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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 -
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 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 -
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 -
Journal of Neuroimmunology Jul 2017Neurotropic viruses are important causes of morbidity and mortality in human populations. Some of these viruses preferentially infect oligodendrocytes in the white... (Review)
Review
Neurotropic viruses are important causes of morbidity and mortality in human populations. Some of these viruses preferentially infect oligodendrocytes in the white matter, causing either direct lysis of infected cells, or more commonly myelin damage as a consequence of the host immune response to the virus. Virus-induced demyelination has similarities to the human disease multiple sclerosis. To study this disease process in experimental animals, mice are infected, most commonly, with neurotropic strains of mouse hepatitis virus, a coronavirus or Theiler's murine encephalomyelitis, a picornavirus. While the diseases caused by these two viruses differ in some aspects, in both cases demyelination is a major consequence of the infection. As in autoimmune disease, therapeutic interventions that diminish an overactive immune response would be useful. However, unlike autoimmune disease, complete suppression would result in unchecked virus replication, generally leading to more severe disease. Here we discuss two approaches that dampen but do not fully suppress the host immune response. Regulatory T cells, especially those that are specific for antigens recognized by pathogenic T cells, and IL-10 are two anti-inflammatory/pro-resolution factors that demonstrate efficacy in experimental models of virus-induced demyelination and may be useful in patients infected with viruses that cause demyelination.
Topics: Animals; Demyelinating Diseases; Humans; Interleukin-10; T-Lymphocytes, Regulatory; Virus Diseases
PubMed: 28065579
DOI: 10.1016/j.jneuroim.2017.01.001 -
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 -
Neuroscience Bulletin Apr 2013Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system, and microglia and macrophages play important roles in its pathogenesis. The... (Review)
Review
Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system, and microglia and macrophages play important roles in its pathogenesis. The activation of microglia and macrophages accompanies disease development, whereas depletion of these cells significantly decreases disease severity. Microglia and macrophages usually have diverse and plastic phenotypes. Both pro-inflammatory and antiinflammatory microglia and macrophages exist in MS and its animal model, experimental autoimmune encephalomyelitis. The polarization of microglia and macrophages may underlie the differing functional properties that have been reported. in this review, we discuss the responses and polarization of microglia and macrophages in MS, and their effects on its pathogenesis and repair. Harnessing their beneficial effects by modulating their polarization states holds great promise for the treatment of inflammatory demyelinating diseases.
Topics: Animals; Cell Polarity; Cytokines; Demyelinating Diseases; Disease Models, Animal; Humans; Inflammation; Macrophages; Microglia
PubMed: 23558588
DOI: 10.1007/s12264-013-1324-0 -
Neuropsychopharmacology : Official... Jan 2009In making a selection of cellular tools and animal models for generating screening assays in the search for new drugs, one needs to take into consideration the... (Review)
Review
In making a selection of cellular tools and animal models for generating screening assays in the search for new drugs, one needs to take into consideration the practicality of their use in the drug discovery process. Conducting high-throughput primary screens using libraries of small molecules, close to 1 million members in size, requires the generation of large numbers of cells which are easily acquired, reliably enriched, and reproducibly responsive to standard positive controls. These cells need to be similar in form and function to their counterparts in human disease. In vitro assays that can be mechanized by using robots can therefore save time and costs. In selecting in vivo models, consideration must be given to the species and strain of animal chosen, the appropriateness of the model to human disease, the extent of animal husbandry required during the in-life pharmacological assessment, the technical aspects of generating the model and harvesting the tissues for analyses, the cost of research tools in terms of time and money (demyelinating and remyelinating agents, amount of compound to be generated), and the length of time required for drug testing in the model. A consideration of the translational aspects of the in vivo model compared to those used in the clinic is also important. These themes will be developed with examples for drug discovery in the field of CNS demyelination and repair, specifically as it pertains to multiple sclerosis.
Topics: Animals; Cell Line; Cells, Cultured; Demyelinating Diseases; Disease Models, Animal; Drug Discovery; Drug Evaluation, Preclinical; Encephalomyelitis, Autoimmune, Experimental; Humans; Multiple Sclerosis
PubMed: 18800062
DOI: 10.1038/npp.2008.145 -
Brain Pathology (Zurich, Switzerland) Apr 2007Most of the research on multiple sclerosis (MS) has focused on the early events that trigger demyelination and subsequent remyelination. Less attention has been given to... (Review)
Review
Most of the research on multiple sclerosis (MS) has focused on the early events that trigger demyelination and subsequent remyelination. Less attention has been given to the factors that directly mediate the demyelination that is the hallmark of the disease. Effector cells or molecules are those factors directly responsible for mediating the damage in the disease. Similarly, there are effector molecules that are critical for remyelination in the central nervous system (CNS). By understanding those effector molecules in demyelination and remyelination that directly influence the pathologic process, we should be able to generate specific therapies with the greatest potential for benefiting MS patients. This review focuses on effector cells and molecules that are critical for demyelination and remyelination in MS but also in experimental models of the disease including experimental autoimmune encephalomyelitis (EAE), virus-induced models of demyelination (Theiler's virus, murine hepatitis virus), and toxic models of demyelination (lysolecithin, ethidium bromide, and cuprizone). These are models in which the effector molecules for demyelination and remyelination have been most precisely evaluated.
Topics: Animals; Central Nervous System; Demyelinating Diseases; Disease Models, Animal; Humans; Multiple Sclerosis
PubMed: 17388953
DOI: 10.1111/j.1750-3639.2007.00065.x -
Neurotherapeutics : the Journal of the... Apr 2011Oligodendrocytes (OLs) are particularly susceptible to the toxicity of the acute lesion environment after spinal cord injury (SCI). They undergo both necrosis and... (Review)
Review
Oligodendrocytes (OLs) are particularly susceptible to the toxicity of the acute lesion environment after spinal cord injury (SCI). They undergo both necrosis and apoptosis acutely, with apoptosis continuing at chronic time points. Loss of OLs causes demyelination and impairs axon function and survival. In parallel, a rapid and protracted OL progenitor cell proliferative response occurs, especially at the lesion borders. Proliferating and migrating OL progenitor cells differentiate into myelinating OLs, which remyelinate demyelinated axons starting at 2 weeks post-injury. The progression of OL lineage cells into mature OLs in the adult after injury recapitulates development to some degree, owing to the plethora of factors within the injury milieu. Although robust, this endogenous oligogenic response is insufficient against OL loss and demyelination. First, in this review we analyze the major spatial-temporal mechanisms of OL loss, replacement, and myelination, with the purpose of highlighting potential areas of intervention after SCI. We then discuss studies on OL protection and replacement. Growth factors have been used both to boost the endogenous progenitor response, and in conjunction with progenitor transplantation to facilitate survival and OL fate. Considerable progress has been made with embryonic stem cell-derived cells and adult neural progenitor cells. For therapies targeting oligogenesis to be successful, endogenous responses and the effects of the acute and chronic lesion environment on OL lineage cells must be understood in detail, and in relation, the optimal therapeutic window for such strategies must also be determined.
Topics: Animals; Cell Differentiation; Demyelinating Diseases; Humans; Nerve Regeneration; Oligodendroglia; Spinal Cord Injuries; Stem Cells
PubMed: 21404073
DOI: 10.1007/s13311-011-0033-5