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Experimental Neurology Sep 2016Remyelination is a major therapeutic goal in human myelin disorders, serving to restore function to demyelinated axons and providing neuroprotection. The target... (Review)
Review
Remyelination is a major therapeutic goal in human myelin disorders, serving to restore function to demyelinated axons and providing neuroprotection. The target disorders that might be amenable to the promotion of this repair process are diverse and increasing in number. They range primarily from those of genetic, inflammatory to toxic origin. In order to apply remyelinating strategies to these disorders, it is essential to know whether the myelin damage results from a primary attack on myelin or the oligodendrocyte or both, and whether indeed these lead to myelin breakdown and demyelination. In some disorders, myelin sheath abnormalities are prominent but demyelination does not occur. This review explores the range of human and animal disorders where myelin pathology exists and focusses on defining the myelin changes in each and their cause, to help define whether they are targets for myelin repair therapy.
Topics: Animals; Demyelinating Diseases; Humans; Myelin Sheath; Nerve Regeneration; Oligodendroglia
PubMed: 27068622
DOI: 10.1016/j.expneurol.2016.04.002 -
International Journal of Molecular... Mar 2019Osmotic demyelination syndrome (ODS) is a disorder of the central myelin that is often associated with a precipitous rise of serum sodium. Remarkably, while the myelin... (Review)
Review
Osmotic demyelination syndrome (ODS) is a disorder of the central myelin that is often associated with a precipitous rise of serum sodium. Remarkably, while the myelin and oligodendrocytes of specific brain areas degenerate during the disease, neighboring neurons and axons appear unspoiled, and neuroinflammation appears only once demyelination is well established. In addition to blood‒brain barrier breakdown and microglia activation, astrocyte death is among one of the earliest events during ODS pathology. This review will focus on various aspects of biochemical, molecular and cellular aspects of oligodendrocyte and astrocyte changes in ODS-susceptible brain regions, with an emphasis on the crosstalk between those two glial cells. Emerging evidence pointing to the initiating role of astrocytes in region-specific degeneration are discussed.
Topics: Animals; Astrocytes; Demyelinating Diseases; Humans; Oligodendroglia; Osmolar Concentration; Osmotic Pressure
PubMed: 30841618
DOI: 10.3390/ijms20051124 -
Current Opinion in Pharmacology Aug 2022Astrocytes are a group of glial cells that exhibit great morphological, transcriptional and functional diversity both in the resting brain and in response to injury. In... (Review)
Review
Astrocytes are a group of glial cells that exhibit great morphological, transcriptional and functional diversity both in the resting brain and in response to injury. In recent years, astrocytes have attracted increasing interest as therapeutic targets for demyelinating diseases. Following a demyelinating insult, astrocytes can adopt a wide spectrum of reactive states, which can exacerbate damage, but may also facilitate oligodendrocyte progenitor cell differentiation and myelin regeneration. In this review, we provide an overview of recent literature on astrocyte-oligodendrocyte interactions in the context of demyelinating diseases. We highlight novel key roles for astrocytes both during demyelination and remyelination with a focus on potential therapeutic strategies to favor a pro-regenerative astrocyte response in (progressive) multiple sclerosis.
Topics: Astrocytes; Demyelinating Diseases; Humans; Myelin Sheath; Oligodendroglia; Remyelination
PubMed: 35809402
DOI: 10.1016/j.coph.2022.102261 -
Journal of Neuroinflammation Jun 2020Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterized by inflammatory and neurodegenerative processes. Despite...
BACKGROUND
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterized by inflammatory and neurodegenerative processes. Despite demyelination being a hallmark of the disease, how it relates to neurodegeneration has still not been completely unraveled, and research is still ongoing into how these processes can be tracked non-invasively. Magnetic resonance imaging (MRI) derived brain network characteristics, which closely mirror disease processes and relate to functional impairment, recently became important variables for characterizing immune-mediated neurodegeneration; however, their histopathological basis remains unclear.
