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Cells Mar 2020Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. Various pre-clinical models with different specific features of... (Review)
Review
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. Various pre-clinical models with different specific features of the disease are available to study MS pathogenesis and to develop new therapeutic options. During the last decade, the model of toxic demyelination induced by cuprizone has become more and more popular, and it has contributed substantially to our understanding of distinct yet important aspects of the MS pathology. Here, we aim to provide a practical guide on how to use the cuprizone model and which pitfalls should be avoided.
Topics: Animals; Body Weight; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Gene Expression Regulation; Multiple Sclerosis
PubMed: 32244377
DOI: 10.3390/cells9040843 -
Pflugers Archiv : European Journal of... Dec 2022The cuprizone model is a widely used model to study the pathogenesis of multiple sclerosis (MS). Due to the selective loss of mature oligodendrocytes and myelin, it is...
The cuprizone model is a widely used model to study the pathogenesis of multiple sclerosis (MS). Due to the selective loss of mature oligodendrocytes and myelin, it is mainly being used to study demyelination and the mechanisms of remyelination, as well as the efficiency of compounds or therapeutics aiming at remyelination. Although early investigations using high dosages of cuprizone reported the occurrence of hydrocephalus, it has long been assumed that cuprizone feeding at lower dosages does not induce changes at the blood-brain barrier (BBB). Here, by analyzing BBB ultrastructure with high-resolution electron microscopy, we report changes at astrocytic endfeet surrounding vessels in the brain parenchyma. Particularly, edema formation around blood vessels and swollen astrocytic endfeet already occurred after feeding low dosages of cuprizone. These findings indicate changes in BBB function that will have an impact on the milieu of the central nervous system (CNS) in the cuprizone model and need to be considered when studying the mechanisms of de- and remyelination.
Topics: Animals; Mice; Cuprizone; Astrocytes; Demyelinating Diseases; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 36241864
DOI: 10.1007/s00424-022-02759-8 -
Journal of Molecular Neuroscience : MN Oct 2021White matter damage is a component of most human stroke and usually accounts for at least half of the lesion volume. Subcortical white matter stroke (WMS) accounts for... (Review)
Review
White matter damage is a component of most human stroke and usually accounts for at least half of the lesion volume. Subcortical white matter stroke (WMS) accounts for 25% of all strokes and causes severe motor and cognitive dysfunction. The adult brain has a very limited ability to repair white matter damage. Pathological analysis shows that demyelination or myelin loss is the main feature of white matter injury and plays an important role in long-term sensorimotor and cognitive dysfunction. This suggests that demyelination is a major therapeutic target for ischemic stroke injury. An acute inflammatory reaction is triggered by brain ischemia, which is accompanied by cytokine production. The production of cytokines is an important factor affecting demyelination and myelin regeneration. Different cytokines have different effects on myelin damage and myelin regeneration. Exploring the role of cytokines in demyelination and remyelination after stroke and the underlying molecular mechanisms of demyelination and myelin regeneration after ischemic injury is very important for the development of rehabilitation treatment strategies. This review focuses on recent findings on the effects of cytokines on myelin damage and remyelination as well as the progress of research on the role of cytokines in ischemic stroke prognosis to provide a new treatment approach for amelioration of white matter damage after stroke.
Topics: Animals; Chemokines; Demyelinating Diseases; Humans; Interleukins; Nerve Regeneration; Receptors, CXCR; Stroke
PubMed: 33970426
DOI: 10.1007/s12031-021-01851-5 -
Aging and Disease May 2024In the central nervous system (CNS), the myelin sheath ensures efficient interconnection between neurons and contributes to the regulation of the proper function of... (Review)
Review
In the central nervous system (CNS), the myelin sheath ensures efficient interconnection between neurons and contributes to the regulation of the proper function of neuronal networks. The maintenance of myelin and the well-organized subtle process of myelin plasticity requires cooperation among myelin-forming cells, glial cells, and neural networks. The process of cooperation is fragile, and the balance is highly susceptible to disruption by microenvironment influences. Reactive microglia play a critical and complicated role in the demyelination and remyelination process. Recent studies have shown that the voltage-gated proton channel Hv1 is selectively expressed in microglia in CNS, which regulates intracellular pH and is involved in the production of reactive oxygen species, underlying multifaceted roles in maintaining microglia function. This paper begins by examining the molecular mechanisms of demyelination and emphasizes the crucial role of the microenvironment in demyelination. It focuses specifically on the role of Hv1 in myelin repair and its therapeutic potential in CNS demyelinating diseases.
Topics: Humans; Microglia; Myelin Sheath; Animals; Demyelinating Diseases; Immunomodulation; Ion Channels; Remyelination; Reactive Oxygen Species
PubMed: 38029392
DOI: 10.14336/AD.2023.1107 -
Journal of Neuroinflammation Aug 2019The association of gut microbiota and diseases of the central nervous system (CNS), including multiple sclerosis (MS), has attracted much attention. Although a previous...
