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PubMed2005

Spinal cord injury is accompanied by chronic progressive demyelination.

Preceding the development of therapeutic strategies for spinal cord injury is an identification of those pathological processes that might serve as therapeutic targets. Although demyelination has been documented as a secondary degenerative component of spinal cord injury in several species including humans, the extent of demyelination and its functional consequence remain unknown. In this report, we document the extent of demyelination and remyelination up to 450 days following contusive spinal cord injury in adult rats. The overall number of demyelinated axons peaked at 1 day post injury, declined by 7-14 days post injury, and then progressively increased up to 450 days post injury. Oligodendrocyte and Schwann cell remyelinated axons appeared by 14 days post injury. Although remyelinated axons were present from 14 to 450 days post injury, remyelination was incomplete, as indicated by the presence of demyelinated axons at every time point examined. These studies demonstrate for the first time that spinal cord injury is accompanied by chronic progressive demyelination, and they substantiate demyelination as a target for therapeutic intervention.

Animals↗
PubMed1993

Class I-deficient resistant mice intracerebrally inoculated with Theiler's virus show an increased T cell response to viral antigens and susceptibility to demyelination.

Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) results in immune-mediated demyelination in susceptible mouse strains. The histology of TMEV-induced demyelination is similar to that seen in patients suffering from multiple sclerosis. It was previously shown that the susceptibility of mice to TMEV-induced demyelination in certain strain combinations is closely associated with the major histocompatibility complex (MHC) class I locus. Here we examine disease susceptibility of beta 2-microglobulin (beta 2M)-deficient transgenic mice lacking class I expression and functional CD8+ T cells. In contrast to TMEV-infected parental C57BL/6 mice, the transgenics develop high levels of virus-specific DTH and T cell proliferation accompanied by an increased frequency of central nervous system (CNS) demyelinating lesions. However, clinical signs of demyelination were not noted. Neither antibody titer nor viral persistence were significantly affected in the beta 2M-deficient mice. These results suggest that in the absence of functional class I/CD8+ cells, the class II-restricted T cell response to TMEV is enhanced and CNS pathogenesis is heightened, although the level is not severe enough to result in clinical disease. When the TMEV-infected mice were subcutaneously immunized with virus, however, the beta 2M-deficient mice displayed clinical symptoms. Therefore, our results strongly suggest that CD8+ T cells do not directly contribute to CNS demyelination. In contrast, such T cells appear to be primarily involved in down-regulation of a potentially damaging CD4+ T cell response in resistant animals, although some of the T cells may play a role in clearing viral persistence in the CNS, resulting in the protection of the host from viral demyelination.

Animals↗
PubMed2002

Modelling large areas of demyelination in the rat reveals the potential and possible limitations of transplanted glial cells for remyelination in the CNS.

Transplantation of myelin-forming glial cells may provide a means of achieving remyelination in situations in which endogenous remyelination fails. For this type of cell therapy to be successful, cells will have to migrate long distances in normal tissue and within areas of demyelination. In this study, 40 Gy of X-irradiation was used to deplete tissue of endogenous oligodendrocyte progenitors (OPCs). By transplanting neonatal OPCs into OPC-depleted tissue, we were able to examine the speed with which neonatal OPCs repopulate OPC-depleted tissue. Using antibodies to NG-2 proteoglycan and in situ hybridisation to detect platelet-derived growth factor alpha-receptor Ralpha (PDGFRalpha) mRNA to visualise OPCs, we were able to show that neonatal OPCs repopulate OPC-depleted normal tissue 3-5 times more rapidly than endogenous OPCs. Transplanted neonatal OPCs restore OPC densities to near-normal values and when demyelinating lesions were made in tissue into which transplanted OPCs had been incorporated 1 month previously, we were able to show that the transplanted cells retain a robust ability to remyelinate axons after their integration into host tissue. In order to model the situation that would exist in a large OPC-depleted area of demyelination such as may occur in humans; we depleted tissue of its endogenous OPC population and placed focal demyelinating lesions at a distance (< or =1 cm) from a source of neonatal OPCs. In this situation, cells would have to repopulate depleted tissue in order to reach the area of demyelination. As the repopulation process would take time, this model allowed us to examine the consequences of delaying the interaction between OPCs and demyelinated axons on remyelination. Using this approach, we have obtained data that suggest that delaying the time of the interaction between OPCs and demyelinated axons restricts the expression of the remyelinating potential of transplanted OPCs.

