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Neuroscience and Biobehavioral Reviews Dec 2019The feeding of cuprizone (CPZ) to animals has been extensively used to model the processes of demyelination and remyelination, with many papers adopting a narrative... (Review)
Review
The feeding of cuprizone (CPZ) to animals has been extensively used to model the processes of demyelination and remyelination, with many papers adopting a narrative linked to demyelinating conditions like multiple sclerosis (MS), the aetiology of which is unknown. However, no current animal model faithfully replicates the myriad of symptoms seen in the clinical condition of MS. CPZ ingestion causes mitochondrial and endoplasmic reticulum stress and subsequent apoptosis of oligodendrocytes leads to central nervous system demyelination and glial cell activation. Although there are a wide variety of behavioural tests available for characterizing the functional deficits in animal models of disease, including that of CPZ-induced deficits, they have focused on a narrow subset of outcomes such as motor performance, cognition, and anxiety. The literature has not been systematically reviewed in relation to these or other symptoms associated with clinical MS. This paper reviews these tests and makes recommendations as to which are the most important in order to better understand the role of this model in examining aspects of demyelinating diseases like MS.
Topics: Animals; Behavior, Animal; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Myelin Sheath; Oligodendroglia
PubMed: 31442519
DOI: 10.1016/j.neubiorev.2019.08.008 -
Central Nervous System Agents in... Jan 2018Chronic demyelinating diseases of the central nervous system (CNS) are autoimmune conditions that, although rarely fatal, may lead to severe disability. Among these... (Review)
Review
BACKGROUND
Chronic demyelinating diseases of the central nervous system (CNS) are autoimmune conditions that, although rarely fatal, may lead to severe disability. Among these diseases, Multiple Sclerosis (MS) and neuromyelitis optica (NMO) are particularly important and subject of worldwide research. MS and NMO are chronic types of CNS disease, with recurrent episodes of demyelination. For many years, these two conditions were considered to be only one, but lately it is known that they have different epidemiological, physiopathological and prognostic characteristics. The present study aims at reviewing the specificities of MS and NMO affecting patients before they complete 18 years of age.
METHODS
Literature review on data about MS and NMO in patients below the age of 18 years.
RESULTS
There are no clinical trials for any drug used to treat MS and NMO in children or adolescents. Data are mainly on anedoctal cases, case series and recommendations from experts. At present, there is no evidence-based treatment to be recommended for patients with MS and NMO before the age of 18 years.
CONCLUSION
Despite being a particularly vulnerable population for severe disability in the future, there are no evidence-based guidelines for the treatment of MS and NMO in children and adolescents.
Topics: Age Factors; Autoantibodies; Child; Demyelinating Diseases; Humans; Multiple Sclerosis; Neuromyelitis Optica
PubMed: 26654228
DOI: 10.2174/1871524916666151210143548 -
International Journal of Molecular... Nov 2018Myelin sheaths on vertebrate axons provide protection, vital support and increase the speed of neuronal signals. Myelin degeneration can be caused by viral, autoimmune... (Review)
Review
Myelin sheaths on vertebrate axons provide protection, vital support and increase the speed of neuronal signals. Myelin degeneration can be caused by viral, autoimmune or genetic diseases. Remyelination is a natural process that restores the myelin sheath and, consequently, neuronal function after a demyelination event, preventing neurodegeneration and thereby neuron functional loss. Pharmacological approaches to remyelination represent a promising new frontier in the therapy of human demyelination pathologies and might provide novel tools to improve adaptive myelination in aged individuals. Recent phenotypical screens have identified agonists of the atypical G protein-coupled receptor Smoothened and inhibitors of the glioma-associated oncogene 1 as being amongst the most potent stimulators of oligodendrocyte precursor cell (OPC) differentiation in vitro and remyelination in the central nervous system (CNS) of mice. Here, we discuss the current state-of-the-art of studies on the role of Sonic Hedgehog reactivation during remyelination, referring readers to other reviews for the role of Hedgehog signaling in cancer and stem cell maintenance.
Topics: Animals; Central Nervous System; Cholesterol; Demyelinating Diseases; Humans; Recovery of Function; Signal Transduction; Smoothened Receptor
PubMed: 30463396
DOI: 10.3390/ijms19113677 -
Clinical and Experimental Nephrology Nov 2022Hyponatremia is one of the most common electrolyte abnormalities. Overcorrection of severe hyponatremia can result in serious neurological complications such as osmotic...
BACKGROUND
Hyponatremia is one of the most common electrolyte abnormalities. Overcorrection of severe hyponatremia can result in serious neurological complications such as osmotic demyelination syndrome, but the incidence and risk factors of overcorrection and osmotic demyelination have not been thoroughly investigated.