BACKGROUND
The association of gut microbiota and diseases of the central nervous system (CNS), including multiple sclerosis (MS), has attracted much attention. Although a previous analysis of MS gut microbiota revealed a reduction in species producing short-chain fatty acids (SCFAs), the influence of these metabolites on demyelination and remyelination, the critical factors of MS pathogenesis, remains unclear.
METHODS
To investigate the relationship between demyelination and gut microbiota, we administered a mixture of non-absorbing antibiotics or SCFAs to mice with cuprizone-induced demyelination and evaluated demyelination and the accumulation of microglia. To analyze the direct effect of SCFAs on demyelination or remyelination, we induced demyelination in an organotypic cerebellar slice culture using lysolecithin and analyzed the demyelination and maturation of oligodendrocyte precursor cells with or without SCFA treatment.
RESULTS
The oral administration of antibiotics significantly enhanced cuprizone-induced demyelination. The oral administration of butyrate significantly ameliorated demyelination, even though the accumulation of microglia into demyelinated lesions was not affected. Furthermore, we showed that butyrate treatment significantly suppressed lysolecithin-induced demyelination and enhanced remyelination in an organotypic slice culture in the presence or absence of microglia, suggesting that butyrate may affect oligodendrocytes directly. Butyrate treatment facilitated the differentiation of immature oligodendrocytes.
CONCLUSIONS
We revealed that treatment with butyrate suppressed demyelination and enhanced remyelination in an organotypic slice culture in association with facilitating oligodendrocyte differentiation. Our findings shed light on a novel mechanism of interaction between the metabolites of gut microbiota and the CNS and may provide a strategy to control demyelination and remyelination in MS.
Topics: Animals; Anti-Bacterial Agents; Butyrates; Cell Differentiation; Cuprizone; Demyelinating Diseases; Gastrointestinal Microbiome; Male; Mice; Mice, Inbred C57BL; Myelin Sheath; Oligodendroglia; Organ Culture Techniques; Remyelination
PubMed: 31399117
DOI: 10.1186/s12974-019-1552-y -
Neurology Dec 2018Chronic inflammatory demyelinating polyneuropathy (CIDP) is a form of chronic neuropathy that is presumably caused by heterogeneous immune-mediated processes. Recent... (Review)
Review
Chronic inflammatory demyelinating polyneuropathy (CIDP) is a form of chronic neuropathy that is presumably caused by heterogeneous immune-mediated processes. Recent advances in the search for autoantibodies against components expressed at nodal regions, such as the nodes of Ranvier and paranodes, have substantially contributed to clarifying the pathogenesis of CIDP in a subpopulation of patients. In particular, immunoglobulin G4 (IgG4) antibodies to paranodal junction proteins, including neurofascin-155 and contactin-1, have attracted the attention of researchers. Paranodal dissection resulting from the attachment of IgG4 at paranodal junctions and the absence of macrophage-induced demyelination are characteristic pathologic features in patients who have these antibodies. By contrast, the mechanisms of neuropathy in cases with classical macrophage-induced demyelination remain unclear despite the long-standing recognition of this process in CIDP. In addition to complement-dependent damage provoked by autoantibodies, recent studies have shed light on antibody-dependent phagocytosis by macrophages without participation of complements. However, a direct association between specific autoantibodies and macrophage-induced demyelination has not been reported. Electron microscopic examination of longitudinal sections of sural nerve biopsy specimens suggested that macrophages recognize specific sites of myelinated fibers as the initial target of demyelination. The site that macrophages select to initiate myelin breakdown is located around the nodal regions in some patients and internode in others. Hence, it seems that the components that distinguish between the nodal regions and internode play a pivotal role in the behavior of macrophages that initiate phagocytosis of myelin. Further studies are needed to elucidate the mechanisms underlying macrophage-induced demyelination from this perspective.
Topics: Axons; Demyelinating Diseases; Humans; Macrophages; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating
PubMed: 30429275
DOI: 10.1212/WNL.0000000000006625 -
Brain Pathology (Zurich, Switzerland) Sep 2018Damage to myelin is a key feature of multiple sclerosis (MS) pathology. Magnetic resonance imaging (MRI) has revolutionized our ability to detect and monitor MS... (Review)
Review
Damage to myelin is a key feature of multiple sclerosis (MS) pathology. Magnetic resonance imaging (MRI) has revolutionized our ability to detect and monitor MS pathology in vivo. Proton density, T and T can provide qualitative contrast weightings that yield superb in vivo visualization of central nervous system tissue and have proved invaluable as diagnostic and patient management tools in MS. However, standard clinical MR methods are not specific to the types of tissue damage they visualize, and they cannot detect subtle abnormalities in tissue that appears otherwise normal on conventional MRIs. Myelin water imaging is an MR method that provides in vivo measurement of myelin. Histological validation work in both human brain and spinal cord tissue demonstrates a strong correlation between myelin water and staining for myelin, validating myelin water as a marker for myelin. Myelin water varies throughout the brain and spinal cord in healthy controls, and shows good intra- and inter-site reproducibility. MS plaques show variably decreased myelin water fraction, with older lesions demonstrating the greatest myelin loss. Longitudinal study of myelin water can provide insights into the dynamics of demyelination and remyelination in plaques. Normal appearing brain and spinal cord tissues show reduced myelin water, an abnormality which becomes progressively more evident over a timescale of years. Diffusely abnormal white matter, which is evident in 20%-25% of MS patients, also shows reduced myelin water both in vivo and postmortem, and appears to originate from a primary lipid abnormality with relative preservation of myelin proteins. Active research is ongoing in the quest to refine our ability to image myelin and its perturbations in MS and other disorders of the myelin sheath.
