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PubMedDate not supplied

Enhancement of demyelination in the central nervous system of Semliki Forest virus infected mice after pretreatment with muramyl dipeptide.

Semliki Forest virus infections in mice produce an encephalitis with demyelination. If before giving the virus the mice are treated with muramyl dipeptide in Freund's incomplete adjuvant, there is a significant increase in demyelination. If ovalbumin is added to the above and then followed after an interval by a second dose of ovalbumin and finally by the virus, the demyelination is further, but only marginally increased. The addition of ovalbumin without muramyl dipeptide in the schedule appears to increase the number of infiltrating cells and to a lesser extent the perivascular cuffing, but does not increase the demyelination as compared to that obtained when Semliki Forest virus is given on its own.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1991

Coronavirus induced primary demyelination: indications for the involvement of a humoral immune response.

Coronavirus MHV-JHM infection of rodents can result in demyelinating encephalomyelitis. We analysed histological changes induced by coronavirus MHV-JHM infection in Lewis rats. Besides an acute disease (AE), chronic panencephalitis (CPE) and subacute demyelinating encephalomyelitis (SDE) were induced. These disease types were differentiated by the incubation period, the localization of lesions, the type of tissue damage and distribution of virus antigen. In AE and CPE, virus antigen was detected in neurons, astrocytes and oligodendrocytes, whereas in SDE neurons lacked virus antigen. Viral nucleocapsid protein (N) was present in the cytoplasm and the spike protein (S) was displayed on the surface of infected neural cells. However, expression of S protein relative to N protein was severely impaired in SDE lesions. Quantitative analysis of infiltrating inflammatory cells revealed that the number of macrophages and T cells were similar in lesions of AE, CPE and SDE. In contrast to that, SDE lesions contained a significantly higher number of IgG + B cells and plasma cells. In addition active demyelinating SDE lesions displayed an enhanced IgG content and deposits of complement C9. These results indicate that virus induced primary demyelination could be a consequence of antibody mediated cytotoxicity. Furthermore, a reduction in the number of cells producing spike protein in the chronic forms of the disease indicates down-regulation of this protein, possibly mediated by anti-S antibodies.

Animals↗
PubMed2006

Polyneuropathy with demyelinating features in mixed cryoglobulinemia with hepatitis C virus infection.

Peripheral neuropathy can arise from various mechanisms during hepatitis C virus (HCV) infection, mainly involving associated mixed cryoglobulinemia. The frequency of demyelinating polyneuropathy is probably underestimated in these patients. We report two cases of demyelinating polyneuropathy in HCV-infected patients. The first case concerned a 76-year-old woman followed for hepatitis C associated with a mixed cryoglobulinemia (type II), who developed a chronic progressive distal motor weakness and sensory disturbances concomitant with a raise in serum aspartate aminotransferase (GOT/AST) and alanine aminotransferase (GPT/ALT) levels. Other laboratory studies were normal except for a decrease in the hemolytic fraction of complement to 75 IU (n = 400-520). The second case was a 68-year-old woman followed for hepatitis C associated with a mixed cryoglobulinemia (type II), who had sensory disturbances in the lower limbs. Laboratory studies were otherwise unremarkable. Cerebrospinal fluid studies showed a normal protein content without pleocytosis in both patients. In both cases nerve conduction studies were suggestive of a mixed axonal and demyelinating sensorimotor neuropathy. Sural nerve biopsy showed segmental demyelination and severe loss of large myelinated fibers as well as some onion bulb formation in both cases. The two patients subsequently improved, the first with an antiviral treatment and the second with oral steroids.

Aged↗
PubMed1988

An in vitro micromethod for the quantitative assessment of central demyelination.

We report the development of a simple and reliable method for the study of demyelination in vitro based on the measurement of 2':3'-cyclic nucleotide 3'-phosphodiesterase in isolated myelin. Using only small quantities of myelin (equivalent to 100 micrograms of myelin protein) the system was tested under conditions that are believed to approximate those found at the site of an inflammatory demyelinating lesion. Treatment with a combination of trypsin, phospholipase A2, and lysophosphatidylcholine was used to evaluate the method. This microsystem has the potential not only for testing the myelinotoxicity of soluble factors but also for investigating the involvement of inflammatory cells in the demyelinating process. Myelin degradation by elicited peritoneal macrophages could be demonstrated at relatively high densities of these cells. Nylon wool purified lymph node T cells from myelin basic protein-primed SJL/J mice, after selective expansion with antigen and interleukin 2, failed to induce any significant myelin breakdown unless a limited number of syngeneic activated macrophages were also present. T cells from mice that had been inoculated with keyhole limpet haemocyanin failed to show any effect. The advantages of this technique over other in vitro systems are that it enables the study of demyelination using syngeneic sources of myelin and defined cell populations.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed2004

Distinct promoters regulate tissue-specific and differential expression of kallikrein 6 in CNS demyelinating disease.

