuprizone intoxication due to their high metabolic demands, a comprehensive overview of the etiology of Cuprizone-induced pathology is still missing to date. In this review we extensively describe the physico-chemical mode of action of Cuprizone and discuss the molecular and enzymatic mechanisms by which Cuprizone induces metabolic stress, oligodendrocyte apoptosis, myelin degeneration and eventually axonal and neuronal pathology. In addition, we describe the dual effector function of the immune system which tightly controls demyelination by effective induction of oligodendrocyte apoptosis, but in contrast also paves the way for fast and efficient remyelination by the secretion of neurotrophic factors and the clearance of cellular and myelinic debris. Finally, we discuss the many clinical symptoms that can be observed following Cuprizone treatment, and how these strengthened the Cuprizone model as a useful tool to study human multiple sclerosis, schizophrenia and epilepsy.
Martin Stangel - One of the best experts on this subject based on the ideXlab platform.
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Investigation of Cuprizone Inactivation by Temperature
Neurotoxicity Research, 2017Co-Authors: Sandra Heckers, Nadine Held, Jessica Kronenberg, André Bleich, Thomas Skripuletz, Viktoria Gudi, Martin StangelAbstract:Animal models, such as Cuprizone (bis-cyclohexanone oxaldihydrazone) feeding, are helpful to study experimental demyelination and remyelination in the context of diseases like multiple sclerosis. Cuprizone is a copper chelator, which when supplemented to the normal food of C57BL/6J mice in a concentration of 0.2% leads to oligodendroglial loss, subsequent microglia and astrocyte activation, resulting in demyelination. Termination of the Cuprizone diet results in remyelination, promoted by newly formed mature oligodendrocytes. The exact mode of Cuprizone’s action is not well understood, and information about its inactivation and cleavage are still not available. The knowledge of these processes could lead to a better understanding of Cuprizone’s mode of action, as well as a safer handling of this toxin. We therefore performed experiments with the aim to inactivate Cuprizone by thermal heating, since it was suggested in the past that Cuprizone is heat sensitive. C57BL/6J mice were fed for 4 weeks with 0.2% Cuprizone, either thermally pretreated (60, 80, 105, 121 °C) or not heated. In addition, primary rat oligodendrocytes, as a known selective toxic target of Cuprizone, were incubated with 350 μM Cuprizone solutions, which were either thermally pretreated or not. Our results demonstrate that none of the tested thermal pretreatment conditions could abrogate or restrict the toxic and demyelinating effects of Cuprizone, neither in vitro nor in vivo. In conclusion, the current study rebuts the hypothesis of Cuprizone as a heat-sensitive compound, as well as the assumption that heat exposure is a reason for an insufficient demyelination of Cuprizone-containing pellets.
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Cuprizone [Bis(Cyclohexylidenehydrazide)] is Selectively Toxic for Mature Oligodendrocytes
Neurotoxicity Research, 2013Co-Authors: Karelle Bénardais, Thomas Skripuletz, Viktoria Gudi, Paraskevi N. Koutsoudaki, Alexandra Kotsiari, Jelena Skuljec, Vikramjeet Singh, Franca Vulinović, Martin StangelAbstract:Cuprizone [bis(cyclohexylidenehydrazide)]-induced toxic demyelination is an experimental animal model commonly used to study de- and remyelination in the central nervous system. In this model, mice are fed with the copper chelator Cuprizone which leads to oligodendrocyte death with subsequent demyelination. The underlying mechanisms of Cuprizone-induced oligodendrocyte death are still unknown, and appropriate in vitro investigations to study these mechanisms are not available. Thus, we studied Cuprizone effects on rat primary glial cell cultures and on the neuroblastoma cell line SH-SY5Y. Treatment of cells with different concentrations of Cuprizone failed to show effects on the proliferation and survival of SH-SY5Y cells, microglia, astrocytes, and oligodendrocyte precursor cells (OPC). In contrast, differentiated mature oligodendrocytes (OL) were found to be significantly affected by Cuprizone treatment. This was accompanied by a reduced mitochondrial potential in Cuprizone-treated OL. These results demonstrate that the main toxic target for Cuprizone is mature OL, whilst other glial cells including OPC are not or only marginally affected. This explains the selective demyelination induced by Cuprizone in vivo.
