-
Cellular and Molecular Life Sciences :... Jul 2020In inflammatory peripheral demyelinating disorders, demyelination represents segmental demyelination in which the myelin sheath of a myelinating Schwann cell (SC) is... (Review)
Review
In inflammatory peripheral demyelinating disorders, demyelination represents segmental demyelination in which the myelin sheath of a myelinating Schwann cell (SC) is completely removed by macrophages or a partial myelin degeneration in the paranode occurring due to autoantibodies attacking the node/paranode. For the segmental demyelination from living myelin-forming SCs, macrophages infiltrate within the endoneurium and insinuate between myelin lamellae and the cytoplasm of SCs, and the myelin is then removed via phagocytosis. During the macrophage invasion into the SC cytoplasm from the node of Ranvier and internodal areas, the attacked SCs do not remain quiescent but transdifferentiate into inflammatory demyelinating SCs (iDSCs), which exhibit unique demyelination pathologies, such as myelin uncompaction from Schmidt-Lanterman incisures with myelin lamellae degeneration. The longitudinal extension of this self-myelin clearance process of iDSCs into the nodal region is associated with the degeneration of nodal microvilli and paranodal loops, which provides a potential locus for macrophage infiltration. In addition to the nodal intrusion, macrophages appear to be able to invade fenestrated internodal plasma membrane or the degenerated outer mesaxon of iDSC. These SC demyelination morphologies indicate that the SC reprogramming to iDSCs may be a prerequisite for macrophage-mediated inflammatory demyelination. In contrast, paranodal demyelination caused by autoantibodies to nodal/paranodal antigens does not result in iDSC-dependent macrophage infiltration and subsequent segmental demyelination. In the context of inflammatory demyelination, the novel perspective of iDSCs provides an important viewpoint to understand the pathophysiology of demyelinating peripheral neuropathies and establish diagnostic and therapeutic strategies.
Topics: Animals; Demyelinating Diseases; Humans; Inflammation; Macrophages; Mice; Myelin Sheath; Peripheral Nervous System Diseases; Schwann Cells; Wallerian Degeneration
PubMed: 31884566
DOI: 10.1007/s00018-019-03431-8 -
Current Opinion in Pharmacology Apr 2022Despite evidence for prominent metabolic dysfunction within multiple sclerosis (MS) lesions, the mechanisms controlling metabolic shifts in oligodendroglia are poorly... (Review)
Review
Despite evidence for prominent metabolic dysfunction within multiple sclerosis (MS) lesions, the mechanisms controlling metabolic shifts in oligodendroglia are poorly understood. The cuprizone model of demyelination and remyelination is a valuable tool for assessing metabolic insult during oligodendrocyte death and myelin degradation, closely resembling the distal oligodendrogliopathy seen in Pattern III MS lesions. In this review we discuss how metabolic processes in oligodendrocytes are disrupted in both MS and the cuprizone model, as well as the evidence for mechanistic target of rapamycin (mTOR) signaling as a key regulator of oligodendroglial metabolic function and efficient remyelination.
Topics: Animals; Cuprizone; Demyelinating Diseases; Humans; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Oligodendroglia; Remyelination; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 35245799
DOI: 10.1016/j.coph.2022.102193 -
Continuum (Minneapolis, Minn.) Aug 2013This article summarizes the pathologic features of multiple sclerosis (MS) and other inflammatory demyelinating diseases and discusses neuropathologic studies that have... (Review)
Review
PURPOSE OF REVIEW
This article summarizes the pathologic features of multiple sclerosis (MS) and other inflammatory demyelinating diseases and discusses neuropathologic studies that have yielded novel insights into potential mechanisms of demyelination.