Kallikrein 6 is a serine protease expressed abundantly in normal adult human and rodent CNS, and therein is regulated by injury. In the case of CNS demyelinating disease, K6 expression in CNS occurs additionally in perivascular and parenchymal inflammatory cells suggesting a role in pathogenesis. Herein we describe two unique transcripts that occur within the human and mouse K6 genes that differ in their 5'-untranslated regions. These transcripts have identical translation initiation sites in exon 3, are expressed in a tissue-specific fashion and are differentially regulated in response to CNS injury. While the human and mouse 5'-transcripts differ in sequence they are identical in genomic organization and tissue-specific expression. The most 5'-transcript, designated transcript 1, includes exon 1-7, and was detectable in all CNS regions, but not in any non-CNS tissues examined (spleen, thymus, liver, kidney, pancreas, submandibular gland and peripheral nerve). In contrast, transcript 2 lacks exon 1, but contains a unique sequence at the 5'-end of exon 2, designated exon 2A. Transcript 2 was expressed both in CNS and in each peripheral tissue. In a murine model of human CNS demyelinating inflammatory disease induced by Theiler's picornovirus, mouse K6 transcript 1 was up-regulated in brain and spinal cord at acute and more chronic phases of CNS inflammation and demyelination, while overall transcript 2 expression was not significantly altered. However, in isolated splenocyte cultures, transcript 2 was up-regulated two-fold by cellular activation. Tissue-specific expression patterns and differential regulation in CNS disease indicates that each K6 5'-transcript is probably regulated by unique promoter elements and may serve as a molecular target to treat inflammatory demyelinating disease.

Animals↗
PubMed1986

Studies on lymphokine-mediated demyelination in organotypic rat cerebellum in culture.

Supernatants of peripheral blood lymphocytes (PBL), containing lymphokines, isolated from MS patients and healthy subjects were tested for demyelinating activity in organotypic culture of the rat cerebellum. PBL were isolated on Ficoll-paque gradient and cultures in RPMI 1640 medium for 72 h with or without phytohemagglutinin and Concanavalin A. Both stimulated and unstimulated PBL supernatants from MS patients consistently demyelinated cerebellum cultures. The supernatants of unstimulated PBL from healthy subjects did not produce demyelination, however, slight effect was present in the cultures treated with PBL stimulated supernatants. The results indicate that lymphokines might be involved in demyelination in MS.

Adult↗
PubMed1996

Animal models of demyelination.

Demyelination is a pathological feature that is characteristic of many diseases of the central nervous system (CNS) including multiple sclerosis (MS), sub-acute sclerosing panencephalomyelitis (SSPE), metachromatic leukodystrophy and Pelizaeus-Merzbacher disease. While demyelination is a pathological end-point that is common to all of these diseases, the cellular and molecular mechanisms responsible for this pathology are very different . These range from genetic defects that affect lipid metabolism in the leukodystrophies, cytopathic effects of viral infection in SSPE to the action of immunological effector mechanisms in MS and the viral encephalopathies. Irrespective of the initial cause of myelin degradation, many of these disorders are associated with some degree of CNS inflammation, as indicated by the local activation of microglia, recruitment of macrophages or the intrathecal synthesis of immunoglobulin. Many of these phenomena are now being duplicated in animal models, providing not only new insights into the pathogenesis of human demyelinating diseases , but also unexpected interrelationships between the immune response in the CNS and the pathogenesis of diseases such as Alzheimers disease and HIV encephalopathy. Autoimmune mediated models of inflammatory demyelinating CNS disease have proved particularly valuable in this respect as they allow the effects of defined immune effector mechanisms to be studied in the absence of CNS infection.

Animals↗
PubMed1998

Central demyelination of the Vth nerve root in trigeminal neuralgia associated with vascular compression.