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De- and remyelination in the CNS white and grey matter induced by Cuprizone: the old, the new, and the unexpected.
Histology and histopathology, 2011Co-Authors: Thomas Skripuletz, Viktoria Gudi, Diane. Hackstette, Martin StangelAbstract:The copper chelator Cuprizone (bis-cyclohexanone oxaldihydrazone) was established as a neurotoxin in rodents in 1966 by Carlton. During the following years the usefulness of Cuprizone feeding in mice to induce oligodendrocyte death with secondary demyelination of the superior cerebellar peduncles was described by Blakemore. In 1998 the Cuprizone model experienced a renaissance as the group of Matsushima described the effects of Cuprizone on the white matter of the cerebrum and focussed on demyelination in the corpus callosum, where the extent of demyelination could be scored more easily and consistently. Since then the toxic Cuprizone model has been widely used to study experimental de- and remyelination in the corpus callosum. Recently, we and others have extended these studies and have shown several new aspects characteristic for this model. Many lessons can be learned from these recent findings that have implications for the basic understanding of remyelination and the design of remyelinating and neuroprotective strategies in demyelinating diseases of the CNS. Although the model is often mentioned in the context of multiple sclerosis, it must always be kept in mind that this model has a fundamentally different induction of demyelination. We highlight the important findings delineated from this model and critically discuss both the advantages and the shortcomings of Cuprizone induced demyelination.
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regional differences between grey and white matter in Cuprizone induced demyelination
Brain Research, 2009Co-Authors: Viktoria Gudi, Thomas Skripuletz, Corinna Trebst, Paraskevi N. Koutsoudaki, Alexandra Kotsiari, Darius Moharreghkhiabani, Jelena Skuljec, Martin StangelAbstract:Cuprizone feeding is a commonly used model to study experimental de- and remyelination, with the corpus callosum being the most frequently investigated white matter tract. We have previously shown that demyelination is also extensive in the cerebral cortex in the Cuprizone model. In the current study, we have performed a detailed analysis of the dynamics of demyelination in the cortex in comparison to the corpus callosum. Prominent and almost complete demyelination in the corpus callosum was observed after 4.5-5 weeks of 0.2% Cuprizone feeding, whereas complete cortical demyelination was only observed after 6 weeks of Cuprizone feeding. Interestingly, remyelination in the corpus callosum occurred even before the termination of Cuprizone administration. Accumulation of microglia in the corpus callosum started as early as week 3 reaching its maximum at week 4.5 and was still significantly elevated at week 6 of Cuprizone treatment. Within the cortex only a few scattered activated microglial cells were found. Furthermore, the intensity of astrogliosis, accumulation of oligodendrocyte progenitor cells and nestin positive cells differed between the two areas investigated. The time course and dynamics of demyelination differ in the corpus callosum and in the cortex, suggesting different underlying pathomechanisms.
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Cerebellar cortical demyelination in the murine Cuprizone model.
