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  • MULTIPLE-SCLEROSIS  (3)
  • 1
    Keywords: proliferation ; SYSTEM ; DISEASE ; PROTEIN ; MICE ; PATIENT ; MARKER ; ANTIGEN ; ANTIGENS ; T cell ; T cells ; T-CELL ; T-CELLS ; culture ; antibodies ; antibody ; MOUSE ; NERVOUS-SYSTEM ; LESIONS ; NUMBER ; COMPONENT ; DAMAGE ; cytoskeleton ; NETHERLANDS ; CD8(+) ; CENTRAL-NERVOUS-SYSTEM ; pathology ; AMYOTROPHIC-LATERAL-SCLEROSIS ; MULTIPLE-SCLEROSIS ; INTERFERON-GAMMA ; inflammation ; CD4(+) T-CELLS ; AUTOIMMUNE ENCEPHALOMYELITIS ; SERUM ; AUTOIMMUNITY ; IMMUNIZATION ; CYTOKINE ; RECOMBINANT ; RE ; SERUM ANTIBODIES ; LEVEL ; multiple sclerosis ; USA ; animal model ; central nervous system ; DEGENERATION ; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS ; correlates ; SENSORY NEURONOPATHY ; axonal damage ; MS LESIONS ; neurofilament light ; PROGRESSIVE MULTIPLE-SCLEROSIS ; spastic paresis
    Abstract: Axonal damage is the major cause of irreversible neurologic disability in patients with multiple sclerosis. Although axonal damage correlates with antibodies against neurotilament light (NF-L) protein, a major component of the axonal cytoskeleton, the possible pathogenic role of autoirnmunity to axonal antigens such as NF-L has so far been ignored. Here we show that Biozzi ABH mice immunized with NF-L protein develop neurologic disease characterized by spastic paresis and paralysis concomitant with axonal degeneration and inflammation primarily in the dorsal column of the spinal cord. The inflammatory central nervous system lesions were dominated by F4/80' macrophages/microglia and relatively low numbers of CD4(+) and CD8(+) T-cells. In splenocyte cultures, proliferation to NF-L was observed in CD4(+) T-cells accompanied by the production of the proinflammatory cytokine interferon-gamma. Elevated levels of circulating antibodies recognizing recombinant mouse NF-L were present in the serum, and immunoglobulin deposits were observed within axons in spinal cord lesions of mice exhibiting clinical disease. These data provide evidence that autoimmunity to NF-L protein induces axonal degeneration and clinical neurologic disease in mice, indicating that autoimmunity to axonal antigens, as described in multiple sclerosis, may be pathogenic rather than acting merely as a surrogate marker for axonal degeneration
    Type of Publication: Journal article published
    PubMed ID: 17413320
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  • 2
    Keywords: APOPTOSIS ; CELLS ; INHIBITOR ; MODEL ; DISEASE ; DAMAGE ; CALCIUM ; MULTIPLE-SCLEROSIS ; inflammation ; SPINAL-CORD ; neurodegeneration ; ENCEPHALOMYELITIS ; DEMYELINATION ; AXONAL-INJURY ; Calpain ; GANGLION-CELL DEATH ; Optic neuritis ; Retinal ganglion cells
    Abstract: Optic neuritis is a common manifestation of multiple sclerosis, an inflammatory demyelinating disease of the CNS. Recently, the neurodegenerative component of multiple sclerosis has come under focus particularly because permanent disability in patients correlates well with neurodegeneration; and observations in both humans and multiple sclerosis animal models highlight neurodegeneration of retinal ganglion cells as an early event. After myelin oligodendrocyte glycoprotein immunization of Brown Norway rats, significant retinal ganglion cell loss precedes the onset of pathologically defined autoimmune optic neuritis. To study the role calcium and calpain activation may play in mediating early degeneration, manganese-enhanced magnetic resonance imaging was used to monitor preclinical calcium elevations in the retina and optic nerve of myelin oligodendrocyte glycoprotein-immunized Brown Norway rats. Calcium elevation correlated with an increase in calpain activation during the induction phase of optic neuritis, as revealed by increased calpain-specific cleavage of spectrin. The relevance of early calpain activation to neurodegeneration during disease induction was addressed by performing treatment studies with the calpain inhibitor calpeptin. Treatment not only reduced calpain activity but also protected retinal ganglion cells from preclinical degeneration. These data indicate that elevation of retinal calcium levels and calpain activation are early events in autoimmune optic neuritis, providing a potential therapeutic target for neuroprotection.
    Type of Publication: Journal article published
    PubMed ID: 23860028
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  • 3
    Keywords: CEREBROSPINAL-FLUID ; MULTIPLE-SCLEROSIS ; BLOOD-BRAIN-BARRIER ; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS ; NMDA RECEPTORS ; RAT MODEL ; AXONAL LOSS ; CNS INFLAMMATION ; NEUROLOGICAL DEFICITS ; NEURONAL APOPTOSIS
    Abstract: Optic neuritis is a common clinical manifestation of the chronic inflammatory CNS disease multiple sclerosis that can result in persistent visual impairment caused by degeneration of optic nerve axons and apoptosis of retinal ganglion cells (RGCs). Using a model of experimental autoimmune encephalomyelitis with optic neuritis (Brown Norway rats), we show that administration of the N-methyl-D-aspartate (NMDA) receptor antagonists memantine or MK801 results in RGC protection, axon protection, and reduced demyelination of optic nerves. Calcium imaging revealed that RGC responses to glutamate stimulation predominantly occurred via NMDA receptors and were inhibited by memantine in a dose-dependent manner. In contrast, oligodendrocytes were mainly responsive through the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptor. This suggests that NMDA receptor blockade protected RGCs directly and that the protection was independent of effects on oligodendrocytes. Moreover, increased RGC survival was observed before the onset of optic nerve demyelination--when RGC degeneration had already started. These results indicate an important pathophysiologic role for NMDA receptor-mediated glutamate toxicity during the induction phase of this disease model and highlight a potential target for therapeutic neuroprotection in human optic neuritis.
    Type of Publication: Journal article published
    PubMed ID: 24806299
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