We have examined the ultrastructure of the trigeminal sensory nerve root in three patients with medically intractable trigeminal neuralgia. In one patient, the nerve root was sandwiched between a large vein and a small pontine artery, in the others compression was due to marked dolichoectasia of a verterbal artery. Because these were not amenable to microvascular decompression, a caudal rhizotomy was performed, by excising a short inferior segment of nerve root in the region of indentation. In all cases, examination revealed a zone of chronic demyelination in the proximal (centrally myelinated) part of the root, near its junction with peripheral nerve. The zone of demyelination contained closely packed axons without intervening glial cytoplasm. Also present were small numbers of thinly myelinated axons. In some cases a single thin myelin sheath encircled several adjacent axons that were still in close apposition. These findings indicate that the trigeminal neuralgia associated with vascular compression is due to demyelination. The demyelination is associated with some evidence of remyelination. The latter phenomenon may account in part for the long periods of remission, especially during the initial period after the onset of trigeminal neuralgia. The partly aberrant nature of the myelination within the region of vascular compression may contribute to the persistence of symptoms in some patients after decompressive surgery.

Aged↗
PubMed1999

Response of glia, mast cells and the blood brain barrier, in transgenic mice expressing interleukin-3 in astrocytes, an experimental model for CNS demyelination.

Transgenic mice overexpressing cytokines facilitate analysis of the effects of these immunomodulators on indigenous cells of the central nervous system. This study examines morphological aspects of demyelination and permeability changes, in a recently described transgenic model (termed GFAP-IL3). GFAP-IL3 mice develop progressive motor disease at approximately 5 months. Lesions identified after disease onset, showed activation of microglia, astroglial proliferation with phagocytosis of lipids, and immigration of macrophages and mast cells into neural parenchyma. Lymphocytes failed to appear until the later stages of the disease. Later, cerebellar and brain stem white matter contained focal demyelinating lesions with intense macrophage infiltration and a proliferative astrocytosis. Dystrophic axonal changes were noted, in addition to demyelination in heavily infiltrated lesions. Mast cells, variably present in the thalamus and meninges of wild type mice, were greatly increased at these sites in GFAP-IL3 mice. Blood-brain barrier (BBB) defects were documented with leakage of intravenously injected horseradish peroxidase. Mast cell infiltration into the CNS and their degranulation at the site of injury, may represent initial events in a spontaneous process of macrophage mediated demyelination in which glial cells and macrophages are both involved in the phagocytic process.

Animals↗
PubMed2001

The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system.

Myelin of the adult CNS is vulnerable to a variety of metabolic, toxic, and autoimmune insults. That remyelination can ensue, following demyelinating insult, has been well demonstrated. Details of the process of remyelination are, however difficult to ascertain since in most experimental models of demyelination/remyelination the severity, localization of lesion site, or time course of the pathophysiology is variable from animal to animal. In contrast, an experimental model in which massive demyelination can be reproducibly induced in large areas of mouse brain is exposure to the copper chelator, cuprizone, in the diet. We review work from several laboratories over the past 3 decades, with emphasis on our own recent studies, which suggest an overall picture of cellular events involved in demyelination/remyelination. When 8 week old C57BL/6 mice are fed 0.2% cuprizone in the diet, mature olidgodendroglia are specifically insulted (cannot fulfill the metabolic demand of support of vast amounts of myelin) and go through apoptosis. This is closely followed by recruitment of microglia and phagoctytosis of myelin. Studies of myelin gene expression, coordinated with morphological studies, indicate that even in the face of continued metabolic challenge, oligodendroglial progenitor cells proliferate and invade demyelinated areas. If the cuprizone challenge is terminated, an almost complete remyelination takes place in a matter of weeks. Communication between different cell types by soluble factors may be inferred. This material is presented in the context of a model compatible with present data -- and which can be tested more rigorously with the cuprizone model. The reproducibility of the model indicates that it may allow for testing of manipulations (e.g. available knockouts or transgenics on the common genetic background, or pharmacological treatments) which may accelerate or repress the process of demyelination and or remyelination.

Animals↗
PubMed2003

Direct comparison of demyelinating disease induced by the Daniel's strain and BeAn strain of Theiler's murine encephalomyelitis virus.

