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PubMed1993

Proliferation of microglia/macrophages in the demyelinating CNS and PNS of twitcher mouse.

In demyelinating lesions in the central and peripheral nervous systems of twitcher mouse, a murine model of globoid cell leukodystrophy, marked increases of [3H]thymidine-labeled elements including Mac-1 immunopositive (Mac-1+) microglia/macrophages was observed. Their proliferative activities were already pronounced at the postnatal day (P) 20, an early stage of demyelination, peaked at P30 and then declined at P45, at the terminal stage of the disease. Many of the [3H]thymidine-labeled Mac-1+ cells had morphological features of ramified microglia. Macrophage-like Mac-1+ cells were less frequently labeled. The results of this study showed that (1) microglia/macrophages proliferated in the genetic demyelinating lesions, (2) many dividing Mac-1+ cells had the shape of ramified microglia and (3) the rate of proliferation declined in later stages when reactive microglia/macrophages were abundant in the lesions. The temporal events of this study suggest that signal(s) from the degenerating myelin or myelin-forming cells stimulate(s) cellular proliferation and that ramified microglia were one of the principal-dividing elements in the lesion. The biological mechanisms underlying the decline of the proliferative activity of microglia require further studies.

Animals↗
PubMed1978

Demyelination of Sternarchus electrocyte fibers by injection of diphtheria toxin.

Diphtheria toxin was injected into the electric organ of the gymnotid fish, Sternarchus albifrons. After 10 days, there was extensive demeylination of electrocyte fibers in the area of injection. Electron microscopy showed that paranodal loops of myelin do not separately cleanly from the axon, and remnants of the myelin loops may persist after demyelination of the internodes is nearly complete. The dense cytoplasmic undercoating of the nodal axolemma may disappear before the paranodal junctions are completely gone. Observations of demyelination of internodes between the elaborate, inexcitable nodes suggest that the presence of myelin may not be necessary for the maintenance of structural differentiation of this region of the axolemma. Use of diphtheria toxin to demyelinate Sternarchus electrocytes may provide a useful system for experimental neuropathological studies.

Animals↗
PubMed1979

Latent herpes simplex virus trigeminal ganglionic infection in mice and demyelination in the central nervous system.

Mice were inoculated with herpes simplex virus (HSV) type 1 by gently scraping the skin of the nose with a fine needle. About 80% of the animals developed latent inapparent HSV infections in trigeminal ganglia. Virus was demonstrable for at least 6 months post inoculation (p.i.) by cocultivation of ganglionic tissue with GMK cells. Histologically, trigeminal ganglia revealed infiltrations of inflammatory cells even 6 months p.i. In addition, lesions occurred in the brainstem corresponding to the entry of trigeminal roots, trigeminal tracts and nuclei. Inflammatory cell infiltration, disruption of myelin sheaths and macrophages laden with myelin degradation products were observed 7 days p.i. Fourteen to 30 days p.i. electron microscopy demonstrated completely naked axons. In the transitional region of the trigeminal root denuded axons occurred in the central part of the region while the peripheral myelin, bordering the demyelinated central segments, was intact. Small areas of demyelination were still detectable 3 and 6 months p.i. but there were then also signs of remyelination. Possible mechanisms causing the demyelinations are discussed.

Animals↗
PubMed1979

Virus-induced demyelination. Production by a viral temperature-sensitive mutant.

Infection of mice with a temperature-sensitive (ts) mutant of Chandipura virus (CV) ts472 CV, induced a slower disease than the respective parental virus and white matter lesions characterized by perivascular mononuclear infiltrates accompanied by primary demyelination. The pattern of these lesions was very similar to that in EAE, a prototypic autoimmune disease and in Theiler's virus infection in which an immunopathologic mechanism of myelin injury is strongly suggested. Results obtained in nude mice supported the possible immunopathological nature of myelin injury in ts472 CV infection. No inflammatory response was elicited in either grey or white matter. However, whereas grey matter presented extensive necrosis, no alterations were present in white matter. Such data suggest that whereas grey matter lesions are produced by direct viral cytolytic activity, white matter pathology is probably dependent on the host immune response for its development. The finding of additional models of virus-induced demyelination with a possible immunopathologic mechanism of myelin injury is significant as it suggests that this type of virus-induced myelin degeneration is not restricted to a single virus like Theiler's, but it may represent a more general mechanism of virus-induced demyelination.

