Chronic Demyelination and Axonal Degeneration in Multiple Sclerosis: Pathogenesis and Therapeutic Implications

Areas of demyelination can be remyelinated by transplanting myelin-forming cells. Schwann cells are the naturally remyelinating cells of the peripheral nervous system and have a number of features that may make them attractive for cell implantation therapies in multiple sclerosis, in which spontaneous but limited Schwann cell remyelination has been well documented. Schwann cells can be expanded in vitro, potentially affording the opportunity of autologous transplantation; and they might also be spared the demyelinating process in multiple sclerosis. Although rat, cat, and monkey Schwann cells have been transplanted into rodent demyelinating lesions, the behavior of transplanted human Schwann cells has not been evaluated. In this study we examined the consequences of injecting human Schwann cells into areas of acute demyelination in the spinal cords of adult rats. We found that transplants containing significant fibroblast contamination resulted in deposition of large amounts of collagen and extensive axonal degeneration. However, Schwann cell preparations that had been purified by positive immunoselection using antibodies to human low-affinity nerve growth factor receptor containing less than 10% fibroblasts were associated with remyelination. This result indicates that fibroblast contamination of human Schwann cells represents a greater problem than would have been appreciated from previous studies.

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Fulminant tumefactive multiple sclerosis: Therapeutic implications of histopathology

Journal of Neurology ◽

10.1007/s00415-008-0883-x ◽

2008 ◽

Vol 255 (8) ◽

pp. 1272-1273 ◽

Cited By ~ 15

Author(s):

M. R. Haupts ◽

S. K. Schimrigk ◽

N. Brune ◽

A. Chan ◽

G. Ahle ◽

...

Keyword(s):

Multiple Sclerosis ◽

Therapeutic Implications ◽

Tumefactive Multiple Sclerosis

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Biological markers in CSF and blood for axonal degeneration in multiple sclerosis

The Lancet Neurology ◽

10.1016/s1474-4422(04)00964-0 ◽

2005 ◽

Vol 4 (1) ◽

pp. 32-41 ◽

Cited By ~ 166

Author(s):

Charlotte E Teunissen ◽

Christine Dijkstra ◽

Chris Polman

Keyword(s):

Multiple Sclerosis ◽

Biological Markers ◽

Axonal Degeneration

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Oligoclonal bands in multiple sclerosis; Functional significance and therapeutic implications. Does the specificity matter?

Multiple Sclerosis and Related Disorders ◽

10.1016/j.msard.2018.07.030 ◽

2018 ◽

Vol 25 ◽

pp. 131-137 ◽

Cited By ~ 13

Author(s):

Gareth Pryce ◽

David Baker

Keyword(s):

Multiple Sclerosis ◽

Functional Significance ◽

Oligoclonal Bands ◽

Therapeutic Implications

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Multiple sclerosis pathogenesis: missing pieces of an old puzzle

Reviews in the Neurosciences ◽

10.1515/revneuro-2018-0002 ◽

2018 ◽

Vol 30 (1) ◽

pp. 67-83 ◽

Cited By ~ 9

Author(s):

Reza Rahmanzadeh ◽

Wolfgang Brück ◽

Alireza Minagar ◽

Mohammad Ali Sahraian

Keyword(s):

Multiple Sclerosis ◽

Cd8 T Cells ◽

Autoimmune Encephalitis ◽

Cd4 T Cell ◽

Experimental Autoimmune Encephalitis ◽

Focal Lesions ◽

Multiple Sclerosis Pathogenesis ◽

Cns Autoimmunity ◽

Ms Pathogenesis ◽

Experimental Autoimmune

Abstract Traditionally, multiple sclerosis (MS) was considered to be a CD4 T cell-mediated CNS autoimmunity, compatible with experimental autoimmune encephalitis model, which can be characterized by focal lesions in the white matter. However, studies of recent decades revealed several missing pieces of MS puzzle and showed that MS pathogenesis is more complex than the traditional view and may include the following: a primary degenerative process (e.g. oligodendroglial pathology), generalized abnormality of normal-appearing brain tissue, pronounced gray matter pathology, involvement of innate immunity, and CD8 T cells and B cells. Here, we review these findings and discuss their implications in MS pathogenesis.

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Nav1.6 promotes inflammation and neuronal degeneration in a mouse model of multiple sclerosis

Journal of Neuroinflammation ◽

10.1186/s12974-019-1622-1 ◽

2019 ◽

Vol 16 (1) ◽

Cited By ~ 5

Author(s):

Barakat Alrashdi ◽

Bassel Dawod ◽

Andrea Schampel ◽

Sabine Tacke ◽

Stefanie Kuerten ◽

...

Keyword(s):

Multiple Sclerosis ◽

Retinal Ganglion Cells ◽

Axonal Degeneration ◽

Ganglion Cells ◽

Neuronal Degeneration ◽

Retinal Ganglion ◽

Autoimmune Encephalomyelitis ◽

Aav Vector ◽

Α Subunit

Abstract Background In multiple sclerosis (MS) and in the experimental autoimmune encephalomyelitis (EAE) model of MS, the Nav1.6 voltage-gated sodium (Nav) channel isoform has been implicated as a primary contributor to axonal degeneration. Following demyelination Nav1.6, which is normally co-localized with the Na+/Ca2+ exchanger (NCX) at the nodes of Ranvier, associates with β-APP, a marker of neural injury. The persistent influx of sodium through Nav1.6 is believed to reverse the function of NCX, resulting in an increased influx of damaging Ca2+ ions. However, direct evidence for the role of Nav1.6 in axonal degeneration is lacking. Methods In mice floxed for Scn8a, the gene that encodes the α subunit of Nav1.6, subjected to EAE we examined the effect of eliminating Nav1.6 from retinal ganglion cells (RGC) in one eye using an AAV vector harboring Cre and GFP, while using the contralateral either injected with AAV vector harboring GFP alone or non-targeted eye as control. Results In retinas, the expression of Rbpms, a marker for retinal ganglion cells, was found to be inversely correlated to the expression of Scn8a. Furthermore, the gene expression of the pro-inflammatory cytokines Il6 (IL-6) and Ifng (IFN-γ), and of the reactive gliosis marker Gfap (GFAP) were found to be reduced in targeted retinas. Optic nerves from targeted eyes were shown to have reduced macrophage infiltration and improved axonal health. Conclusion Taken together, our results are consistent with Nav1.6 promoting inflammation and contributing to axonal degeneration following demyelination.

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