Topics: Animals; Demyelinating Diseases; Humans; Magnetic Resonance Imaging; Myelin Sheath; Remyelination; Water
PubMed: 30375119
DOI: 10.1111/bpa.12645 -
Epilepsia Mar 2021Loss of myelin and altered oligodendrocyte distribution in the cerebral cortex are commonly observed both in postsurgical tissue derived from different focal epilepsies... (Review)
Review
Loss of myelin and altered oligodendrocyte distribution in the cerebral cortex are commonly observed both in postsurgical tissue derived from different focal epilepsies (such as focal cortical dysplasias and tuberous sclerosis) and in animal models of focal epilepsy. Moreover, seizures are a frequent symptom in demyelinating diseases, such as multiple sclerosis, and in animal models of demyelination and oligodendrocyte dysfunction. Finally, the excessive activity reported in demyelinated axons may promote hyperexcitability. We hypothesize that the extracellular potassium rise generated during epileptiform activity may be amplified by the presence of axons without appropriate myelin coating and by alterations in oligodendrocyte function. This process could facilitate the triggering of recurrent spontaneous seizures in areas of altered myelination and could result in further demyelination, thus promoting epileptogenesis.
Topics: Animals; Axons; Demyelinating Diseases; Epilepsy; Humans; Models, Biological; Myelin Sheath; Seizures
PubMed: 33493363
DOI: 10.1111/epi.16824 -
Continuum (Minneapolis, Minn.) Jun 2016This review summarizes a general approach to pediatric demyelination as well as specific features of each of the acquired demyelinating syndromes to help clinicians in... (Review)
Review
PURPOSE OF REVIEW
This review summarizes a general approach to pediatric demyelination as well as specific features of each of the acquired demyelinating syndromes to help clinicians in their evaluation of children with these disorders. Case studies are included to illustrate the expanding phenotype of many of these syndromes.
RECENT FINDINGS
With the creation of consensus definitions for the pediatric acquired demyelinating syndromes, recognition of demyelination in children has increased, as has understanding of the clinical and radiologic features, prognosis, and response to treatment. Collaborative studies and multicenter clinical trials are ongoing and needed to appropriately evaluate emerging therapies for some of the chronic demyelinating disorders, such as multiple sclerosis and neuromyelitis optica (NMO) spectrum disorder.
SUMMARY
This review will aid the clinician in identifying key features of the pediatric acquired demyelinating syndromes and highlights a general approach for the diagnosis and treatment of these disorders.
Topics: Child; Child, Preschool; Demyelinating Diseases; Encephalomyelitis, Acute Disseminated; Female; Humans; Male; Methylprednisolone; Multiple Sclerosis; Myelitis, Transverse; Neuromyelitis Optica
PubMed: 27261688
DOI: 10.1212/CON.0000000000000326 -
Multiple Sclerosis and Related Disorders Oct 2017Incidental white matter lesions (WML) are increasingly seen on brain magnetic resonance imaging (MRI) in clinical practice. Demyelination consistent with MS is seen in... (Review)
Review
BACKGROUND
Incidental white matter lesions (WML) are increasingly seen on brain magnetic resonance imaging (MRI) in clinical practice. Demyelination consistent with MS is seen in 0.1-0.7% of the population as evident by autopsy and MRI studies. The term radiologically isolated syndrome (RIS) was coined to define a subgroup of patients with demyelinating lesions highly suggestive of multiple sclerosis (MS). The Okuda criteria for diagnosing RIS help in stratifying the risk of conversion to MS but RIS is still not considered a distinct MS phenotype.
METHODS
The authors reviewed the current literature on diagnostic criteria, natural history and treatment indications in RIS, to assess the challenges faced in diagnosing and treating such patients in clinical practice.
RESULTS
Typically, one-third of patients convert to clinically definite MS within 5 years, with some progressing directly into primary progressive MS (PPMS). The main risk factors for conversion are: age < 37 years, male gender and presence of spinal cord lesions. Patients with RIS have evidence of early axonal loss, brain atrophy, cognitive deficits, increased anxiety and depression, and subclinical inflammatory disease.
CONCLUSION
Patients with RIS at high risk of clinical conversion might be considered for treatment, although this is still a controversial issue. Prospective follow-up of RIS patients by an MS specialist is recommended.
Topics: Brain; Demyelinating Diseases; Disease Progression; Humans; Spinal Cord
PubMed: 29055465
DOI: 10.1016/j.msard.2017.08.016