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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 -
Journal of Neurology, Neurosurgery, and... Dec 2005A pathological classification has been developed of early active multiple sclerosis (MS) lesions that reveals four patterns of tissue injury: I-T cell/macrophage...
BACKGROUND
A pathological classification has been developed of early active multiple sclerosis (MS) lesions that reveals four patterns of tissue injury: I-T cell/macrophage associated; II-antibody/complement associated; III-distal oligodendrogliopathy, and IV-oligodendrocyte degeneration in the periplaque white matter. Mechanisms of demyelination in early MS may differ among the subgroups. Previous studies on biopsied MS have lacked clinicopathological correlation and follow up. Critics argue that observations are not generalisable to prototypic MS.
OBJECTIVE
To describe the clinicopathological characteristics of the MS Lesion Project biopsy cohort.
METHODS
Clinical characteristics and disability of patients with pathologically confirmed inflammatory demyelinating disease (excluding ADEM) classified immunopathologically (n = 91) and patients from the Olmsted County MS prevalence cohort (n = 218) were determined.
RESULTS
Most patients who underwent biopsy and had pathologically proved demyelinating disease ultimately developed definite (n = 70) or probable (n = 12) MS (median follow up 4.4 years). Most had a relapsing remitting course and 73% were ambulatory (EDSS < or =4) at last follow up. Nine patients remained classified as having an isolated demyelinating syndrome at last follow up. Patients with different immunopathological patterns had similar clinical characteristics. Although presenting symptoms and sex ratios differed, the clinical course in biopsy patients was similar to the prevalence cohort. Median EDSS was <4.0 in both cohorts when matched for disease duration, sex, and age.
CONCLUSIONS
Most patients undergoing biopsy, who had pathologically confirmed demyelinating disease, were likely to develop MS and remain ambulatory after a median disease duration of 4.4 years. The immunopathological patterns lacked specific clinical correlations and were not related to the timing of the biopsy. These data suggest that pathogenic implications derived largely from MS biopsy studies may be extrapolated to the general MS population.
Topics: Adolescent; Adult; Aged; Biopsy; Child; Cohort Studies; Demyelinating Diseases; Disease Progression; Female; Humans; Inflammation; Male; Middle Aged; Multiple Sclerosis; Prognosis; Quality of Life
PubMed: 16291895
DOI: 10.1136/jnnp.2004.060624 -
Drugs Dec 2013We review the current state of knowledge of remyelination in multiple sclerosis (MS), concentrating on advances in the understanding of the pathology and the... (Review)
Review
We review the current state of knowledge of remyelination in multiple sclerosis (MS), concentrating on advances in the understanding of the pathology and the regenerative response, and we summarise progress on the development of new therapies to enhance remyelination aimed at reducing progressive accumulation of disability in MS. We discuss key target pathways identified in experimental models, as although most identified targets have not yet progressed to the stage of being tested in human clinical trials, they may provide treatment strategies for demyelinating diseases in the future. Finally, we discuss some of the problems associated with testing this class of drugs, where they might fit into the therapeutic arsenal and the gaps in our knowledge.
Topics: Animals; Clinical Trials as Topic; Demyelinating Diseases; Disease Progression; Drug Evaluation, Preclinical; Humans; Multiple Sclerosis
PubMed: 24242317
DOI: 10.1007/s40265-013-0146-8 -
Journal of Pharmacological Sciences Nov 2020Chronic microglial activation is associated with the pathogenesis of several CNS disorders. Microglia show phenotypic diversity and functional complexity in diseased... (Review)
Review
Chronic microglial activation is associated with the pathogenesis of several CNS disorders. Microglia show phenotypic diversity and functional complexity in diseased CNS. Thus, understanding the pathology-specific heterogeneity of microglial behavior is crucial for the future development of microglia-modulating therapy for variety of CNS disorders. This review summarizes up-to-date knowledge on how microglia contribute to CNS homeostasis during development and throughout adulthood. We discuss the heterogeneity of microglial phenotypes in the context of CNS disorders with an emphasis on neurodegenerative diseases, demyelinating diseases, CNS trauma, and epilepsy. We conclude this review with a discussion about the disease-specific heterogeneity of microglial function and how it could be exploited for therapeutic intervention.
Topics: Central Nervous System Diseases; Demyelinating Diseases; Epilepsy; Homeostasis; Humans; Microglia; Neurodegenerative Diseases; Phenotype
PubMed: 32921391
DOI: 10.1016/j.jphs.2020.07.004 -
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 -
Current Issues in Molecular Biology Nov 2021Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous disease affecting the peripheral nervous system that is caused by either the demyelination of Schwann...
Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous disease affecting the peripheral nervous system that is caused by either the demyelination of Schwann cells or degeneration of the peripheral axon. Currently, there are no treatment options to improve the degeneration of peripheral nerves in CMT patients. In this research, we assessed the potency of farnesol for improving the demyelinating phenotype using an animal model of CMT type 1A. In vitro treatment with farnesol facilitated myelin gene expression and ameliorated the myelination defect caused by overexpression, the major causative gene in CMT. In vivo administration of farnesol enhanced the peripheral neuropathic phenotype, as shown by rotarod performance in a mouse model of CMT1A. Electrophysiologically, farnesol-administered CMT1A mice exhibited increased motor nerve conduction velocity and compound muscle action potential compared with control mice. The number and diameter of myelinated axons were also increased by farnesol treatment. The expression level of myelin protein zero (MPZ) was increased, while that of the demyelination marker, neural cell adhesion molecule (NCAM), was reduced by farnesol administration. These data imply that farnesol is efficacious in ameliorating the demyelinating phenotype of CMT, and further elucidation of the underlying mechanisms of farnesol's effect on myelination might provide a potent therapeutic strategy for the demyelinating type of CMT.
Topics: Animals; Biomarkers; Charcot-Marie-Tooth Disease; Demyelinating Diseases; Disease Models, Animal; Disease Susceptibility; Farnesol; Female; Gene Expression; Male; Mice; Myelin Proteins; Phenotype; Schwann Cells
PubMed: 34889893
DOI: 10.3390/cimb43030138 -
Frontiers in Immunology 2022Differential diagnosis of demyelinating diseases of the central nervous system is a challenging task that is prone to errors and inconsistent reading, requiring...
BACKGROUND
Differential diagnosis of demyelinating diseases of the central nervous system is a challenging task that is prone to errors and inconsistent reading, requiring expertise and additional examination approaches. Advancements in deep-learning-based image interpretations allow for prompt and automated analyses of conventional magnetic resonance imaging (MRI), which can be utilized in classifying multi-sequence MRI, and thus may help in subsequent treatment referral.
METHODS
Imaging and clinical data from 290 patients diagnosed with demyelinating diseases from August 2013 to October 2021 were included for analysis, including 67 patients with multiple sclerosis (MS), 162 patients with aquaporin 4 antibody-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD), and 61 patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Considering the heterogeneous nature of lesion size and distribution in demyelinating diseases, multi-modal MRI of brain and/or spinal cord were utilized to build the deep-learning model. This novel transformer-based deep-learning model architecture was designed to be versatile in handling with multiple image sequences (coronal T2-weighted and sagittal T2-fluid attenuation inversion recovery) and scanning locations (brain and spinal cord) for differentiating among MS, NMOSD, and MOGAD. Model performances were evaluated using the area under the receiver operating curve (AUC) and the confusion matrices measurements. The classification accuracy between the fusion model and the neuroradiological raters was also compared.
RESULTS
The fusion model that was trained with combined brain and spinal cord MRI achieved an overall improved performance, with the AUC of 0.933 (95%CI: 0.848, 0.991), 0.942 (95%CI: 0.879, 0.987) and 0.803 (95%CI: 0.629, 0.949) for MS, AQP4+ NMOSD, and MOGAD, respectively. This exceeded the performance using the brain or spinal cord MRI alone for the identification of the AQP4+ NMOSD (AUC of 0.940, brain only and 0.689, spinal cord only) and MOGAD (0.782, brain only and 0.714, spinal cord only). In the multi-category classification, the fusion model had an accuracy of 81.4%, which was significantly higher compared to rater 1 (64.4%, p=0.04<0.05) and comparable to rater 2 (74.6%, p=0.388).
CONCLUSION
The proposed novel transformer-based model showed desirable performance in the differentiation of MS, AQP4+ NMOSD, and MOGAD on brain and spinal cord MRI, which is comparable to that of neuroradiologists. Our model is thus applicable for interpretating conventional MRI in the differential diagnosis of demyelinating diseases with overlapping lesions.