Brain pathology (Zurich Switzerland), 2009Co-Authors: Thomas Skripuletz, Viktoria Gudi, Maren Lindner, Paraskevi N. Koutsoudaki, Jens-heiko Bussmann, Refik Pul, Darius Moharregh-khiabani, Martin StangelAbstract:In multiple sclerosis, demyelination occurs beside the white-matter structures and in the cerebral and cerebellar cortex. We have previously shown that, in the Cuprizone model, demyelination is present not only in the corpus callosum but also in the cerebral cortex. Here, we have performed a detailed analysis of the dynamics of de- and remyelination in the cerebellar cortex and white matter at nine timepoints in two cerebellar regions. To induce demyelination, C57BL/6 mice were fed with 0.2% Cuprizone for 12 weeks followed by a recovery of 8 weeks. Both cortex and white-matter structures were significantly demyelinated after 12 weeks of Cuprizone feeding. Remyelination occurred after withdrawal of Cuprizone but was less prominent in the more caudal cerebellar region. Microglia infiltration was prominent in all analyzed cerebellar areas, preceding demyelination by approximately 2-4 weeks, and was delayed in the more caudal cerebellar region. Astrogliosis was also seen but did not reach the extent observed in the cerebrum. In summary, Cuprizone feeding provides an excellent model for the investigation of de- and remyelination processes in the cerebellar cortex and white matter. Furthermore, demyelination, microglia and astrocyte changes were different in the cerebellum as compared with the cerebrum, indicating region-dependent pathomechanisms.
Markus Kipp - One of the best experts on this subject based on the ideXlab platform.
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Animal Weight Is an Important Variable for Reliable Cuprizone-Induced Demyelination.
Journal of molecular neuroscience : MN, 2019Co-Authors: Patrizia Leopold, Christoph Schmitz, Markus KippAbstract:An elegant model to study mechanisms operant during oligodendrocyte degeneration and subsequent demyelination is the Cuprizone model. In that model, mice are intoxicated with the copper chelation agent Cuprizone which results in early oligodendrocyte stress, oligodendrocyte apoptosis, and, finally, demyelination. Here, we systematically investigated to what extent the animals' weight at the beginning of the Cuprizone intoxication period is critical for the reproducibility of the Cuprizone-induced pathology. We can demonstrate that a negative correlation exists between the two variables "extent of Cuprizone-induced demyelination" and "starting weight." Demyelination and microglia activation were more severe in low weight compared to heavy weight mice. These findings are highly relevant for the experimental design using the Cuprizone model.
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Water-Soluble Cuprizone Derivative: Synthesis, Characterization, and in Vitro Studies
2019Co-Authors: Martin Fries, Cordian Beyer, Markus Kipp, Meike Mertens, Nico Teske, Thomas Willms, Arto Valkonen, Kari Rissanen, Markus Albrecht, Tim ClarnerAbstract:The Cuprizone mouse model is one of the most accepted model systems for the investigation of oligodendrocyte degeneration, a process critically involved in the pathogenesis of diseases such as multiple sclerosis or schizophrenia. In order to substitute the in vivo experiments by in vitro approaches, the amine derivative BiMPi is introduced as a water-soluble alternative to Cuprizone. Regarding superoxide dismutase activity, toxicity for oligodendrocytes, and disturbance of mitochondrial membrane potential, BiMPi shows similar in vitro effects as is observed in vivo for Cuprizone
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phosphatidylcholine 36 1 concentration decreases along with demyelination in the Cuprizone animal model and in post mortem multiple sclerosis brain tissue
Journal of Neurochemistry, 2018Co-Authors: Marcolivier Trepanier, Stella Nyamoya, Kayla D Hildebrand, Sandra Amor, Richard P Bazinet, Markus KippAbstract:: Multiple sclerosis is a demyelinating and inflammatory disease. Myelin is enriched in lipids, and more specifically, oleic acid. The goal of this study was to evaluate the concentration of oleic acid following demyelination and remyelination in the Cuprizone model, test if these changes occurred in specific lipid species, and whether differences in the Cuprizone model correlate with changes observed in post-mortem human brains. Eight-week-old C57Bl/6 mice were fed a 0.2% Cuprizone diet for 5 weeks and some animals allowed to recover for 11 days. Demyelination, inflammation, and lipid concentrations were measured in the corpus callosum. Standard fatty acid techniques and liquid chromatography combined with tandem mass spectrometry were performed to measure concentrations of fatty acids in total brain lipids and a panel of lipid species within the phosphatidylcholine (PC). Similar measurements were conducted in post-mortem brain tissues of multiple sclerosis patients and were compared to healthy controls. Five weeks of Cuprizone administration resulted in demyelination followed by significant remyelination after 11 days of recovery. Compared to control, oleic acid was decreased after 5 weeks of Cuprizone treatment and increased during the recovery phase. This decrease in oleic acid was associated with a specific decrease in the PC 36:1 pool. Similar results were observed in human post-mortem brains. Decreases in myelin content in the Cuprizone model were accompanied by decreases in oleic acid concentration and is associated with PC 36:1 suggesting that specific lipids could be a potential biomarker for myelin degeneration. The biological relevance of oleic acid for disease progression remains to be verified.