Animals↗
PubMed2003

Inhibition of glial cell proinflammatory activities by peroxisome proliferator-activated receptor gamma agonist confers partial protection during antimyelin oligodendrocyte glycoprotein demyelination in vitro.

Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is a member of the nuclear hormone superfamily originally characterized as a regulator of adipocyte differentiation and lipid metabolism. In addition, PPAR-gamma has important immunomodulatory functions. If the effect of PPAR-gamma's activation in T-cell-mediated demyelination has been recently demonstrated, nothing is known about the role of PPAR-gamma in antibody-induced demyelination in the absence of T-cell interactions and monocyte/macrophage activation. Therefore, we investigated PPAR-gamma's involvement by using an in vitro model of inflammatory demyelination in three-dimensional aggregating rat brain cell cultures. We found that PPAR-gamma was not constitutively expressed in these cultures but was strongly up-regulated following demyelination mediated by antibodies directed against myelin oligodendrocyte glycoprotein (MOG) in the presence of complement. Pioglitazone, a selective PPAR-gamma agonist, partially protected aggregates from anti-MOG demyelination. Heat shock responses and the expression of the proinflammatory cytokine tumor necrosis factor-alpha were diminished by pioglitazone treatment. Therefore, pioglitazone protection seems to be linked to an inhibition of glial cell proinflammatory activities following anti-MOG induced demyelination. We show that PPAR-gamma agonists act not only on T cells but also on antibody-mediated demyelination. This may represent a significant benefit in treating multiple sclerosis patients.

Analysis of Variance↗
PubMed2004

Lysolecithin induces demyelination in vitro in a cerebellar slice culture system.

Demyelination is a hallmark of several human diseases, including multiple sclerosis. To understand better the process of demyelination and remyelination, we explored the use of an in vitro organotypic cerebellar slice culture system. Parasagittal slices of postnatal Day 10 (P10) rat cerebella cultured in vitro demonstrated significant myelination after 1 week in culture. Treatment of the cultures at 7 days in vitro (DIV) with the bioactive lipid lysolecithin (lysophosphatidylcholine) for 15-17 hr in vitro produced marked demyelination. This demyelination was observed by immunostaining for the myelin components myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), and 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNPase). After a transient demyelinating insult with lysolecithin in vitro, the cultures recovered with oligodendrocyte differentiation recapitulating a normal time course; there was initially re-expression of CNPase and MBP during this recovery, and this was followed by MOG. In addition, there seemed to be some limited remyelination during the recovery phase. Lysolecithin thus induces demyelination in an in vitro organotypic cerebellar slice culture system, providing a model system for studying myelination, demyelination, and remyelination in vitro.

2',3'-Cyclic Nucleotide 3'-Phosphodiesterase↗
PubMed2000

Interferon-gamma protects against cuprizone-induced demyelination.

Evidence suggests that interferon-gamma (IFN-gamma), a proinflammatory cytokine secreted by activated T lymphocytes, contributes a deleterious effect to immune-mediated demyelinating disorders such as multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Nevertheless, mouse strains that are normally resistant to EAE induction become susceptible when the gene encoding either IFN-gamma or its receptor is mutated, demonstrating that the role that this cytokine plays in demyelinating disorders is complex. We have examined the effect of IFN-gamma in a chemically induced model of CNS demyelination. Mice that receive through their diet the copper chelator cuprizone display extensive demyelination of the corpus callosum. Remarkably, transgenic mice that ectopically express low levels of IFN-gamma in the CNS did not display evidence of demyelination when treated with cuprizone, nor did they shows signs of oligodendroglial death, astrogliosis, or microgliosis, which are typically seen in treated animals. Myelin protein gene expression was, however, dramatically reduced in both the treated control and the transgenic animals, indicating that demyelination is not an obligatory consequence of a large diminution of myelin protein synthesis. Interestingly, the CNS of the IFN-gamma-expressing mice contained elevated levels of insulin-like growth factor I, which has been demonstrated to have a protective effect against the demyelinating action of cuprizone.