We compared CNS disease following intracerebral injection of SJL mice with Daniel's (DA) and BeAn 8386 (BeAn) strains of Theiler's murine encephalomyelitis virus (TMEV). In tissue culture, DA was more virulent then BeAn. There was a higher incidence of demyelination in the spinal cords of SJL/J mice infected with DA as compared to BeAn. However, the extent of demyelination was similar between virus strains when comparing those mice that developed demyelination. Even though BeAn infection resulted in lower incidence of demyelination in the spinal cord, these mice showed significant brain disease similar to that observed with DA. There was approximately 100 times more virus specific RNA in the CNS of DA infected mice as compared to BeAn infected mice. This was reflected by more virus antigen positive cells (macrophages/microglia and oligodendrocytes) in the spinal cord white matter of DA infected mice as compared to BeAn. There was no difference in the brain infiltrating immune cells of DA or BeAn infected mice. However, BeAn infected mice showed higher titers of TMEV specific antibody. Functional deficits as measured by Rotarod were more severe in DA infected versus BeAn infected mice. These findings indicate that the diseases induced by DA or BeAn are distinct.

Analysis of Variance↗
PubMed1992

Ectopic activity in demyelinated spinal root axons of the rat.

1. We have provoked ectopic discharges from demyelinated rat spinal roots by applying 1 mM-4-aminopyridine (4-AP), and recorded membrane currents and action potentials extracellularly by spike-triggered averaging. The demyelination was caused by intrathecal injection of diphtheria toxin, 6-9 days previously. 2. Mapping the distribution of membrane currents in the vicinity of an ectopic site showed that in most cases (eight out of twelve recorded) the impulses arose from one end of a continuously conducting internode, and conducted in both directions. In the remaining cases the impulses also arose from a site of demyelination. 3. The 4-AP-induced activity resembled the activity occurring spontaneously in some preparations, and was often highly regular (5-20 Hz). Recordings of membrane potential revealed a pacemaker potential, which was localized to the site of impulse initiation. One ectopic site was tested with applied currents and found to have a linear current-frequency relation for steady currents. 4. The time course of the pacemaker potential resembled that of the small after-hyperpolarization seen in normal fibres, due to a slow K+ conductance (GKs). Tetraethylammonium and barium ions, which block GKs, made spontaneously active fibres fire much more rapidly, or to fire bursts of action potentials. 5. Possible mechanisms for these ectopic discharges are discussed. GKs appears to contribute to the pacing of the activity, but not its generation. The increased excitability of the active fibres could not be attributed directly to the loss of myelin, nor to extracellular K+ accumulation. We suggest that they may have been depolarized by stretch-activated or ligand-gated channels in the demyelinated axon membrane.

4-Aminopyridine↗
PubMed2002

Contact-dependent demyelination by Mycobacterium leprae in the absence of immune cells.

Demyelination results in severe disability in many neurodegenerative diseases and nervous system infections, and it is typically mediated by inflammatory responses. Mycobacterium leprae, the causative organism of leprosy, induced rapid demyelination by a contact-dependent mechanism in the absence of immune cells in an in vitro nerve tissue culture model and in Rag1-knockout (Rag1-/-) mice, which lack mature B and T lymphocytes. Myelinated Schwann cells were resistant to M. leprae invasion but undergo demyelination upon bacterial attachment, whereas nonmyelinated Schwann cells harbor intracellular M. leprae in large numbers. During M. leprae-induced demyelination, Schwann cells proliferate significantly both in vitro and in vivo and generate a more nonmyelinated phenotype, thereby securing the intracellular niche for M. leprae.

Animals↗
PubMed1987

Monoclonal anti-I-A antibody reverses chronic paralysis and demyelination in Theiler's virus-infected mice: critical importance of timing of treatment.

Susceptibility to demyelination caused by the WW isolate of Theiler's murine encephalomyelitis viruses is linked to class II genes of the major histocompatibility complex. SJL/J (H-2s) mice, expressing only I-As class II gene products of the major histocompatibility complex, are highly susceptible to Theiler's murine encephalomyelitis virus infection with the WW virus isolate, with chronic paralysis and severe inflammation and demyelination in the central nervous system. The effect of in vivo administration of anti-I-As monoclonal antibodies on Theiler's murine encephalomyelitis virus infection was observed. SJL/J mice were treated in various protocols pre- or postinfection. Anti-I-As monoclonal antibody reversed chronic paralysis and reduced inflammation and demyelination when given after the establishment of persistent infection. The effect was long lasting, but clinical signs, inflammation, and demyelination recurred 2 months after treatment ceased. Anti-I-As antibodies had no effect on viral titers within the central nervous system. The timing of the administration of monoclonal antibodies was critical. Administration of anti-I-As before the establishment of the persistent infection resulted in fatal encephalitis.