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phosphatidylcholine 36 1 concentration decreases along with demyelination in the Cuprizone animal model and in post mortem multiple sclerosis brain tissue
Journal of Neurochemistry, 2018Co-Authors: Marcolivier Trepanier, Stella Nyamoya, Kayla D Hildebrand, Sandra Amor, Richard P Bazinet, Markus KippAbstract:Multiple sclerosis is a demyelinating and inflammatory disease. Myelin is enriched in lipids, and more specifically, oleic acid. The goal of this study was to evaluate the concentration of oleic acid following demyelination and remyelination in the Cuprizone model, test if these changes occurred in specific lipid species, and whether differences in the Cuprizone model correlate with changes observed in post-mortem human brains. Eight-week-old C57Bl/6 mice were fed a 0.2% Cuprizone diet for 5 weeks and some animals allowed to recover for 11 days. Demyelination, inflammation, and lipid concentrations were measured in the corpus callosum. Standard fatty acid techniques and liquid chromatography combined with tandem mass spectrometry were performed to measure concentrations of fatty acids in total brain lipids and a panel of lipid species within the phosphatidylcholine (PC). Similar measurements were conducted in post-mortem brain tissues of multiple sclerosis patients and were compared to healthy controls. Five weeks of Cuprizone administration resulted in demyelination followed by significant remyelination after 11 days of recovery. Compared to control, oleic acid was decreased after 5 weeks of Cuprizone treatment and increased during the recovery phase. This decrease in oleic acid was associated with a specific decrease in the PC 36:1 pool. Similar results were observed in human post-mortem brains. Decreases in myelin content in the Cuprizone model were accompanied by decreases in oleic acid concentration and is associated with PC 36:1 suggesting that specific lipids could be a potential biomarker for myelin degeneration. The biological relevance of oleic acid for disease progression remains to be verified.
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Cuprizone-Containing Pellets Are Less Potent to Induce Consistent Demyelination in the Corpus Callosum of C57BL/6 Mice
Journal of Molecular Neuroscience, 2017Co-Authors: Tanja Hochstrasser, Gianna Lisa Exner, Stella Nyamoya, Christoph Schmitz, Markus KippAbstract:The chopper chelator Cuprizone serves as a valuable chemical tool to induce consistent and reproducible demyelination in the central nervous system. However, the daily preparation of fresh Cuprizone powder mixed in finely ground rodent chow might well be a particular health problem. Alternative methods, such as the fabrication of Cuprizone-containing pellets, are available. The effectiveness of this method is, however, not known. In the present study, we compared whether intoxication of C57BL/6 mice with 0.25% Cuprizone mixed into ground rodent chow does induce demyelination to a similar extent compared to a Cuprizone-pellet intoxication protocol. We found that feeding of 0.25% Cuprizone in ground chow provides a strong, well-defined, and reproducible demyelination along with increased accumulation of microglia and axonal damage in the corpus callosum, whereas all analyzed parameters were significantly less distinct in mice fed with Cuprizone-containing pellets at an equivalent concentration of Cuprizone at week 5. Even a higher concentration of Cuprizone in pellet formulation was less potent compared to do so. This study illustrates that the established protocol of Cuprizone intoxication (i.e., mixed in ground rodent chow) is the gold standard method to achieve consistent and reproducible demyelination. Why Cuprizone loses its effectiveness in pellet formulation needs to be addressed in subsequent studies.
