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Cells Sep 2020The water channel protein aquaporin-4 (AQP4) is required for a normal rate of water exchange across the blood-brain interface. Following the discovery that AQP4 is a...
The water channel protein aquaporin-4 (AQP4) is required for a normal rate of water exchange across the blood-brain interface. Following the discovery that AQP4 is a possible autoantigen in neuromyelitis optica, the function of AQP4 in health and disease has become a research focus. While several studies have addressed the expression and function of AQP4 during inflammatory demyelination, relatively little is known about its expression during non-autoimmune-mediated myelin damage. In this study, we used the toxin-induced demyelination model cuprizone as well as a combination of metabolic and autoimmune myelin injury (i.e., Cup/EAE) to investigate AQP4 pathology. We show that during toxin-induced demyelination, diffuse AQP4 expression increases, while polarized AQP4 expression at the astrocyte endfeet decreases. The diffuse increased expression of AQP4 was verified in chronic-active multiple sclerosis lesions. Around inflammatory brain lesions, AQP4 expression dramatically decreased, especially at sites where peripheral immune cells penetrate the brain parenchyma. Humoral immune responses appear not to be involved in this process since no anti-AQP4 antibodies were detected in the serum of the experimental mice. We provide strong evidence that the diffuse increase in anti-AQP4 staining intensity is due to a metabolic injury to the brain, whereas the focal, perivascular loss of anti-AQP4 immunoreactivity is mediated by peripheral immune cells.
Topics: Animals; Aquaporin 4; Autoimmune Diseases; Brain; Brain Injuries; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Gene Expression Regulation; Humans; Inflammation; Mice; Multiple Sclerosis; Myelin Sheath; Neuromyelitis Optica
PubMed: 32998402
DOI: 10.3390/cells9102187 -
Folia Morphologica 2022Myelination is a sequential process that is tightly controlled by a number of intrinsic and extrinsic factors. Any central nervous system disease in which the neuronal...
BACKGROUND
Myelination is a sequential process that is tightly controlled by a number of intrinsic and extrinsic factors. Any central nervous system disease in which the neuronal myelin sheath is damaged is referred to as demyelinating disease. The present work was designed to study the histopathological, ultrastructural and immunohistochemical changes in rat brain, mainly corpus callosum (CC), following oral administration of cuprizone (CPZ), and the role of N-acetylcysteine (NAC) in reducing these changes.
MATERIALS AND METHODS
Demyelination was induced by CPZ administration for short (4 weeks) and long (8 weeks) periods. NAC was given concomitantly and sequentially for similar periods. Spontaneous recovery after cessation of CPZ followed by no medication was also investigated. At the end of each experimental period, both cerebral hemispheres were extracted and prepared for light and electron microscopic examination and immuno-histochemical study.
RESULTS
The obtained results showed a direct proportion between the duration of CPZ administration and the severity of demyelination. The co-administration of CPZ and NAC, had a fair protective impact that was stronger than the sequential administration of the two drugs. Incomplete spontaneous remyelination was observed after cessation of CPZ, being more evident in short than in long period group, indicating that when CPZ administration is prolonged, remyelination is delayed.
CONCLUSIONS
In the light of the above results, it could be concluded that NAC has neuroprotective effects and has the potential to be a novel therapeutic approach for the treatment of demyelinating diseases such as multiple sclerosis; however, treatment should begin as soon as the disease manifests.
Topics: Acetylcysteine; Animals; Corpus Callosum; Cuprizone; Demyelinating Diseases; Myelin Sheath; Rats
PubMed: 33954959
DOI: 10.5603/FM.a2021.0044 -
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 -
International Journal of Molecular... May 2021Herpes simplex virus type 1 (HSV-1) is a neurotropic alphaherpesvirus that can infect the peripheral and central nervous systems, and it has been implicated in... (Review)
Review
Herpes simplex virus type 1 (HSV-1) is a neurotropic alphaherpesvirus that can infect the peripheral and central nervous systems, and it has been implicated in demyelinating and neurodegenerative processes. Transposable elements (TEs) are DNA sequences that can move from one genomic location to another. TEs have been linked to several diseases affecting the central nervous system (CNS), including multiple sclerosis (MS), a demyelinating disease of unknown etiology influenced by genetic and environmental factors. Exogenous viral transactivators may activate certain retrotransposons or class I TEs. In this context, several herpesviruses have been linked to MS, and one of them, HSV-1, might act as a risk factor by mediating processes such as molecular mimicry, remyelination, and activity of endogenous retroviruses (ERVs). Several herpesviruses have been involved in the regulation of human ERVs (HERVs), and HSV-1 in particular can modulate HERVs in cells involved in MS pathogenesis. This review exposes current knowledge about the relationship between HSV-1 and human ERVs, focusing on their contribution as a risk factor for MS.
