Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “DEMYELINATION”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 109 records · Page 6Linked to original sources
PubMed2002

Sequential diffusion-weighted magnetic resonance imaging study of lysophosphatidyl choline-induced experimental demyelinating lesion: an animal model of multiple sclerosis.

PURPOSE: To differentiate the surrounding edema from the focal demyelinating lesion during the early phase of the lesion using an apparent diffusion coefficient (ADC), and to monitor the changes in ADCs during the complete progression of a lysophosphatidyl choline (LPC)-induced experimental demyelinating lesion, an animal model of multiple sclerosis (MS). MATERIAL AND METHODS: Eighteen rats divided into two groups-demyelinating lesion (group I, N = 12) and vehicle group (saline injected; group II, N = 6)-were studied. A 0.2-microl quantity of 1% LPC solution in isotonic saline was injected in the rat brain internal capsule (IC) area to create the demyelinating lesion. Six rats were used exclusively for histology. Diffusion-weighted (DW) images were acquired at different diffusion weightings on the 3rd, 5th, 10th, 15th, and 20th days after LPC injection. ADC was measured from three regions of interest (ROIs) within the IC: focal demyelinating lesion (area A), surrounding area of the lesion (area B), and contralateral IC area (area C). RESULTS: Histology revealed demyelination of the IC area during the early phase of lesion progression up to day 10 and remyelination thereafter. Elevated ADCs were observed for the surrounding edematous area (area B), compared to the focal demyelinating lesion (area A) during the early phase of the demyelination process, while substantial reduction of ADCs was noticed during remyelination for both regions. CONCLUSION: Measurement of ADC showed clear differentiation of the surrounding edema from the LPC-induced focal demyelinating lesion in rats, especially during the early phase of the lesion progression.

Analysis of Variance↗
PubMed1995

Demyelination induced by murine coronavirus JHM infection of congenitally immunodeficient mice.

Mouse hepatitis virus JHM (JHMV or MHV-4) induces demyelination in rodents and has been studied as a model for the human disease, multiple sclerosis (MS). As is proposed in MS, the mechanism of subacute demyelination induced by JHMV appears to be primarily immunopathological, since demyelination in JHMV-infected mice is abrogated by immunosuppressive doses of irradiation and restored by adoptive transfer of splenocytes. Thy-1+ cells play a critical role in transmitting disease to these recipient mice. To further characterize cells which may mediate JHMV-induced immunopathology, we inoculated congenitally immunodeficient mice with JHMV. By 12 days post-inoculation, both immunocompetent C57BL/6J controls and athymic nude C57BL/6 mice had severe paralysis and demyelination. In marked contrast, C57BL/6 mice with the severe combined immune deficiency (SCID) mutation had little or no paralysis or demyelination. Adoptive transfer of immune spleen cells from nude mice to infected SCID mice produced paralysis and demyelination. These findings suggest that a cell population present in immunocompetent C57BL/6J and nude mice but absent or non-functional in irradiated and SCID mice is essential for JHMV-induced demyelination. Identification of cells which mediate demyelination in this experimental system may have implications for our understanding of coronavirus pathogenesis and human demyelinating diseases.

Animals↗
PubMed1990

Schwann cell proliferation following lysolecithin-induced demyelination.