Caroline Guglielmetti - One of the best experts on this subject based on the ideXlab platform.
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longitudinal monitoring of metabolic alterations in Cuprizone mouse model of multiple sclerosis using 1h magnetic resonance spectroscopy
NeuroImage, 2015Co-Authors: Jasmien Orije, Jelle Praet, Caroline Guglielmetti, Peter Ponsaerts, Firat Kara, Annemie Van Der Linden, Marleen VerhoyeAbstract:Abstract Non-invasive measures of well-known pathological hallmarks of multiple sclerosis (MS) such as demyelination, inflammation and axonal injury would serve as useful markers to monitor disease progression and evaluate potential therapies. To this end, in vivo localized proton magnetic resonance spectroscopy (1H-MRS) provides a powerful means to monitor metabolic changes in the brain and may be sensitive to these pathological hallmarks. In our study, we used the Cuprizone mouse model to study pathological features of MS, such as inflammation, de- and remyelination, in a highly reproducible manner. C57BL/6J mice were challenged with a 0.2% Cuprizone diet for 6-weeks to induce demyelination, thereafter the mice were put on a Cuprizone free diet for another 6 weeks to induce spontaneous remyelination. We employed in vivo 1H-MRS to longitudinally monitor metabolic changes in the corpus callosum of Cuprizone-fed mice during the demyelination (weeks 4 and 6) and spontaneous remyelination (week 12) phases. The MRS spectra were quantified with LCModel and since the total creatine (tCr) levels did not change over time or between groups, metabolite concentrations were expressed as ratios relative to tCr. After 4 and 6 weeks of Cuprizone treatment a significant increase in taurine/tCr and a significant reduction in total N-acetylaspartate/tCr, total choline-containing compounds/tCr and glutamate/tCr could be observed compared to mice under normal diet. At week 12, when almost full remyelination was established, no statistically significant metabolic differences were present between the control and Cuprizone group. Our results suggest that these metabolic changes may represent sensitive markers for Cuprizone induced demyelination, axonal injury and inflammation. To the best of our knowledge, this is the first longitudinal in vivo 1H-MRS study that monitored biochemical changes in the corpus callosum of Cuprizone fed mice.
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Cuprizone‐induced demyelination and demyelination‐associated inflammation result in different proton magnetic resonance metabolite spectra
NMR in biomedicine, 2015Co-Authors: Jelle Praet, Caroline Guglielmetti, Zwi N Berneman, Jasmien Orije, Firat Kara, Marleen Verhoye, Eva Santermans, Jasmijn Daans, Niel Hens, Peter PonsaertsAbstract:Conventional MRI is frequently used during the diagnosis of multiple sclerosis but provides only little additional pathological information. Proton MRS (1H-MRS), however, provides biochemical information on the lesion pathology by visualization of a spectrum of metabolites. In this study we aimed to better understand the changes in metabolite concentrations following demyelination of the white matter. Therefore, we used the Cuprizone model, a well-established mouse model to mimic type III human multiple sclerosis demyelinating lesions. First, we identified CX3CL1/CX3CR1 signaling as a major regulator of microglial activity in the Cuprizone mouse model. Compared with control groups (heterozygous CX3CR1+/− C57BL/6 mice and wild type CX3CR1+/+ C57BL/6 mice), microgliosis, astrogliosis, oligodendrocyte cell death and demyelination were shown to be highly reduced or absent in CX3CR1−/− C57BL/6 mice. Second, we show that 1H-MRS metabolite spectra are different when comparing Cuprizone-treated CX3CR1−/− mice showing mild demyelination with Cuprizone-treated CX3CR1+/+ mice showing severe demyelination and demyelination-associated inflammation. Following Cuprizone treatment, CX3CR1+/+ mice show a decrease in the Glu, tCho and tNAA concentrations as well as an increased Tau concentration. In contrast, following Cuprizone treatment CX3CR1−/− mice only showed a decrease in tCho and tNAA concentrations. Therefore, 1H-MRS might possibly allow us to discriminate demyelination from demyelination-associated inflammation via changes in Tau and Glu concentration. In addition, the observed decrease in tCho concentration in Cuprizone-induced demyelinating lesions should be further explored as a possible diagnostic tool for the early identification of human MS type III lesions. Copyright © 2015 John Wiley & Sons, Ltd.