METHODS
In order to determine the MRI-derived correlates of myelin dynamics and to test if brain network characteristics derived from diffusion tensor imaging reflect microstructural tissue reorganization, we took advantage of the cuprizone model of general demyelination in mice and performed longitudinal histological and imaging analyses with behavioral tests. By introducing cuprizone into the diet, we induced targeted and consistent demyelination of oligodendrocytes, over a period of 5 weeks. Subsequent myelin synthesis was enabled by reintroduction of normal food.
RESULTS
Using specific immune-histological markers, we demonstrated that 2 weeks of cuprizone diet induced a 52% reduction of myelin content in the corpus callosum (CC) and a 35% reduction in the neocortex. An extended cuprizone diet increased myelin loss in the CC, while remyelination commenced in the neocortex. These histologically determined dynamics were reflected by MRI measurements from diffusion tensor imaging. Demyelination was associated with decreased fractional anisotropy (FA) values and increased modularity and clustering at the network level. MRI-derived modularization of the brain network and FA reduction in key anatomical regions, including the hippocampus, thalamus, and analyzed cortical areas, were closely related to impaired memory function and anxiety-like behavior.
CONCLUSION
Network-specific remyelination, shown by histology and MRI metrics, determined amelioration of functional performance and neuropsychiatric symptoms. Taken together, we illustrate the histological basis for the MRI-driven network responses to demyelination, where increased modularity leads to evolving damage and abnormal behavior in MS. Quantitative information about in vivo myelination processes is mirrored by diffusion-based imaging of microstructural integrity and network characteristics.
Topics: Animals; Brain; Chelating Agents; Cuprizone; Demyelinating Diseases; Diffusion Tensor Imaging; Female; Mice; Mice, Inbred C57BL; Myelin Sheath; Nerve Net; Remyelination
PubMed: 32532336
DOI: 10.1186/s12974-020-01827-z -
Current Neuropharmacology 2019Demyelinating diseases of the central nervous system (CNS) comprise a group of neurological disorders characterized by progressive (and eventually irreversible) loss of... (Review)
Review
INTRODUCTION
Demyelinating diseases of the central nervous system (CNS) comprise a group of neurological disorders characterized by progressive (and eventually irreversible) loss of oligodendrocytes and myelin sheaths in the white matter tracts. Some of myelin disorders include: Multiple sclerosis, Guillain-Barré syndrome, peripheral nerve polyneuropathy and others. To date, the etiology of these disorders is not well known and no effective treatments are currently available against them. Therefore, further research is needed to gain a better understand and treat these patients. To accomplish this goal, it is necessary to have appropriate animal models that closely resemble the pathophysiology and clinical signs of these diseases. Herein, we describe the model of toxic demyelination induced by cuprizone (CPZ), a copper chelator that reduces the cytochrome and monoamine oxidase activity into the brain, produces mitochondrial stress and triggers the local immune response. These biochemical and cellular responses ultimately result in selective loss of oligodendrocytes and microglia accumulation, which conveys to extensive areas of demyelination and gliosis in corpus callosum, superior cerebellar peduncles and cerebral cortex. Remarkably, some aspects of the histological pattern induced by CPZ are similar to those found in multiple sclerosis. CPZ exposure provokes behavioral changes, impairs motor skills and affects mood as that observed in several demyelinating diseases. Upon CPZ removal, the pathological and histological changes gradually revert. Therefore, some authors have postulated that the CPZ model allows to partially mimic the disease relapses observed in some demyelinating diseases.
CONCLUSION
for five decades, the model of CPZ-induced demyelination is a good experimental approach to study demyelinating diseases that has maintained its validity, and is a suitable pharmacological model for reproducing some key features of demyelinating diseases, including multiple sclerosis.
Topics: Animals; Brain; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Oligodendroglia; Reproducibility of Results
PubMed: 28714395
DOI: 10.2174/1570159X15666170717120343 -
Neurotherapeutics : the Journal of the... Jul 2023Recent evidence suggests that the glucagon-like peptide-1 receptor (GLP-1R) agonists have neuroprotective activities in the CNS in animal models of Parkinson's disease,...