Schwann cell division, meticulously regulated throughout development, occurs at an extremely low level in normal adult nerves. Loss of the myelin sheath in disease results in active proliferation of Schwann cells. The dividing cells are usually thought to be the Schwann cells of the demylinated fibres and their daughters. In this study we asked if other populations of Schwann cells might also divide following focal monophasic demyelination, and if the proliferating Schwann cells would be found only in the foci of demyelination. [3H]thymidine incorporation was examined by autoradiography at intervals after topical application of lysolecithin (lysophosphatidyl choline) to rat sciatic nerves. The postlabelling intervals were set to identify premitotic cells, cells shortly after mitosis (perimitotic cells) and postmitotic cells, as well as to provide cumulative labelling over 3 days. The affected nerves had three distinct zones. The first was a zone of nearly complete demyelination immediately beneath the perineurium. The subjacent zone was normal morphologically except for numerous supernumerary Schwann cells, displacement of some Schwann cell perikarya, ultrastructural changes in a few myelinated fibres, and rare demyelinated and remyelinated fibres. The third zone, beneath the first two, was normal. In the focus of demyelination there were large numbers of Schwann cells in S phase on days 4 and 6. These cells included premyelinating Schwann cells that were contacting or ensheathing demyelinated axons or collateral axonal sprouts. The subjacent region also contained dividing Schwann cells, most of which were Schwann cells of unmyelinated Remak fibres. In addition, occasional Schwann cells of thickly myelinated fibres (fibres that had not previously undergone demyelination) were labelled by the premitotic schedule; most of these fibres had morphological abnormalities in the Schwann cell perikaryon or myelin sheath. In many, the perikaryon of the Schwann cell was beginning to separate from the rest of the Schwann cell cytoplasm and the myelin sheath. These changes suggested that these fibres were destined to undergo subsequent demyelination, a hypothesis supported by the absence of any normal myelinated fibres with labelled Schwann cell nuclei in nerves removed 1 week after labelling. Thus, this model provided no evidence for division by Schwann cells that continued to maintain myelin sheaths. Taken together, these results suggest that there is a 'surround' of Schwann cell proliferation around foci of demyelination; in this surround multiple populations of Schwann cells are recruited to proliferate, including Schwann cells of intact unmyelinated fibres. Structurally normal unmyelinated fibres appear to provide an unexpected source of new Schwann cells in nerve disease.

Administration, Topical↗
PubMed2000

Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation.

Damage to axons is taken as a key factor of disability in multiple sclerosis, but its pathogenesis is largely unknown. Axonal injury is believed to occur as a consequence of demyelination and was recently shown to be a feature even of the early disease stages. The present study was aimed at characterizing the association of axonal injury and histopathological hallmarks of multiple sclerosis such as demyelination, cellular infiltration and expression of inflammatory mediators. Therefore, axon reduction and signs of acute axonal damage were quantified in early lesion development of chronic multiple sclerosis and correlated with demyelinating activity and inflammation. Patients with secondary progressive multiple sclerosis revealed the most pronounced axonal injury, whereas primary progressive multiple sclerosis patients surprisingly showed relatively little acute axonal injury. Acute axonal damage, as defined by the accumulation of amyloid precursor protein (APP), was found to occur not only in active demyelinating but also in remyelinating and inactive demyelinated lesions with a large inter-individual variability. Only few remyelinating lesions were adjacent to areas of active demyelination. In this minority of lesions, axonal damage may have originated from the neighbourhood. APP expression in damaged axons correlated with the number of macrophages and CD8-positive T lymphocytes within the lesions, but not with the expression of tumour necrosis factor-alpha (TNF-alpha) or inducible nitric oxide synthase (iNOS). Axonal injury is therefore, at least in part, independent of demyelinating activity, and its pathogenesis may be different from demyelination. This has major implications for therapeutic strategies, which aim at preventing both demyelination and axonal loss.

Adolescent↗
PubMed1992

Herpes simplex virus type I (HSV I)-induced multifocal central nervous system (CNS) demyelination in mice.

Multifocal central nervous system (CNS) demyelination develops in the brains of SJL/J, PL/J, and A/J mice following lip inoculation with a specific strain of herpes simplex virus I (HSV I). The lesions in all three inbred strains of mice share similar characteristics including demyelination, relative preservation of axons, and a mononuclear cell (MNC) infiltrate. The lesions, developing during the early phase of demyelination, also appear sequentially in the CNS (trigeminal root entry zone of the brainstem greater than cerebellum greater than cerebral hemispheres) of all three strains of mice but differ in the time of their initial appearance following infection as well as their morphology. In SJL/J mice, new areas of demyelination are observed for only 24 days following lip inoculation with virus. Late stage multifocal CNS demyelination persists throughout 28 weeks postinoculation (pi) in PL/J mice while in A/J mice the development of new areas of demyelination are restricted to 8 weeks pi. Although mononuclear inflammatory cells are present in the new areas of demyelination in either PL/J or A/J mice, viral antigens are not detected in the CNS beyond 12 days pi. In contrast, in situ hybridization studies using 35S-cDNA HSV probes and performed beyond day 12 pi identify probe-positive cells central to a number of the multifocal CNS demyelinating lesions in A/J mice. Results from studies with inbred and congenic strains of mice indicate that the major histocompatibility complex (H-2) does not determine the development of multifocal CNS demyelination following lip inoculation with HSV I but does influence the morphological appearance of the lesions that do develop.