RECENT FINDINGS
The pathologic hallmark of MS consists of focal demyelinated plaques within the CNS, with variable degrees of inflammation, gliosis, and neurodegeneration. Active MS lesions show a profound pathologic heterogeneity with four major patterns of immunopathology, suggesting that the targets of injury and mechanisms of demyelination in MS may be different in different disease subgroups. Recent pathologic studies have suggested that the subarachnoid space and cortex may be initial sites and targets of the MS disease process, that inflammatory cortical demyelination is present early in MS, and that meningeal inflammation may drive cortical and white matter injury in some MS patients.
SUMMARY
MS is heterogeneous with respect to clinical, genetic, radiographic, and pathologic features; surrogate MRI, clinical, genetic, serologic, and/or CSF markers for each of the four immunopatterns need to be developed in order to recognize them in the general nonbiopsied MS population. Inflammatory cortical demyelination is an important early event in the pathogenesis of MS and may be driven by meningeal inflammation. These observations stress the importance of developing imaging techniques able to capture early inflammatory cortical demyelination in order to better understand the disease pathogenesis and to determine the impact of potential disease-modifying therapies on the cortex.
Topics: Adult; Cerebral Cortex; Chronic Disease; Demyelinating Diseases; Encephalomyelitis, Acute Disseminated; Fatal Outcome; Female; Humans; Leukoencephalitis, Acute Hemorrhagic; Leukoencephalopathies; Meningitis; Multiple Sclerosis; Neuromyelitis Optica; Young Adult
PubMed: 23917093
DOI: 10.1212/01.CON.0000433291.23091.65 -
Neurologic Clinics May 2013Diabetes is the most common cause of neuropathy in United States and neuropathies are the most common complication of diabetes mellitus, affecting up to 50% of patients... (Review)
Review
Diabetes is the most common cause of neuropathy in United States and neuropathies are the most common complication of diabetes mellitus, affecting up to 50% of patients with type 1 and type 2 diabetes mellitus. Symptoms usually include numbness, tingling, pain, and weakness. Dizziness with postural changes can be seen with autonomic neuropathy. Metabolic, vascular, and immune theories have been proposed for the pathogenesis of diabetic neuropathy. Axonal damage and segmental demyelination can be seen with diabetic neuropathies. Management of diabetic neuropathy should begin at the initial diagnosis of diabetes and mainly requires tight and stable glycemic control.
Topics: Demyelinating Diseases; Diabetic Neuropathies; Humans; Metabolic Diseases; Neuritis; Pain Management; Phenotype
PubMed: 23642717
DOI: 10.1016/j.ncl.2013.02.004 -
Journal of Physiology and Biochemistry Aug 2023Resveratrol is known to exhibit neuroprotective effects in many neurological disorders via autophagy modulation. However, controversial results have been reported about...
Resveratrol is known to exhibit neuroprotective effects in many neurological disorders via autophagy modulation. However, controversial results have been reported about the therapeutic potential of resveratrol and the implication of autophagy in demyelinating diseases. This study aimed to evaluate the autophagic changes in cuprizone-intoxicated C57Bl/6 mice and explore the effect of autophagy activation by resveratrol on the demyelination and remyelination processes. Mice were fed with chow containing 0.2% cuprizone for 5 weeks, followed by a cuprizone-free diet for 2 weeks. Resveratrol (250 mg/kg/day) and/or chloroquine (an autophagy inhibitor; 10 mg/kg/day) were given for 5 weeks starting from the third week. At the end of the experiment, animals were tested on rotarod and then sacrificed for biochemical assessment, luxol fast blue (LFB) staining, and transmission electron microscopy (TEM) imaging of the corpus callosum. We observed that cuprizone-induced demyelination was associated with impaired degradation of autophagic cargo, induction of apoptosis, and manifest neurobehavioral disturbances. Oral treatment with resveratrol promoted motor coordination and improved remyelination with regular compacted myelin in most axons without a significant impact on myelin basic protein (MBP) mRNA expression. These effects are mediated, at least in part, via activating autophagic pathways that may involve SIRT1/FoxO1 activation. This study verified that resveratrol dampens cuprizone-induced demyelination, and partially enhances myelin repair through modulation of the autophagic flux, since interruption of the autophagic machinery by chloroquine reversed the therapeutic potential of resveratrol.