Recent evidence suggests that the glucagon-like peptide-1 receptor (GLP-1R) agonists have neuroprotective activities in the CNS in animal models of Parkinson's disease, Alzheimer's disease, and multiple sclerosis (MS). This study aimed to investigate whether a novel long-acting GLP-1R agonist, NLY01, could limit demyelination or improve remyelination as occurs in MS using the cuprizone (CPZ) mouse model. Herein, we assessed the expression of GLP-1R on oligodendrocytes in vitro and found that mature oligodendrocytes (Olig2PDGFRa) express GLP-1R. We further confirmed this observation in the brain by immunohistochemistry and found that Olig2CC1 cells express GLP-1R. We next administered NLY01 twice per week to C57B6 mice while on CPZ chow diet and found that NLY01 significantly reduced demyelination with greater weight loss than vehicle-treated controls. Because GLP-1R agonists are known to have anorexigenic effect, we then administered CPZ by oral gavage and treated the mice with NLY01 or vehicle to ensure the dose consistency of CPZ ingestion among mice. Using this modified approach, NLY01 was no longer effective in reducing demyelination of the corpus callosum (CC). We next sought to examine the effects of NLY01 treatment on remyelination after CPZ intoxication and during the recovery period using an adoptive transfer-CPZ (AT-CPZ) model. We found no significant differences between the NLY01 and vehicle groups in the amount of myelin or the number of mature oligodendrocytes in the CC. In summary, despite the promising anti-inflammatory and neuroprotective effects of GLP-1R agonists that have been previously described, our experiments provided no evidence to support a beneficial effect of NLY01 on limiting demyelination or enhancing remyelination. This information may be useful in selecting proper outcome measures in clinical trials of this promising class of drugs in MS.
Topics: Mice; Animals; Cuprizone; Glucagon-Like Peptide-1 Receptor; Demyelinating Diseases; Remyelination; Myelin Sheath; Multiple Sclerosis; Disease Models, Animal; Mice, Inbred C57BL
PubMed: 37296356
DOI: 10.1007/s13311-023-01390-4 -
Current Opinion in Pharmacology Oct 2022Amino acids and their derivatives function as building blocks as well as signaling molecules to modulate various cellular processes in living organisms. In mice, amino... (Review)
Review
Amino acids and their derivatives function as building blocks as well as signaling molecules to modulate various cellular processes in living organisms. In mice, amino acids accumulate in demyelinated lesions and return to basal levels during remyelination. Studies have found that amino acids and their metabolites modulate immune activity in the central nervous system (CNS) and influence oligodendrocyte differentiation and remyelination efficiency. In this review, we discuss current studies on amino acid metabolism in the context of CNS remyelination. By understanding the mechanisms of amino acid signaling and metabolism in demyelinated lesions, we may deepen our understanding of compartmentalized CNS inflammation in demyelinating disease like multiple sclerosis (MS) and provide evidence to develop novel pharmacological therapies targeting amino acid metabolism to prevent disease worsening.
Topics: Amino Acids; Animals; Central Nervous System; Demyelinating Diseases; Mice; Microglia; Multiple Sclerosis; Oligodendroglia; Remyelination
PubMed: 36067684
DOI: 10.1016/j.coph.2022.102287 -
Neuropharmacology Nov 2016White matter disease afflicts both developing and mature central nervous systems. Both cell intrinsic and extrinsic dysregulation result in profound changes in cell... (Review)
Review
White matter disease afflicts both developing and mature central nervous systems. Both cell intrinsic and extrinsic dysregulation result in profound changes in cell survival, axonal metabolism and functional performance. Experimental models of developmental white matter (WM) injury and demyelination have not only delineated mechanisms of signaling and inflammation, but have also paved the way for the discovery of pharmacological approaches to intervention. These reagents have been shown to enhance protection of the mature oligodendrocyte cell, accelerate progenitor cell recruitment and/or differentiation, or attenuate pathological stimuli arising from the inflammatory response to injury. Here we highlight reports of studies in the CNS in which compounds, namely peptides, hormones, and small molecule agonists/antagonists, have been used in experimental animal models of demyelination and neonatal brain injury that affect aspects of excitotoxicity, oligodendrocyte development and survival, and progenitor cell function, and which have been demonstrated to attenuate damage and improve WM protection in experimental models of injury. The molecular targets of these agents include growth factor and neurotransmitter receptors, morphogens and their signaling components, nuclear receptors, as well as the processes of iron transport and actin binding. By surveying the current evidence in non-immune targets of both the immature and mature WM, we aim to better understand pharmacological approaches modulating endogenous oligodendroglia that show potential for success in the contexts of developmental and adult WM pathology. This article is part of the Special Issue entitled 'Oligodendrocytes in Health and Disease'.