Topics: Animals; Biological Evolution; DNA Transposable Elements; Demyelinating Diseases; Disease Susceptibility; Endogenous Retroviruses; Herpes Simplex; Herpesvirus 1, Human; Humans; Multiple Sclerosis; Retroelements
PubMed: 34072259
DOI: 10.3390/ijms22115738 -
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 -
Current Neurology and Neuroscience... Nov 2019Pediatric central nervous system demyelinating diseases include multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and acute disseminated... (Review)
Review
PURPOSE OF REVIEW
Pediatric central nervous system demyelinating diseases include multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and acute disseminated encephalomyelitis (ADEM). As diagnostic criteria become more inclusive, the risk of misdiagnosis of atypical demyelinating diseases of rheumatologic, infectious, and autoimmune etiology increases.
RECENT FINDINGS
We review mimics of multiple sclerosis, neuromyelitis optica spectrum disorder, and acute disseminated encephalomyelitis, including rheumatologic diseases: systemic lupus erythematosus and neuro-Behçet disease; infectious diseases: human immunodeficiency virus, progressive multifocal leukoencephalopathy, and subacute sclerosis panencephalitis; and autoimmune diseases including X-linked Charcot-Marie-Tooth disease, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) and autoimmune glial fibrillary acidic protein (GFAP) encephalopathy. Atypical demyelinating disease may mimic classic neuroinflammatory diseases of the central nervous system. Imaging may meet criteria for a diagnosis of multiple sclerosis, or patients may present with optic neuritis and transverse myelitis consistent with neuromyelitis optica spectrum or myelin oligodendrocyte glycoprotein (MOG) antibody disorders. Through careful history-taking and review of atypical MRI findings, we may avoid misdiagnosis and mistreatment.
Topics: Autoantibodies; Child; Demyelinating Diseases; Diagnosis, Differential; Encephalomyelitis, Acute Disseminated; Humans; Magnetic Resonance Imaging; Multiple Sclerosis; Neuromyelitis Optica
PubMed: 31773416
DOI: 10.1007/s11910-019-1015-y -
Neuroscience Letters Jun 2020The oligodendrocyte lineage cell is crucial to proper brain function. During central nervous system development, oligodendrocyte progenitor cells (OPCs) migrate and... (Review)
Review
The oligodendrocyte lineage cell is crucial to proper brain function. During central nervous system development, oligodendrocyte progenitor cells (OPCs) migrate and proliferate to populate the entire brain and spinal cord, and subsequently differentiate into mature oligodendrocytes that wrap neuronal axons in an insulating myelin layer. When damage occurs to the myelin sheath, OPCs are activated and recruited to the demyelinated site, where they differentiate into oligodendrocytes that remyelinate the denuded axons. The process of OPC attraction and differentiation is influenced by a multitude of factors from the cell's niche. Matrix metalloproteinases (MMPs) are powerful and versatile enzymes that do not only degrade extracellular matrix proteins, but also cleave cell surface receptors, growth factors, signaling molecules, proteases and other precursor proteins, leading to their activation or degradation. MMPs are markedly upregulated during brain development and upon demyelinating injury, where their broad functions influence the behavior of neural progenitor cells (NPCs), OPCs and oligodendrocytes. In this review, we focus on the role of MMPs in (re)myelination. We will start out in the developing brain with describing the effects of MMPs on NPCs, OPCs and eventually oligodendrocytes. Then, we will outline their functions in oligodendrocyte process extension and developmental myelination. Finally, we will review their potential role in demyelination, describe their significance in remyelination and discuss the evidence for a role of MMPs in remyelination failure, focusing on multiple sclerosis. In conclusion, MMPs shape the oligodendrocyte (niche) both during development and upon demyelination, and thus are important players in directing the fate and behavior of oligodendrocyte lineage cells throughout their life cycle.