Animals↗
PubMed1980

Remyelination by cells introduced into a stable demyelinating lesion in the central nervous system.

Schwann cells from an autogeneic peripheral nerve source were injected into an established demyelinating lesion produced by the direct micro-injection of diphtheria toxin into the cat spinal cord. In control diphtheria toxin lesions, which were not injected with Schwann cells, demyelination and some oligodendrocyte remyelination was seen but Schwann cell remyelination was not observed. In diphtheria toxin lesions which were wholly confined to the posterior columns, Schwann cell myelin was not seen before 3 weeks after cell injection. The Schwann cell myelinated fibres occurred singly or in small groups within the posterior columns and were considered to have been myelinated by injected Schwann cells. By one month Schwann cell myelinated fibres had thick myelin sheaths but many demyelinated axons remained. By contrast, in more extensive diphtheria toxin lesions there was widespread Schwann cell remyelination of central axons at all stages examined after cell injection. The Schwann cell myelinated fibres were grouped in large numbers around the damaged dorsal root entry zones, the likely source of Schwann cells in these lesions. It is concluded that CNS remyelination may be improved by the injection of peripheral Schwann cells although the extent of remyelination is limited. One facet limiting remyelination may be the concentration of Schwann cells that it is possible to inject with present techniques. Functional recovery remains to be investigated.

Animals↗
PubMed1980

Nerve conduction during peripheral demyelination and remyelination.

The changes in the conduction properties of peripheral nerve fibres of the mouse were examined during the phases of segmental demyelination, and remyelination, following the intraneural injection of lysophosphatidyl choline (LPC). In this lesion the sequence of the morphological changes was well synchronised in the different calibre fibres and this permitted a closer correlation to be made between the histological and physiological events than has been possible with other experimental models. Conduction in the nerve fibres was blocked during demyelination and for 1--2 days after the axons were completely free of myelin. In many fibres, however, conduction was later restored at about the time the demyelinated axon membrane became reassociated with debris-free Schwann cells, but prior to remyelination; at this time the fibres were unable to conduct closely spaced impulses and the conduction velocity was low. During the subsequent period of remyelination the ability of the fibres to conduct closely spaced impulses was fully restored and the conduction velocity progressively increased; the remyelinated internodes remained both thinner and shorter than normal. The physiological properties of the fibres were described in terms of their refractory periods of transmission (RPTs) as well as their conduction velocities; only the description in terms of the RPT correlated well with the histological events and with the degree of the behavioural deficit.

Action Potentials↗
PubMed1981

Central nervous system demyelination in Venezuelan equine encephalomyelitis infection.

Arboviruses are important pathogens for both animals and humans. Venezuelan equine encephalomyelitis virus (VEEV) is an arbovirus whose pathogenicity for grey matter structures has been previously studied. To our knowledge, the present study is the first to describe extensive inflammation and demyelination in spinal cord white matter of mice infected with VEEV. To probe a possible immunepathogenesis of white matter alterations in this infection, nude mice and heterozygous controls were similarly infected. Whereas controls still showed inflammatory demyelination, nude mice showed no white matter changes in the absence of a mononuclear inflammatory response. These results suggest that white matter changes in VEEV infection are dependent upon the host immune-response, rather than produced by primary viral cytolytic activity. Such findings are similar to those we and others obtained in a number of different viral infections and support the possibility that the host immune response may be the common denominator leading to myelin injury in a variety of viral diseases. The hypothesis of "by-stander killing" of myelin is discussed as a possible host-mediated mechanism of demyelination in viral infections.

Animals↗
PubMed1981

Demyelination in vitro. Absorption studies demonstrate that galactocerebroside is a major target.

Myelinated cultures of mouse spinal cord have been exposed to sera raised in rabbits against whole white matter (anti-WM), myelin basic protein (anti-MBP) and galactocerebroside (anti-GC), the major glycolipid of CNS myelin, to determine which factor in central nervous system (CNS) tissue in vitro is the target of serum demyelinating and myelin swelling antibodies. The sera were tested by radioimmunoassay for activity against MBP and against GC and were also specifically absorbed with MBP, GC and control antigens. Studies were also performed with and without active complement. The findings show that demyelination and myelin swelling in vitro are caused by antibodies against GC and not against MBP. Ultrastructurally, the effects of anti-WM and anti-GC sera with and without complement were indistinguishable. This study demonstrates that GC is a major target in antibody-mediated demyelination.