Topics: Animals; Anti-Inflammatory Agents; Brain Injuries; Cell Differentiation; Demyelinating Diseases; Disease Models, Animal; Humans; Nerve Regeneration; White Matter
PubMed: 26116759
DOI: 10.1016/j.neuropharm.2015.06.008 -
Neurochemistry International Mar 2023Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system characterized by remyelination failure, axonal degeneration, and...
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system characterized by remyelination failure, axonal degeneration, and progressive worsening of motor functions. Animal models of demyelination are frequently used to develop and evaluate therapies for MS. We recently reported that focal internal capsule (IC) demyelination in mice with lysophosphatidylcholine injection induced acute motor deficits followed by recovery through remyelination. However, it remains unknown whether the IC demyelination mouse model can be used to evaluate changes in motor functions caused by pharmacological treatments that promote remyelination using behavioral testing and histological analysis. In this study, we examined the effect of clemastine, an anti-muscarinic drug that promotes remyelination, in the mouse IC demyelination model. Clemastine administration improved motor function and changed forepaw preference in the IC demyelinated mice. Moreover, clemastine-treated mice showed increased mature oligodendrocyte density, reduced axonal injury, an increased number of myelinated axons and thicker myelin in the IC lesions compared with control (PBS-treated) mice. These results suggest that the lysophosphatidylcholine-induced IC demyelination model is useful for evaluating changes in motor functions following pharmacological treatments that promote remyelination.
Topics: Mice; Animals; Remyelination; Demyelinating Diseases; Lysophosphatidylcholines; Clemastine; Internal Capsule; Myelin Sheath; Multiple Sclerosis; Oligodendroglia; Mice, Inbred C57BL; Disease Models, Animal; Cuprizone
PubMed: 36754122
DOI: 10.1016/j.neuint.2023.105505 -
Tidsskrift For Den Norske Laegeforening... Feb 2017BACKGROUND Mitochondria play an important role in the pathogenesis of various neurodegenerative disorders, including Parkinson's disease. Neurodegenerative changes occur... (Review)
Review
BACKGROUND Mitochondria play an important role in the pathogenesis of various neurodegenerative disorders, including Parkinson's disease. Neurodegenerative changes occur early in the course of multiple sclerosis (MS). This article aims to present information on a possible association between mitochondrial dysfunction and multiple sclerosis.MATERIAL AND METHOD The article is based on original and review articles selected following a literature search in PubMed, restricted to articles written in English, and concluded in May 2016. The literature search resulted in a total of 2276 articles. After a discretionary evaluation by the authors, 71 articles were read in full. Of these, 19 were used as references. In addition, we included 15 articles from reference lists and seven from the authors' own literature archive.RESULTS Mitochondrial changes have been demonstrated in affected areas of the brains of patients with MS. Although some of the changes may be attributed to mitochondrial damage that is secondary to inflammation, others may be compensatory due to the increased energy demands of demyelinated axons. The type of mitochondrial damage varies and is dependent on the pathology that triggers it.INTERPRETATION Mitochondrial damage secondary to inflammation, combined with increased energy demands secondary to demyelination, may result in a chronic energy deficiency in the central nervous system. This in turn may lead to neurodegeneration. Improved knowledge of the role of mitochondria in MS, both secondary to inflammation and possibly as a direct contributor to neurodegeneration, may provide a better understanding of the pathogenesis of the disease and perhaps contribute to new treatment options.
Topics: Demyelinating Diseases; Humans; Inflammation; Mitochondria; Multiple Sclerosis; Nerve Degeneration
PubMed: 28225235
DOI: 10.4045/tidsskr.16.0210