Topics: Animals; Demyelinating Diseases; Humans; Myelin Sheath; Nerve Regeneration; Oligodendrocyte Precursor Cells; Oligodendroglia; Remyelination
PubMed: 32315713
DOI: 10.1016/j.neulet.2020.134980 -
Reviews in the Neurosciences 2015Leukoaraiosis (LA), also called white matter lesions (WMLs) and white matter hyperintensities (WMHs), is a frequent neuroimaging finding commonly seen on magnetic... (Review)
Review
Leukoaraiosis (LA), also called white matter lesions (WMLs) and white matter hyperintensities (WMHs), is a frequent neuroimaging finding commonly seen on magnetic resonance imaging brain scans of elderly people with prevalence ranging from 50% to 100%. Although it remains asymptomatic, LA is not considered to be benign, and it is showed to be related to a host of poor clinical outcomes and increases the risk of disability, dementia, depression, stroke, and the overall morbidity and mortality. Pathologically, LA is characterized by loss of myelin and axons, patchy demyelination, and denudation of ependyma in regions of WMH. Age and hypertension are the most importantly established risk factors for LA. However, the precise pathogenic mechanisms remain unclear. Together with the previous findings, our recent genetic results strongly supported that LA is associated with immune response and neuroinflammation. Therefore, we confidently hypothesized that LA was not only a common neuroimaging phenomenon in the elderly but also an emerging neuroinflammatory disorder in the central nervous system. This article focusing on neuroimaging classification, genetics basis, and putative molecular mechanism introduced the basic knowledge and current status of LA and put forward some of our research ideas and results from our molecular genetics research, which may pave the way for deciphering the putative pathogenic mechanism, risk factor, epigenetic index, and its application in diagnostic agents or drug target for prevention and treatment. Thus, it could provide clinicians and researchers with a specific and modern overview of LA to enable the understanding of recent progress and future directions in this illness.
Topics: Brain; Demyelinating Diseases; Humans; Inflammation; Leukoaraiosis; Magnetic Resonance Imaging; Tomography, X-Ray Computed; White Matter
PubMed: 25781674
DOI: 10.1515/revneuro-2014-0082 -
Journal of Crohn's & Colitis Dec 2020
Topics: Demyelinating Diseases; Humans; Immunotherapy; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha
PubMed: 33026456
DOI: 10.1093/ecco-jcc/jjaa144 -
International Journal of Surgery... Mar 2024Trigeminal neuralgia (TN) is the most common neuropathic disorder in the maxillofacial region. The etiology and pathogenesis of TN have not been clearly determined to...
BACKGROUND
Trigeminal neuralgia (TN) is the most common neuropathic disorder in the maxillofacial region. The etiology and pathogenesis of TN have not been clearly determined to date, although there are many hypotheses.
OBJECTIVE
The goal of this study was to investigate the interactions between different types of cells in TN, particularly the impact and intrinsic mechanism of demyelination on the trigeminal ganglion, and to identify new important target genes and regulatory pathways in TN.
METHODS
TN rat models were prepared by trigeminal root compression, and trigeminal nerve tissues were isolated for spatial transcriptome sequencing. The gene expression matrix was reduced dimensionally by PCA and presented by UMAP. Gene function annotation was analyzed by Metascape. The progression of certain clusters and the developmental pseudotime were analyzed using the Monocle package. Modules of the gene coexpression network between different groups were analyzed based on weighted gene coexpression network analysis and assigned AddModuleScore values. The intercellular communication of genes in these networks via ligand-receptor interactions was analyzed using CellPhoneDB analysis.
RESULTS
The results suggested that the trigeminal ganglion could affect Schwann cell demyelination and remyelination responses through many ligand-receptor interactions, while the effect of Schwann cells on the trigeminal ganglion was much weaker. Additionally, ferroptosis may be involved in the demyelination of Schwann cells.
CONCLUSIONS
This study provides spatial transcriptomics sequencing data on TN, reveals new markers, and redefines the relationship between the ganglion and myelin sheath, providing a theoretical basis and supporting data for future mechanistic research and drug development.
Topics: Rats; Animals; Trigeminal Neuralgia; Ligands; Transcriptome; Trigeminal Nerve; Demyelinating Diseases
PubMed: 38270619
DOI: 10.1097/JS9.0000000000001110