Animals↗
PubMed1990

Strains from both Theiler's virus subgroups encode a determinant for demyelination.

The GDVII strain and other members of the GDVII subgroup of Theiler's murine encephalomyelitis viruses (TMEV) cause an acute lethal neuronal infection in mice, whereas the DA strain and other members of the TO subgroup of TMEV cause a chronic demyelinating disease associated with a persistent virus infection. We used GDVII/DA chimeric infectious cDNAs to produce intratypic recombinant viruses in order to clarify reasons for the TMEV subgroup-specific difference in demyelinating activity. We found that both the GDVII and DA strains contain a genetic determinant(s) for demyelinating activity. No demyelination occurs following GDVII strain inoculation because this strain produces an early neuronal disease that kills mice before white matter disease and persistent infection can occur.

Animals↗
PubMed1991

Determinants of persistence and demyelination of the DA strain of Theiler's virus are found only in the VP1 gene.

The DA strain of Theiler's virus persists in the central nervous systems of mice and causes chronic inflammation and demyelination. The GDVII strain, on the other hand, causes an acute encephalitis that kills the host in a matter of days. We constructed a series of recombinants between two infectious cDNA clones of the genomes of DA and GDVII viruses. Analysis of the phenotypes of the recombinant viruses yielded the following results. (i) Determinants of persistence and demyelination are found only in the VP1 capsid protein of DA virus. (ii) Whereas the VP1 capsid protein of DA virus is able to fully attenuate the neurovirulence of GDVII virus and to allow the chimeric virus to persist and demyelinate, the VP1 capsid protein of GDVII virus is unable to render DA virus neurovirulent. (iii) The mere attenuation of the neurovirulence of GDVII virus does not allow it to persist and demyelinate.

Animals↗
PubMed1997

Association between susceptibility to Theiler's virus-induced demyelination and T-cell receptor Jbeta1-Cbeta1 polymorphism rather than Vbeta deletion.

Theiler's murine encephalomyelitis virus (TMEV) induces demyelinating disease in susceptible mouse strains after intracerebral inoculation. The clinical symptoms and histopathology of the central nervous system appear to be similar to those of human multiple sclerosis (MS), and thus, this system provides an excellent infectious animal model for studying MS. The virus-induced demyelination is immune mediated, and the genes involved in the immune response such as those for the T-cell receptor beta-chain and major histocompatibility complex (MHC) haplotypes are known to influence disease susceptibility. To define whether the T-cell receptor Jbeta-Cbeta or Vbeta genes are associated with susceptibility, we have analyzed F2 mice from crosses of susceptible SJL/J (Vbeta(a)-JCbeta(b)) mice and resistant C57L (Vbeta(a)-JCbeta(a)) mice. Our results indicate that susceptibility to TMEV-induced demyelination is associated with restriction fragment length polymorphism reflecting the T-cell receptor Jbeta1-Cbeta1 region rather than the Vbeta polymorphism. This association becomes stronger when the MHC haplotype is considered in the linkage analysis. However, differences in the T-cell receptor alpha-chain haplotype have no significant influence on the pathogenesis of TMEV-induced demyelination.

Animals↗
PubMed1998

A protein critical for a Theiler's virus-induced immune system-mediated demyelinating disease has a cell type-specific antiapoptotic effect and a key role in virus persistence.

TO subgroup strains of Theiler's murine encephalomyelitis virus (TMEV) induce a persistent central nervous system infection and demyelinating disease in mice. This disease serves as an experimental model of multiple sclerosis (MS) because the two diseases have similar inflammatory white matter pathologies and because the immune system appears to mediate demyelination in both processes. We previously reported (H. H. Chen, W. P. Wong, L. Zhang, P. L. Ward, and R. P. Roos, Nat. Med. 1:927-931, 1995) that TO subgroup strains use an alternative initiation codon (in addition to the AUG used to synthesize the picornavirus polyprotein from one long open reading frame) to translate L*, a novel protein that is out of frame with the polyprotein and which plays a key role in the demyelinating disease. We now demonstrate that L* has antiapoptotic activity in macrophage cells and is critical for virus persistence. The antiapoptotic action of L* as well as the differential translation of L* and virion capsid proteins may foster virus persistence in macrophages and interfere with virus clearance. The regulation of apoptotic activity in inflammatory cells may be important in the pathogenesis of TMEV-induced demyelinating disease as well as MS.

Animals↗