Absorption↗
PubMed1981

The demyelinating effect of corneal HSV infections in normal and nude (athymic) mice.

Nude (athymic) mice and their immune competent Balb/c litter mates were infected with herpes simplex virus (HSV) type I on the scarified cornea. Seven to eight days after infection the trigeminal root entry zone was examined by light and electron microscopy. The immune competent Balb/c litter mates demonstrated marked central nervous system (CNS) demyelination when compared to the T cell-deficient animals who showed mild edematous change and minimal CNS demyelination ultrastructurally 7 days after infection. Viral titers were similar in both groups at this time. These studies further substantiate a role for the cell-mediated immune system in the CNS demyelination 1 week after corneal infection with HSV.

Animals↗
PubMed1984

Demyelination following diphtheria toxin in the presence of axonal atrophy.

In 23 guinea-pigs a constricting ligature was placed on the tibial nerve in the thigh on one side, in order to produce axonal atrophy in the distal part of the nerve. Either before or after ligature, 10 of the guinea-pigs received subcutaneous diphtheria toxin into the abdominal wall, in a dose insufficient to cause generalised paralysis or reduced motor conduction velocity (MCV). In 7 of the 10 animals, MCV distal to the ligature fell below the range seen after ligature alone. In animals which had received toxin histological studies revealed paranodal and segmental demyelination in the distal tibial nerve, which was more extensive on the side of the ligature than in the opposite leg. Occasional paranodal but no segmental demyelination was seen distal to ligature alone. These results indicate that a small dose of systemic diphtheria toxin is more likely to produce peripheral nerve demyelination if an axonal abnormality is also present.

Action Potentials↗
PubMed1984

Experimental demyelinating optic neuropathy induced by intra-neural injection of galactocerebroside antiserum.

The morphological changes induced by microinjection of galactocerebroside (Gal-C) antiserum into the rat optic nerve are described. Light and electron microscopic observations were made 2-20 days post-injection. The severity and extent of the lesion varied according to the volume of antiserum injected and the depth of penetration into the nerve. With small volumes of antiserum (1-3 microliters), primary demyelination was the principal change found from 2 days onwards and by 10 days there was evidence of remyelination by oligodendroglia. Some fibres undergoing Wallerian-type degeneration were also found. The injection of larger volumes of antiserum (5-10 microliters) produced a more extensive lesion with marked axonal degeneration in addition to demyelination at the periphery of the lesion. These findings show that Gal-C antiserum can cause demyelination of central nerve fibres when the blood-brain barrier is bypassed.

Animals↗
PubMed1985

Fine structure of astrocytic processes during serum-induced demyelination in vitro.

Astrocytic changes were examined ultrastructurally during serum-induced demyelination in organotypic cultures of mouse spinal cord tissue. The myelin sheaths of most myelinated fibers showed myelin breakdown. Sheet-like astrocytic processes completely and closely surrounded the demyelinating fibers and frequently engulfed myelin fragments. These processes were virtually devoid of glial filaments or microtubules and contained flocculogranular material, round and elongated cisterns and glycogen granules. Penetration of the myelin sheath by astrocytic processes was only rarely found. The cell body of the astrocyte was never insinuated between the myelin sheath and the axon. No endocytosis of myelin droplets via coated pits on the surface of astrocytes was observed. In comparison with phagocytic mononuclear cells in vivo, astrocytes in vitro dispose of myelin debris less actively. Astrocytes in serum-induced demyelination probably play a nonspecific but fundamental role during degeneration in segregating damaged nerve fibers from surrounding neuronal elements.

Animals↗
PubMed1986

Quantitation of myelination and demyelination by the measurement of myelin basic protein by ELISA.

Utilizing a competitive inhibition enzyme-linked immunosorbent assay (ELISA) we measured the amount of myelin basic protein (MBP) in brain, liver, and kidney of newborn mouse and compared these values with myelinated cerebellar explant cultures under various conditions. Explant cultures demyelinated with anti-myelin serum showed a 90% decrease in MBP when compared with controls. These results correlated with myelination and demyelination as observed by light microscopy. Newborn tissues including brain showed only negligible activity for MBP. This technique provides a sensitive and objective method for quantitating in-vitro demyelination.

Animals↗
PubMed1987

The C57BL mice: an animal model for inflammatory demyelinating polyneuropathy.