Animals↗
PubMed1983

Virologic models of chronic relapsing demyelinating disease.

The present report, compares two murine models of virus induced chronic relapsing demyelination. MHV-induced demyelination in the BALB/c mouse results from the direct virus mediated cytolysis of oligodendrocytes. Extensive remyelination by oligodendrocytes is noted. Recurrent demyelination occurs in small areas. Infectious virus persists and viral antigens are localized within oligodendrocytes and their processes. TMEV-induced demyelination in SJL/J mice is associated with perivascular inflammatory infiltrates and is diminished by immunosuppressive measures. Remyelination by oligodendrocytes is delayed and incomplete. Chronic demyelination is widespread and associated with perivascular inflammatory infiltrates. The virus persists and viral antigen is localized within oligodendrocytes. The findings indicate virus persistence in oligodendrocytes in both models. Demyelination follows the disintegration of infected oligodendrocytes. Virus replication in oligodendrocytes is responsible for cell lysis in the MHV model whereas immune mediated injury of infected oligodendrocytes is considered to play a role in the pathogenesis of demyelination in the TMEV model.

Animals↗
PubMed1992

Action potential refractory period in axonal demyelination: a computer simulation.

Axonal demyelination leads to an increase in the refractory period for propagation of the action potential. Computer simulations were used to investigate the mechanism by which changes in the passive properties of the internodal membrane increase the refractory period. The properties of the voltage dependent ion channels can be altered to restore conduction in demyelinated nerve fibers. The ability of these alterations to decrease the refractory period of demyelinated model nerve fibers was compared. The model nerve fiber contained six nodes. The action potential was stimulated at node one and propagated to node six. The internode between nodes three and four was demyelinated in a graded manner. The absolute refractory period for propagation of the action potential through the demyelinated internode increased as the number of myelin wraps was reduced to less than 25% of the normal value. The increase in refractory period was found to be due to a reduction in the rate or repolarization of the action potential at node three. The delay in repolarization reduced the rate of recovery of inactivated Na channels and slowed the closing of K channels. The rate of repolarization of node three was reduced by the conduction delay for the depolarization of node four caused by demyelination of the preceding internode. In these simulations the increase in refractory period due to demyelination was eliminated by slowing the onset of Na channel inactivation. A small reduction of the K conductance also decreased the refractory period. However, larger reductions eliminated this effect.

Action Potentials↗
PubMed1978

Multiple sclerosis: demyelination and myelination inhibition of organotypic tissue cultures of the spinal cord by sera of patients with multiple sclerosis and other neurological diseases.

Sera from 44 patients with Multiple Sclerosis, of three patients with neurological syndromes compatible with Multiple Sclerosis, of 34 patients suffering from other neurological diseases and of 25 pregnant healthy young women were tested for their demyelinating activity in myelinated tissue cultures. In order to leave the investigators unprejudiced, all sera were coded and intermixed with controls of rabbit EAE serum which had a potent demyelinating capacity. Demyelination was graded (from 0--4), heat lability at 56 degrees C (complement dependency?) was also tested with each serum. Only demyelination of a degree of 2 and more, which was abolished by heating to 56 degrees C, was counted as positive. Six of the 44 sera from MS patients (13.6%), 19 of 37 sera from neurological patients and none of the healthy young women demyelinated. Thus, serum demyelination of tissue cultures seems to be a nonspecific indicator of chronic disease of the nervous system and is of considerable general neurological interest, but does not indicate a demyelinating disease. Myelination inhibition was not observed with any of the human sera tested for it.