Topics: Animals; Mice; Cuprizone; Demyelinating Diseases; Resveratrol; Myelin Sheath; Autophagy; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 37131098
DOI: 10.1007/s13105-023-00959-z -
International Journal of Molecular... Nov 2022Demyelinating disorders show impaired remyelination due to failure in the differentiation of oligodendrocyte progenitor cells (OPCs) into mature myelin-forming...
Demyelinating disorders show impaired remyelination due to failure in the differentiation of oligodendrocyte progenitor cells (OPCs) into mature myelin-forming oligodendrocytes, a process driven by microglia-OPC crosstalk. Through conducting a transcriptomic analysis of microarray studies on the demyelination-remyelination cuprizone model and using human samples of multiple sclerosis (MS), we identified molecules involved in this crosstalk. Differentially expressed genes (DEGs) of specific regions/cell types were detected in GEO transcriptomic raw data after cuprizone treatment and in MS samples, followed by functional analysis with GO terms and WikiPathways. Additionally, microglia-OPC crosstalk between microglia ligands, OPC receptors and target genes was examined with the NicheNet model. We identified 108 and 166 DEGs in the demyelinated corpus callosum (CC) at 2 and 4 weeks of cuprizone treatment; 427 and 355 DEGs in the remyelinated (4 weeks of cuprizone treatment + 14 days of normal diet) compared to 2- and 4-week demyelinated CC; 252 DEGs in MS samples and 2730 and 12 DEGs in OPC and microglia of 4-week demyelinated CC. At this time point, we found 95 common DEGs in the CC and OPCs, and one common DEG in microglia and OPCs, mostly associated with myelin and lipid metabolism. Crosstalk analysis identified 47 microglia ligands, 43 OPC receptors and 115 OPC target genes, all differentially expressed in cuprizone-treated samples and associated with myelination. Our differential expression pipeline identified demyelination/remyelination transcriptomic biomarkers in studies using diverse platforms and cell types/tissues. Cellular crosstalk analysis yielded novel markers of microglia ligands, OPC receptors and target genes.
Topics: Mice; Animals; Humans; Oligodendrocyte Precursor Cells; Demyelinating Diseases; Mice, Inbred C57BL; Remyelination; Cuprizone; Oligodendroglia; Myelin Sheath; Cell Differentiation; Microglia; Multiple Sclerosis; Disease Models, Animal
PubMed: 36499195
DOI: 10.3390/ijms232314868 -
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 -
Neuropharmacology Nov 2016Progressive multiple sclerosis (MS) is a severely disabling neurological condition, and an effective treatment is urgently needed. Recently, high-dose biotin has emerged... (Review)
Review
Progressive multiple sclerosis (MS) is a severely disabling neurological condition, and an effective treatment is urgently needed. Recently, high-dose biotin has emerged as a promising therapy for affected individuals. Initial clinical data have shown that daily doses of biotin of up to 300 mg can improve objective measures of MS-related disability. In this article, we review the biology of biotin and explore the properties of this ubiquitous coenzyme that may explain the encouraging responses seen in patients with progressive MS. The gradual worsening of neurological disability in patients with progressive MS is caused by progressive axonal loss or damage. The triggers for axonal loss in MS likely include both inflammatory demyelination of the myelin sheath and primary neurodegeneration caused by a state of virtual hypoxia within the neuron. Accordingly, targeting both these pathological processes could be effective in the treatment of progressive MS. Biotin is an essential co-factor for five carboxylases involved in fatty acid synthesis and energy production. We hypothesize that high-dose biotin is exerting a therapeutic effect in patients with progressive MS through two different and complementary mechanisms: by promoting axonal remyelination by enhancing myelin production and by reducing axonal hypoxia through enhanced energy production. This article is part of the Special Issue entitled 'Oligodendrocytes in Health and Disease'.