METHODS
This is a single-center retrospective cohort study of 50 patients admitted through the emergency department with initial serum sodium (serum Na) < 125 mEq/L between January 2015 and December 2017. Incidence and risk factors of overcorrection and osmotic demyelination were examined. Overcorrection was defined as an increase in serum sodium concentration > 10 mEq/L at 24 h and/or > 18 mEq/L at 48 h, respectively.
RESULTS
Six patients (12%) and one patient (2%) had overcorrection at 24 h and 48 h, respectively. A total of 5 (10%) patients had a brain MRI completed after overcorrection, and no patient showed radiologic evidence of osmotic demyelination. Symptomatic hyponatremia at presentation and 3% saline use were associated with the risk of overcorrection in univariable analysis (p < 0.001; p = 0.006, respectively).
CONCLUSIONS
Among patients admitted with severe hyponatremia, overcorrection occurred in 14%. Symptomatic hyponatremia at presentation and 3% saline use were associated with the risk of overcorrection.
Topics: Demyelinating Diseases; Electrolytes; Emergency Service, Hospital; Humans; Hyponatremia; Incidence; Retrospective Studies; Risk Factors; Sodium
PubMed: 35870090
DOI: 10.1007/s10157-022-02252-7 -
Neurochemistry International Jun 2019Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). In MS, a long disease duration is known to be a strong risk factor...
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). In MS, a long disease duration is known to be a strong risk factor for converting the clinical course of the disease from relapse remitting MS to secondary progressing MS. There is a hypothesis that long sustained demyelination may exhaust neurons, however, pathological changes induced in neurons following demyelination remain unknown. Cuprizone administration can induce and sustain demyelination in the mouse CNS. We examined pathological changes in mice following long sustained demyelination caused by up to 34-week cuprizone administration. Twelve-week cuprizone administration induced severe demyelination in the cerebral cortex, corpus callosum and deep cerebellar nuclei. Demyelination persisted up to 34 weeks, as shown by myelin basic protein immunohistochemistry. In contrast, cuprizone administration developed demyelination in the striatum by week 34. In these demyelinated regions, no neuronal loss was observed. However, in the striatum and deep cerebellar nuclei, cuprizone-induced demyelination changed the intracellular distribution of parvalbumin (PV). Furthermore, in the striatum, there was an increase in PV in the demyelinated axons and most PV immunoreactivity did not co-localize with SMI32 immunoreactivity in mice with 34-week cuprizone administration. Further, mice with 34-week cuprizone administration showed motor coordination dysfunction in the balance beam test. However, 12-week withdrawal from the cuprizone diet induced remyelination in the regions and motor coordination dysfunction recovered. These results indicate that 34-week cuprizone administration induces and sustains demyelination and results in reversible motor coordination dysfunction. The change of intracellular PV distribution suggests that PV may protect demyelinated axons by Ca buffering. This model may be useful to investigate pathological and behavioral changes following demyelination in the CNS.
Topics: Animals; Brain; Chelating Agents; Cuprizone; Demyelinating Diseases; Drug Administration Schedule; Female; Mice; Mice, Inbred C57BL; Time Factors
PubMed: 30940543
DOI: 10.1016/j.neuint.2019.03.018 -
Glia Jan 2024Damage of myelin is a component of many diseases in the central nervous system (CNS). The activation and maturation of the quiescent oligodendrocyte progenitor cells...
Damage of myelin is a component of many diseases in the central nervous system (CNS). The activation and maturation of the quiescent oligodendrocyte progenitor cells (OPCs) are the crucial cellular processes for CNS remyelination, which is influenced by neuroinflammation in the lesion microenvironment. Endothelial cells derived from human induced pluripotent stem cells (hiPSC-ECs) have shown promise in restoring function in various preclinical animal models. Here we ask whether and whether transplantation of hiPSC-ECs could benefit remyelination in a mouse model of CNS demyelination. Our results show that in vitro, hiPSC-ECs increase OPC proliferation, migration and differentiation via secreted soluble factors including brain-derived neurotrophic factor (BDNF). hiPSC-ECs also promote the survival of oligodendrocyte lineage cells in vitro and in vivo. Transplantation of hiPSC-ECs into a toxin-induced demyelination lesion in mouse corpus callosum (CC) leads to increased density of oligodendrocyte lineage cells and level of myelin in demyelinated area, correlated with a decreased neuroinflammation and an increased proportion of pro-regenerative M2 phenotype in microglia/macrophages. The hiPSC-EC-exposed oligodendrocyte lineage cells showed significant increase in the level of phosphorylated S6 ribosomal protein (pS6) both in vitro and in vivo, indicating an involvement of mTORC1 pathway. These results suggest that hiPSC-ECs may benefit myelin protection and regeneration which providing a potential source of cell therapy for a wide range of diseases and injuries associated with myelin damage.