Animals↗
PubMed1980

In vivo demyelination by antimyelin antibodies.

Central nervous system (CNS) myelin-specific antiserum was capable of initiating primary demyelination within 24 h following injection into the dorsal column of guinea pig spinal cord. Control serum injected in the same manner did not produce demyelination. The demyelinating lesions occurred as focal linear plaques of completely denuded intact axons surrounded by partially demyelinated and myelinated normal axons. Antiserum-mediated demyelination was followed by mononuclear cell infiltration 7-10 days later. Ultrastructural examination revealed vesiculation of myelin followed by cleavage of myelin lamellae at the intraperiod line. Remyelination began between 7 and 10 days following injection and correlated well with clinical evidence of recovery. The results of this study point to the importance of circulating antimyelin antibodies in the pathogenesis of demyelinating encephalitis. The model represents an in vivo approach to the study of the pathogenesis of immune-mediated myelinolysis in demyelinating disorders like multiple sclerosis (MS), subacute sclerosing panencephalitis (SSPE), and canine distemper encephalitis (CDE).

Animals↗
PubMed2002

Demyelination precedes oligodendrocyte loss in canine distemper virus-induced encephalitis.

Canine distemper virus (CDV), a negative-stranded RNA morbillivirus, causes a persistent infection within the central nervous system resulting in a progressive, multifocal demyelinating disease. Demyelination is thought to be caused by a selective alteration of the myelin-producing oligodendrocytes. Metabolic impairment and morphological changes of the oligodendrocytes after CDV infection have previously been observed in vitro as well as in vivo. Until now it has been suggested that the oligodendrocytes completely disappear from CDV-induced demyelinating lesions. However, ultrastructural analysis in brain tissue sections and immunohistochemical examination of oligodendrocytes in dog brain cell cultures contradicted these observations. In this study oligodendrocytes from different categories of CDV-induced lesions were examined by in situ hybridization for proteolipid protein mRNA and--as a new tool employed on canine brain tissue sections--by immunohistochemistry using a monoclonal antibody against 2',3'-cyclic nucleotide 3'-phosphodiesterase, a myelin-specific enzyme. A down-regulation in the myelin gene transcription was detected already before demyelination occurred. However, a decrease in the number of oligodendrocytes was not observed until demyelination became evident. Although there was further depletion of oligodendrocytes in plaques with progressive demyelination, we demonstrated for the first time that these cells were still present in a significant amount even in chronic, completely demyelinated distemper lesions.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1997

Action potentials and ionic currents through paranodally demyelinated human motor nerve fibres: computer simulations.

The relationship between the changes in the passive paranodal properties of the myelinated human motor nerve fibres and the conduction abnormalities obtained is examined on the basis of a double-cable model. Simulated systematic demyelination (all paranodal regions uniformly affected) and focal demyelination (paranodal regions at each end of a single internode affected) of the fibres are defined as a reduction of the paranodal seal resistance. By increasing the degree of demyelination, the kinetics of the action potentials and ionic currents in different segments of the fibres are explored. The altered paranodal seal resistance is found to be a factor impeding the invasion of the demyelinated regions by an action potential. We established that the conduction along the most severely demyelinated fibres (i.e. in the case of systematically demyelinated fibres) is more affected than along the focally demyelinated fibres.

Action Potentials↗
PubMed1993

MHC class II antigen expression and T-cell infiltration in the demyelinating CNS and PNS of the twitcher mouse.