Topics: Aquaporin 4; Deep Learning; Humans; Multiple Sclerosis; Neuroimaging; Neuromyelitis Optica; Spinal Cord
PubMed: 35774780
DOI: 10.3389/fimmu.2022.897959 -
International Journal of Molecular... May 2021Several virus-induced models were used to study the underlying mechanisms of multiple sclerosis (MS). The infection of susceptible mice with Theiler's murine... (Review)
Review
Several virus-induced models were used to study the underlying mechanisms of multiple sclerosis (MS). The infection of susceptible mice with Theiler's murine encephalomyelitis virus (TMEV) establishes persistent viral infections and induces chronic inflammatory demyelinating disease. In this review, the innate and adaptive immune responses to TMEV are discussed to better understand the pathogenic mechanisms of viral infections. Professional (dendritic cells (DCs), macrophages, and B cells) and non-professional (microglia, astrocytes, and oligodendrocytes) antigen-presenting cells (APCs) are the major cell populations permissive to viral infection and involved in cytokine production. The levels of viral loads and cytokine production in the APCs correspond to the degrees of susceptibility of the mice to the TMEV-induced demyelinating diseases. TMEV infection leads to the activation of cytokine production via TLRs and MDA-5 coupled with NF-κB activation, which is required for TMEV replication. These activation signals further amplify the cytokine production and viral loads, promote the differentiation of pathogenic Th17 responses, and prevent cellular apoptosis, enabling viral persistence. Among the many chemokines and cytokines induced after viral infection, IFN α/β plays an essential role in the downstream expression of costimulatory molecules in APCs. The excessive levels of cytokine production after viral infection facilitate the pathogenesis of TMEV-induced demyelinating disease. In particular, IL-6 and IL-1β play critical roles in the development of pathogenic Th17 responses to viral antigens and autoantigens. These cytokines, together with TLR2, may preferentially generate deficient FoxP3CD25 regulatory cells converting to Th17. These cytokines also inhibit the apoptosis of TMEV-infected cells and cytolytic function of CD8 T lymphocytes (CTLs) and prolong the survival of B cells reactive to viral and self-antigens, which preferentially stimulate Th17 responses.
Topics: Adaptive Immunity; Animals; Antigen-Presenting Cells; Astrocytes; Cardiovirus Infections; Cytokines; Demyelinating Diseases; Disease Models, Animal; Humans; Immunity, Innate; Mice; Microglia; Multiple Sclerosis; Oligodendroglia; Signal Transduction; Theilovirus
PubMed: 34067536
DOI: 10.3390/ijms22105254 -
Biochimica Et Biophysica Acta Feb 2011Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system which responds to anti-inflammatory treatments in the early disease phase.... (Review)
Review
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system which responds to anti-inflammatory treatments in the early disease phase. However, the pathogenesis of the progressive disease phase is less well understood, and inflammatory as well as neurodegenerative mechanisms of tissue damage are currently being discussed. This review summarizes current knowledge on the interrelation between inflammation, demyelination, and neurodegeneration derived from the study of human autopsy and biopsy brain tissue and experimental models of MS.
Topics: Animals; Autoantigens; Autoimmunity; Axons; Demyelinating Diseases; Humans; Inflammation; Multiple Sclerosis; Nerve Degeneration; Neurons
PubMed: 20637864
DOI: 10.1016/j.bbadis.2010.07.007 -
The Journal of Pathology Feb 2021Autophagy is a constitutive process that degrades, recycles and clears damaged proteins or organelles, yet, despite activation of this pathway, abnormal proteins... (Review)
Review
Autophagy is a constitutive process that degrades, recycles and clears damaged proteins or organelles, yet, despite activation of this pathway, abnormal proteins accumulate in neurons in neurodegenerative diseases and in oligodendrocytes in white matter disorders. Here, we discuss the role of autophagy in white matter disorders, including neurotropic infections, inflammatory diseases such as multiple sclerosis, and in hereditary metabolic disorders and acquired toxic-metabolic disorders. Once triggered due to cell stress, autophagy can enhance cell survival or cell death that may contribute to oligodendrocyte damage and myelin loss in white matter diseases. For some disorders, the mechanisms leading to myelin loss are clear, whereas the aetiological agent and pathological mechanisms are unknown for other myelin disorders, although emerging studies indicate that a common mechanism underlying these disorders is dysregulation of autophagic pathways. In this review we discuss the alterations in the autophagic process in white matter disorders and the potential use of autophagy-modulating agents as therapeutic approaches in these pathological conditions. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
Topics: Autophagy; Cell Death; Cell Survival; Demyelinating Diseases; Humans; Leukoencephalopathies; Multiple Sclerosis; Oligodendroglia; United Kingdom; White Matter
PubMed: 33135781
DOI: 10.1002/path.5576