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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 -
Muscle & Nerve Sep 2015This article reviews the electrodiagnostic (EDX) prognostic factors for focal traumatic and nontraumatic peripheral nerve injuries. Referring physicians and patients... (Review)
Review
This article reviews the electrodiagnostic (EDX) prognostic factors for focal traumatic and nontraumatic peripheral nerve injuries. Referring physicians and patients often benefit from general and nerve-specific prognostic information from the EDX consultant. Knowing the probable outcome from a nerve injury allows the referring physician to choose the best treatment options for his/her patients. Nerve injuries are variable in their mechanism, location, and pathophysiology. The general effects of the injuries on nerve and muscle are well known, but more research is needed for nerve-specific information. Several factors currently known to influence prognosis include: nature of the nerve trauma, amount of axon loss, recruitment in muscles supplied by the nerve, the extent of demyelination, and the distance to reinnervate functional muscles. This article reviews these general concepts and also nerve-specific EDX measures that predict outcome after focal neuropathies.
Topics: Action Potentials; Demyelinating Diseases; Electrodiagnosis; Humans; Neural Conduction; Peripheral Nerve Injuries; Peripheral Nerves; Peripheral Nervous System Diseases; Prognosis
PubMed: 25989907
DOI: 10.1002/mus.24709 -
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 -
Journal of the Neurological Sciences May 2016
Topics: Demyelinating Diseases; Humans; Polyradiculoneuropathy; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating
PubMed: 27084210
DOI: 10.1016/j.jns.2016.02.023 -
Multiple Sclerosis (Houndmills,... Jul 2016The availability of magnetic resonance imaging (MRI) has led to increasing recognition that multiple sclerosis (MS), tumefactive demyelination (TD) and Baló's... (Review)
Review
The availability of magnetic resonance imaging (MRI) has led to increasing recognition that multiple sclerosis (MS), tumefactive demyelination (TD) and Baló's concentric sclerosis (BCS) share many overlapping features. Baló-like lesions, which exhibit limited features of BCS, may represent an intermediate between BCS and typical MS demyelination. Lesions labeled as tumefactive are typically larger, but otherwise have much in common with conventional MS lesions, and TD and BCS lesions can also overlap. In this article, we explore the similarities between typical MS, TD and BCS cases, and reflect on the potential insights that intermediate or overlapping phenotypes may contribute towards an understanding of MS immunopathogenesis, and question whether these atypical forms of demyelination should be classified as separate demyelinating diseases, as different lesional manifestations of demyelination of any cause or as part of a spectrum with conventional MS.
Topics: Brain; Demyelinating Diseases; Diagnosis, Differential; Diffuse Cerebral Sclerosis of Schilder; Humans; Magnetic Resonance Imaging; Multiple Sclerosis; Predictive Value of Tests; Prognosis
PubMed: 27037180
DOI: 10.1177/1352458516641776 -
Glia Jul 2015Myelin integrity is crucial for central nervous system (CNS) physiology while its preservation and regeneration after spinal cord injury (SCI) is key to functional... (Review)
Review
Myelin integrity is crucial for central nervous system (CNS) physiology while its preservation and regeneration after spinal cord injury (SCI) is key to functional restoration. Disturbance of nodal organization acutely after SCI exposes the axon and triggers conduction block in the absence of overt demyelination. Oligodendrocyte (OL) loss and myelin degradation follow as a consequence of secondary damage. Here, we provide an overview of the major biological events and underlying mechanisms leading to OL death and demyelination and discuss strategies to restrain these processes. Another aspect which is critical for SCI repair is the enhancement of endogenously occurring spontaneous remyelination. Recent findings have unveiled the complex roles of innate and adaptive immune responses in remyelination and the immunoregulatory potential of the glial scar. Moreover, the intimate crosstalk between neuronal activity, oligodendrogenesis and myelination emphasizes the contribution of rehabilitation to functional recovery. With a view toward clinical applications, several therapeutic strategies have been devised to target SCI pathology, including genetic manipulation, administration of small therapeutic molecules, immunomodulation, manipulation of the glial scar and cell transplantation. The implementation of new tools such as cellular reprogramming for conversion of one somatic cell type to another or the use of nanotechnology and tissue engineering products provides additional opportunities for SCI repair. Given the complexity of the spinal cord tissue after injury, it is becoming apparent that combinatorial strategies are needed to rescue OLs and myelin at early stages after SCI and support remyelination, paving the way toward clinical translation.
Topics: Animals; Demyelinating Diseases; Humans; Myelin Sheath; Oligodendroglia; Spinal Cord Injuries; Spinal Cord Regeneration
PubMed: 25731941
DOI: 10.1002/glia.22809 -
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 -
NEJM Evidence Oct 2023In Volume 2, Number 4 of , we published an article entitled, "Osmotic Demyelination Syndrome in Patients Hospitalized with Hyponatremia" by MacMillan et al. The article...
In Volume 2, Number 4 of , we published an article entitled, "Osmotic Demyelination Syndrome in Patients Hospitalized with Hyponatremia" by MacMillan et al. The article was accompanied by an editorial entitled "Hyponatremia Treatment Guidelines - Have They Gone Too Far?" by Ayus and Moritz. After these articles were published, a group of readers shared feedback about the data presented and the conclusions drawn; their comments are detailed as "Remarks from Readers." We relayed these points to the authors of the original article and the editorial; their responses follow.
Topics: Humans; Hyponatremia; Demyelinating Diseases; Patients
PubMed: 38320188
DOI: 10.1056/EVIDe2300228 -
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