The expression of the major histocompatibility complex class II antigens (Ia) was investigated in the central and peripheral nervous systems of the twitcher mouse, an authentic murine model of globoid cell leukodystrophy (Krabbe disease) in humans. In this mutant, demyelination is noted as early as postnatal day 10 in the peripheral nerve and day 20 in the spinal cord. Emergence of Ia antigen expressing cells (Ia+ cells) was largely coincident with the initiation of demyelination, suggesting the importance of local factors for the induction of Ia antigens. Ia+ cells gradually increased in number with the progression of demyelination, but reached a plateau between postnatal days 30 and 40, then rapidly decreased despite continuous demyelination in both central and peripheral nervous systems. The only exception was in the spinal cord where Ia+ cells were numerous even at postnatal day 50. The cells expressing L3T4 antigen (L3T4+ cells), which is a mouse CD4 antigen, and the interleukin-2 receptor antigen expressing cells (IL-2R+ cells), also appeared in the regions where Ia+ cells were observed. L3T4+ cells were still abundant after P45, when Ia+ and IL-2R+ cells decreased. Combined autoradiographic and immunocytochemical studies demonstrated mitotic activity in a few Ia+ cells. However, low labeling indices of Ia+ cells in both cerebrum and sciatic nerve suggest that the increase of Ia+ cells was largely due to either induction of Ia antigens on local cells or new recruitment of Ia+ cells from the circulation. Expression of Ia antigens associated with an emergence of L3T4+ or IL-2R+ cells in the demyelinating lesions may indicate involvement of immunological responses in the pathogenesis of this metabolic demyelinating disorder. Alternatively, these apparent immunological phenomena may be tentative and non-specific local reactions to degenerating tissue components such as myelin. The mechanism(s) regulating the expression of Ia antigens in this genetic metabolic demyelinating disease is yet to be determined.

Animals↗
PubMed1979

Recurrent demyelination in chronic central nervous system infection produced by Theiler's murine encephalomyelitis virus.

A morphologic study of demyelination produced by Theiler's encephalomyelitis virus (TMEV) infection in C3H/He mice was performed. Demyelination in this strain of mouse was less intense and had a milder gliomesodermal response than that observed in SJL mice. As early as 80 days after infection numerous remyelinated axons were present in C3H/He mice, and later, extensive remyelination was observed and was mainly by Schwann cells. About one-third of remyelinated plaques showed recurrent demyelinating activity at 200 days. The best evidence of recurrent demyelination was the loss of myelin by abons which had been previously remyelinated by Schwann cells. In addition, acute areas of demyelination were also seen in spinal cords which contained chronic or quiescent plaques. The demonstration of recurrent demyelination in TMEV infection is important for it increases the relevance of this model to multiple sclerosis (MS). In addition TMEV infection of C3H/He mice appears to be an excellent model for further studies of Schwann cell remyelination and recurrent demyelination in the central nervous system (CNS).

Animals↗
PubMed1984

Intra-axonal virus in demyelinative lesions of experimental herpes simplex type 2 infection.

Three-week-old mice which had been infected intracerebrally with herpes simplex virus type 2 (HSV-2) were examined electron-microscopically for the presence of intra-axonal virus in or near optic nerve and spinal cord demyelinative lesions. Acute lesions and their margins frequently contained a very small proportion of abnormal axons, and in a few of these mature virus particles, nucleocapsids, or other incomplete forms were found. A similar range of particle morphology was present in the cytoplasm of infected and degenerating glia. Axons containing similar particles were not identified in fibers in normal white matter surrounding demyelinative lesions. It is proposed that neuronal infection and axonal transport of virus may lead to foci of oligodendroglial infection, destruction and central nervous system (CNS) demyelination near to or remote from the cell bodies of infected neurons. In some instances, the topography of lesions could reflect a tract association. Anatomical features of nervous tissue could favor amplification of demyelination from a relatively minimal neuronal infection, with little evidence of tract degeneration. This hypothesis is consistent with the great predominance of demyelination relative to gray matter disease seen experimentally in non-fatal CNS infections with HSV-2. It would also explain the marked tendency for demyelinative lesions in at least certain CNS locations to be greatly elongated in the long axis of fiber tracts. This mechanism could be of importance in other animal models of virus-induced demyelination, and perhaps also in multiple sclerosis.

Animals↗
PubMed1985

Vesicular demyelination induced by raised intracellular calcium.