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Cuprizone‐induced demyelination and demyelination‐associated inflammation result in different proton magnetic resonance metabolite spectra
NMR in biomedicine, 2015Co-Authors: Jelle Praet, Caroline Guglielmetti, Zwi N Berneman, Jasmien Orije, Firat Kara, Marleen Verhoye, Eva Santermans, Jasmijn Daans, Niel Hens, Peter PonsaertsAbstract:Conventional MRI is frequently used during the diagnosis of multiple sclerosis but provides only little additional pathological information. Proton MRS ((1) H-MRS), however, provides biochemical information on the lesion pathology by visualization of a spectrum of metabolites. In this study we aimed to better understand the changes in metabolite concentrations following demyelination of the white matter. Therefore, we used the Cuprizone model, a well-established mouse model to mimic type III human multiple sclerosis demyelinating lesions. First, we identified CX3 CL1/CX3 CR1 signaling as a major regulator of microglial activity in the Cuprizone mouse model. Compared with control groups (heterozygous CX3 CR1(+/-) C57BL/6 mice and wild type CX3 CR1(+/+) C57BL/6 mice), microgliosis, astrogliosis, oligodendrocyte cell death and demyelination were shown to be highly reduced or absent in CX3 CR1(-/-) C57BL/6 mice. Second, we show that (1) H-MRS metabolite spectra are different when comparing Cuprizone-treated CX3 CR1(-/-) mice showing mild demyelination with Cuprizone-treated CX3 CR1(+/+) mice showing severe demyelination and demyelination-associated inflammation. Following Cuprizone treatment, CX3 CR1(+/+) mice show a decrease in the Glu, tCho and tNAA concentrations as well as an increased Tau concentration. In contrast, following Cuprizone treatment CX3 CR1(-/-) mice only showed a decrease in tCho and tNAA concentrations. Therefore, (1) H-MRS might possibly allow us to discriminate demyelination from demyelination-associated inflammation via changes in Tau and Glu concentration. In addition, the observed decrease in tCho concentration in Cuprizone-induced demyelinating lesions should be further explored as a possible diagnostic tool for the early identification of human MS type III lesions.
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cellular and molecular neuropathology of the Cuprizone mouse model clinical relevance for multiple sclerosis
Neuroscience & Biobehavioral Reviews, 2014Co-Authors: Jelle Praet, Caroline Guglielmetti, Zwi N Berneman, Annemarie Van Der Linden, Peter PonsaertsAbstract:The Cuprizone mouse model allows the investigation of the complex molecular mechanisms behind nonautoimmune-mediated demyelination and spontaneous remyelination. While it is generally accepted that oligodendrocytes are specifically vulnerable to Cuprizone intoxication due to their high metabolic demands, a comprehensive overview of the etiology of Cuprizone-induced pathology is still missing to date. In this review we extensively describe the physico-chemical mode of action of Cuprizone and discuss the molecular and enzymatic mechanisms by which Cuprizone induces metabolic stress, oligodendrocyte apoptosis, myelin degeneration and eventually axonal and neuronal pathology. In addition, we describe the dual effector function of the immune system which tightly controls demyelination by effective induction of oligodendrocyte apoptosis, but in contrast also paves the way for fast and efficient remyelination by the secretion of neurotrophic factors and the clearance of cellular and myelinic debris. Finally, we discuss the many clinical symptoms that can be observed following Cuprizone treatment, and how these strengthened the Cuprizone model as a useful tool to study human multiple sclerosis, schizophrenia and epilepsy.