Recently it has been reported that the C57BL mice can be used as a model of benign monoclonal gammopathy (MG). Since experimental models have until now failed to reproduce specific lesions of human dysglobulinemic polyneuropathies, we decided to investigate the peripheral nerve of these mice. The sciatic nerve and the serum from 14 C57BL mice were examined: 9 of these animals were found to have an IgG, kappa light chain MG, while in the other 5 no abnormalities were detected in the serum. In the 14 mice, features of demyelination were found in certain fibers, as well as onion-bulb formations around other myelinated fibers. Features of active demyelination were found in 10 animals and it must be underlined that three of these had no serum abnormalities. The decrease of the conduction velocities and the temperature coefficients Q10 of the C57BL mice suggest a good correlation between morphological and functional parameters. This strongly suggests that this strain of mice provides a suitable model for inflammatory demyelinating polyneuropathy (IDPN).

Animals↗
PubMed1987

Decrease in oligodendrocyte carbonic anhydrase activity preceding myelin degeneration in cuprizone induced demyelination.

Both immunohistochemical and biochemical evidence is presented to show for the first time that carbonic anhydrase II (CA II) activity falls in the brain of mice in cuprizone (bis(cyclohexanone)oxalyldihydrazone) induced demyelination well before demyelination develops. This fall began during the first week, whereas the first signs of myelin degeneration induced by cuprizone did not appear until 3 weeks and demyelination in the superior cerebellar peduncle in the mouse took 6-8 weeks to develop. The findings suggest that oligodendrocyte CA II activity is essential either for the survival of oligodendrocytes or for the maintenance of central myelin.

Animals↗
PubMed1987

Myelin proteolipid protein induces demyelinating disease in mice.

Using two methods of immunization (A and B), 5/10 (A) and 27/45 (B), BALB/c by J mice immunized with human myelin proteolipid protein developed a demyelinating disease with a spectrum of chronic progressive to relapsing-remitting courses. Demyelinative lesions were seen histopathologically in all clinically affected animals that were examined. Many of the clinically unaffected animals also had histopathologic evidence of demyelination. Some of the animals had evidence of multiple ages of foci of activity. Evidence is presented that contamination with myelin basic protein could not account for the disease. This is a new model for multiple sclerosis in mice.

Animals↗
PubMed1995

Fulminant Guillain-Barré syndrome with quadriplegia and total paresis of motor cranial nerves as a result of segmental demyelination.

Guillain-Barré syndrome (GBS) is a subacute demyelinating polyneuropathy with a monophasic course. Rarely, demyelination may be so severe as to produce electrically unexcitable nerves. We present a patient with fulminant onset of symptoms who was quadriplegic and had bilateral involvement of all motor cranial nerves. Serial EMGs indicated that segmental demyelination was responsible for these clinical findings.

Cranial Nerve Diseases↗
PubMed1989

Characterization of coronavirus JHM variants isolated from Wistar Furth rats with a viral-induced demyelinating disease.

Murine hepatitis virus (MHV) can cause neurological disease when inoculated intracerebrally (ic) into mice and rats. Specifically the JHM strain of MHV (MHV-JHM) generally causes an acute encephalitis when inoculated ic into 2-day-old Wistar Furth rats. In contrast, JHM generally produces a chronic demyelinating disease with resulting posterior paralysis when inoculated ic into 10-day-old Wistar Furth rats. In addition, while JHM readily produces a productive infection in a mouse fibroblast cell line (L-2), it does not form syncytia or replicate well in a tissue cell line of glial origin (G26-24). We have isolated and characterized three MHV-JHM viral variants from the central nervous system of two Wistar Furth rats with a MHV-JHM-induced demyelinating disease. The pattern of viral-specific mRNA for all three of these variants differed from what was observed for the wild-type parental MHV-JHM that had been passaged only in tissue culture. One of these variants, ATllf cord virus, which induced a chronic demyelinating disease in 2- or 10-day-old intracerebrally inoculated Wistar Furth rats, had a deletion in the coding region of the peplomer glycoprotein mRNA. In addition, this variant formed massive syncytia and replicated well in G26-24 cells. We have not detected this deletion in the other two JHM variants, ATllf brain virus and ATlle brain virus. ATllf brain virus and ATlle brain virus primarily produced an acute encephalitis when reinoculated into 2- or 10-day-old Wistar Furth rats. In addition, these two variants did not form syncytia and had a reduced ability to replicate in G26-24 cells.

Animals↗