Topics: Animals; Biotin; Demyelinating Diseases; Disease Progression; Dose-Response Relationship, Drug; Humans; Hypoxia; Multiple Sclerosis; Vitamin B Complex
PubMed: 26327679
DOI: 10.1016/j.neuropharm.2015.08.028 -
Physiological Research 2011Over a century ago, hyperplasia and hypertrophy of astrocytes was noted as a histopathological hallmark of multiple sclerosis and was hypothesized to play an important... (Review)
Review
Over a century ago, hyperplasia and hypertrophy of astrocytes was noted as a histopathological hallmark of multiple sclerosis and was hypothesized to play an important role in the development and course of this disease. However until today, the factual contribution of astrocytes to multiple sclerosis is elusive. Astrocytes may play an active role during degeneration and demyelination by controlling local inflammation in the CNS, provoking damage of oligodendrocytes and axons, and glial scarring but might also be beneficial by creating a permissive environment for remyelination and oligodendrocyte precursor migration, proliferation, and differentiation. Recent findings from our lab suggest that brain lipid binding protein (FABP7) is implicated in the course of multiple sclerosis and the regulation of astrocyte function. The relevance of our findings and data from other groups are highlighted and discussed in this paper in the context of myelin repair.
Topics: Animals; Astrocytes; Carrier Proteins; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Fatty Acid-Binding Protein 7; Fatty Acid-Binding Proteins; Humans; Multiple Sclerosis; Myelin Sheath; Nerve Tissue Proteins; Signal Transduction; Tumor Suppressor Proteins
PubMed: 21777034
DOI: 10.33549/physiolres.932168 -
Experimental Neurology Apr 2020Due to the limitation in treatment window of the rtPA (recombinant tissue plasminogen activator), the development of delayed treatment for stroke is needed. We...
Due to the limitation in treatment window of the rtPA (recombinant tissue plasminogen activator), the development of delayed treatment for stroke is needed. We previously reported that there is a difference in neurogenesis and neuroblast migration patterns in different mouse stroke models (proximal and distal middle cerebral artery occlusion models, pMCAo or dMCAo). Specifically, compared to robust neurogenesis and substantial migration of newly born neuroblasts in pMCAo model, dMCAo only illicit limited neurogenesis and migration of neuroblasts towards ischemic area. One potential reason for this difference is the relative location of ischemic area to white matter and the neurogenic niche (subventricular zone, SVZ). Specifically, white matter could serve as a physical barrier or inhibitory factor to neurogenesis and migration in the dMCAo model. Given that a major difference in human and rodent brains is the content of white matter in the brain, in this study, we further characterize these two models and test the important hypothesis that white matter is an important contributing inhibitory factor for the limited neurogenesis in the dMCAo model. We utilized a genetically inducible NSC-specific reporter mouse line (nestin-CreERT2-R26R-YFP) to label and track NSC proliferation, survival and differentiation in ischemic brain. To test whether myelin is inhibitory to neurogenesis in dMCAo model, we demyelinated mouse brains using cuprizone treatment after stroke and examined whether there is enhanced neurogenesis or migration of neuroblasts cells in stroke mice treated with cuprizone. Our data suggests that demyelination of the brain does not result in enhanced neurogenesis or migration of neuroblasts, supporting that myelin is not a major inhibitory factor for stroke-induced neurogenesis. In addition, our results suggest that in non-stroke mice, demyelination causes decreased neurogenesis in adult brain, indicating a potential positive role of myelin in maintenance of adult neural stem cell niche.
Topics: Animals; Behavior, Animal; Brain Ischemia; Cell Differentiation; Cell Movement; Cell Proliferation; Cell Survival; Chelating Agents; Cuprizone; Demyelinating Diseases; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Neural Stem Cells; Neurogenesis; Stroke; White Matter
PubMed: 31904386
DOI: 10.1016/j.expneurol.2019.113168