Incubation of nerve with high concentrations of the divalent cation ionophore A23187 produces myelin vesiculation (Schlaepfer 1977). This observation has now been extended using segments of rat ventral or dorsal root incubated with high (19 microM, 10 micrograms/ml) or low (1-1.5 microM) concentrations of A23187, or another divalent ionophore, ionomycin. Low concentrations of A23187 induced no vesiculation within a 2-h period. However, subsequent incubation of these roots in fresh, ionophore-free medium for 20 h, resulted in a prominent vesicular demyelination at the Schmidt-Lanterman incisures and paranodes of many fibres. At this time (22 h) the Schwann cells associated with some demyelinating internodes appeared vital upon ultrastructural examination: the cells also excluded the nuclear dye nigrosin. High concentrations of A23187 induced a similar vesicular demyelination in affected fibres within only 15-20 min. While the Schwann cells continued to exclude nigrosin for a further 4 h, their ultrastructural appearance indicated that they were probably in the early stages of necrosis. Incubation of moribund root with the ionophore produced no myelin vesiculation. At all ionophore concentrations, the myelin vesiculation was dependent upon the presence of extracellular Ca2+, and could be modulated in severity by varying this concentration. Other divalent cations (Ba2+, Co2+, Mg2+, Mn2+, Ni2+, Sr2+) could not substitute for Ca2+. The vesiculation induced by A23187 could be entirely prevented by the addition of Zn2+ (greater than or equal to 1 microM), Ni2+ (greater than or equal to 1-10 microM), Co2+ (greater than or equal to 100 microM) or Mn2+ (greater than or equal to 100 microM) to the bathing medium. A23187 applied to only part of an isolated internode resulted in a localization of the myelin disruption to that region. Ionomycin (greater than or equal to 1 microM), an ionophore with a greater selectivity for Ca2+ than A23187, also induced a prompt Ca2+-dependent myelin vesiculation. We conclude that vesicular demyelination can be initiated in vital Schwann cells by a raised intracellular Ca2+ concentration. Such demyelination does not necessarily lead to Schwann cell death. The possible relevance of the findings to vesicular demyelinating neuropathies is discussed, and a hypothesis regarding the mechanism of demyelination is advanced.

Animals↗
PubMed1989

Demyelination in spinal cord injury.

Morphological and physiological studies demonstrate that demyelination constitutes a significant component of the pathology in compressive spinal cord injury. In many cases of spinal cord injury, a rim of demyelinated axons surrounds a central core of hemorrhagic necrosis. This provides a pathophysiological basis for "discomplete" spinal cord injuries, characterized by apparently complete transection as judged by clinical criteria, but with neurophysiological evidence of conduction through the level of damage. Recovery of conduction in demyelinated axons may permit recovery of function, and can be mediated by several mechanisms, including remyelination by oligodendrocytes or Schwann cells. Alternatively, conduction of action potentials can occur in the absence of remyelination, but this requires plasticity of the demyelinated axon. The biophysics of conduction favors recovery of electrogenesis after demyelination of small diameter axons. This may account, in part, for the observation that functional recovery is more common after demyelination of visual, compared to spinal, axons. Restoration or modification of conduction in demyelinated fibers represents an important strategy for promoting functional recovery in spinal cord injury.

Axons↗
PubMed1982

The effect of short-term and chronic immunosuppression on Theiler's virus demyelination.

Theiler's virus (TV)-infected mice were treated with antithymocyte serum (ATS), cyclophosphamide or pepstatin (a protease inhibitor) to determine the effect on demyelination. When ATS and cyclophosphamide were begun at the time of infection there was significantly less demyelination at 2.5-3.5 weeks than in pepstatin or non-treated infected controls. When immunosuppression was continued for 5 weeks, or when it was not started until 5 weeks post-infection, no significant decrease in demyelination was seen compared to controls. The findings indicate that timing of immunosuppression is critical in determining the extent of TV demyelination. Such demyelination may occur by different mechanisms that are active at different times. The "bystander effect' may be important in early demyelination, but late demyelination may be due to other causes, such as oligodendrocyte lytic infection.

Animals↗