Topics: Humans; Mice; Animals; Induced Pluripotent Stem Cells; Remyelination; Brain-Derived Neurotrophic Factor; Demyelinating Diseases; Endothelial Cells; Neuroinflammatory Diseases; Myelin Sheath; Central Nervous System; Oligodendroglia; Cell Differentiation; Mice, Inbred C57BL
PubMed: 37675625
DOI: 10.1002/glia.24466 -
Neurobiology of Disease Jan 2023Multiple sclerosis (MS) is the most common demyelinating disease that attacks the central nervous system. Dietary intake of cuprizone (CPZ) produces demyelination...
Multiple sclerosis (MS) is the most common demyelinating disease that attacks the central nervous system. Dietary intake of cuprizone (CPZ) produces demyelination resembling that of patients with MS. Given the role of the vagus nerve in gut-microbiota-brain axis in development of MS, we performed this study to investigate whether subdiaphragmatic vagotomy (SDV) affects demyelination in CPZ-treated mice. SDV significantly ameliorated demyelination and microglial activation in the brain compared with sham-operated CPZ-treated mice. Furthermore, 16S ribosomal RNA analysis revealed that SDV significantly improved the abnormal gut microbiota composition of CPZ-treated mice. An untargeted metabolomic analysis demonstrated that SDV significantly improved abnormal blood levels of metabolites in CPZ-treated mice compared with sham-operated CPZ-treated mice. Notably, there were correlations between demyelination or microglial activation in the brain and the relative abundance of several microbiome populations, suggesting a link between gut microbiota and the brain. There were also correlations between demyelination or microglial activation in the brain and blood levels of metabolites. Together, these data suggest that CPZ produces demyelination in the brain through the gut-microbiota-brain axis via the subdiaphragmatic vagus nerve.
Topics: Animals; Mice; Brain; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Mice, Inbred C57BL; Microbiota; Microglia; Multiple Sclerosis; Vagus Nerve
PubMed: 36493975
DOI: 10.1016/j.nbd.2022.105951 -
Scientific Reports Aug 2021Lysophosphatidylcholine (LPC)-induced demyelination is a versatile animal model that is frequently used to identify and examine molecular pathways of demyelination and...
Lysophosphatidylcholine (LPC)-induced demyelination is a versatile animal model that is frequently used to identify and examine molecular pathways of demyelination and remyelination in the central (CNS) and peripheral nervous system (PNS). However, identification of focally demyelinated lesion had been difficult and usually required tissue fixation, sectioning and histological analysis. Recently, a method for labeling and identification of demyelinated lesions in the CNS by intraperitoneal injection of neutral red (NR) dye was developed. However, it remained unknown whether NR can be used to label demyelinated lesions in PNS. In this study, we generated LPC-induced demyelination in sciatic nerve of mice, and demonstrated that the demyelinated lesions at the site of LPC injection were readily detectable at 7 days postlesion (dpl) by macroscopic observation of NR labeling. Moreover, NR staining gradually decreased from 7 to 21 dpl over the course of remyelination. Electron microscopy analysis of NR-labeled sciatic nerves at 7 dpl confirmed demyelination and myelin debris in lesions. Furthermore, fluorescence microscopy showed NR co-labeling with activated macrophages and Schwann cells in the PNS lesions. Together, NR labeling is a straightforward method that allows the macroscopic detection of demyelinated lesions in sciatic nerves after LPC injection.
Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Calcium-Binding Proteins; Coloring Agents; Demyelinating Diseases; Lysosomal-Associated Membrane Protein 2; Lysosomes; Macrophage Activation; Male; Mice, Inbred C57BL; Microfilament Proteins; Neutral Red; Receptors, Cell Surface; Schwann Cells; Sciatic Nerve; Mice
PubMed: 34413421
DOI: 10.1038/s41598-021-96395-4 -
Neurological Sciences : Official... Sep 2023
Topics: Humans; Demyelinating Diseases; Pyrimidines
PubMed: 37133687
DOI: 10.1007/s10072-023-06827-4 -
NMR in Biomedicine Apr 2015Conventional MRI is frequently used during the diagnosis of multiple sclerosis but provides only little additional pathological information. Proton MRS ((1) H-MRS),... (Comparative Study)
Comparative Study
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.
Topics: Animals; Aspartic Acid; Brain Chemistry; Choline; Creatine; Cuprizone; Demyelinating Diseases; Dipeptides; Disease Models, Animal; Female; Gliosis; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Neuroimaging; Oligodendroglia; Phosphocreatine; Proton Magnetic Resonance Spectroscopy
PubMed: 25802215
DOI: 10.1002/nbm.3277