Animals↗
PubMed2006

Cortical demyelination can be modeled in specific rat models of autoimmune encephalomyelitis and is major histocompatibility complex (MHC) haplotype-related.

In recent years, a number of histopathologic studies revealed the presence of cortical demyelination in multiple sclerosis (MS). The underlying mechanisms responsible for cortical demyelination are unresolved. Recently, the presence of cortical lesions in autoimmune encephalomyelitis (EAE) induced in marmosets and Lewis rats has been demonstrated. So far, it is not known whether cortical demyelinated lesions are also present in other models of EAE. In this study, we analyzed a large spectrum of different rat strains actively immunized with myelin oligodendrocyte glycoprotein (MOG), a model strongly mimicking MS for cortical demyelination. By using sets of rat strains with the constant EAE-permissive LEW nonmajor histocompatability complex (MHC) genome, but different MHC haplotypes, we demonstrated that considerable cortical demyelination was only found in LEW.1AR1 (RT1) and LEW.1W (RT1) strains. These rat strains have the isotypes and alleles RT1.BD in the MHC II region and RT1.C in the nonclassic MHC I region in common. Because cortical demyelination was most prominent in LEW.1AR1 rats, an additional strong influence is promoted by the RT1.A MHC class I allele. Demyelination was accompanied by microglia infiltration and deposition of immunoglobulins on myelin sheaths. Our study shows that extensive cortical demyelination can be reproducibly induced in certain rat strains by active immunization with MOG. Furthermore, our findings suggest that cortical demyelination in EAE depends on particular combinations of MHC I and class II isotypes and alleles. The mechanisms for this influence and any similar effects in humans will be important to define.

Alleles↗
PubMed1996

Morphology of oligodendrocytes during demyelination in optic nerves of mice infected with Semliki Forest virus.

Multiple sclerosis (MS) is a demyelinating disease which affects oligodendrocytes, the myelinating cells of the CNS. Demyelination is known to occur in the optic nerves of Balb/c mice infected with the avirulent A7(74) strain of Semliki Forest virus (SFV), and many of the changes are similar to those of patients with MS. The aim of the present study was to determine how demyelination proceeds in individual oligodendrocytes in SFV infection, to help in understanding the pathology of demyelination and remyelination in MS. The whole-cell morphology of individual oligodendrocyte units (defined as the oligodendrocyte, its processes and the internodal myelin segments of the axons it ensheaths) was characterized using intracellular dye injection in isolated intact optic nerves. In untreated control mice, oligodendrocytes had a relatively uniform morphology and each cell on average provided 20 or so nearby axons with single myelin sheaths with internodal lengths of approximately equal to 150 microns. In SFV infected mice, during the peak of demyelination at post-inoculation days 14-21, 55% of oligodendrocytes displayed a range of morphological abnormalities, which most likely represented sequential changes in oligodendrocytes during demyelination. Thus, at the earliest stage of demyelination oligodendrocytes developed swellings or vacuolations along their internodal myelin sheaths, which became gradually attenuated and were completely lost in extreme cases. The results show that whole oligodendrocyte units were affected during SFV-induced demyelination and this is the basis of the focal nature of lesions in this viral model of MS. Individual oligodendrocyte units which had lost their full complement of myelin sheaths had the appearance of immature oligodendrocytes, suggesting they had undergone dedifferentiation. We concluded that these cells may not be destroyed during demyelination and it is possible they are capable of remyelination which is a feature of SFV infection in mice and MS in humans.

Animals↗
PubMed2005

Viral expression of CCL2 is sufficient to induce demyelination in RAG1-/- mice infected with a neurotropic coronavirus.

Mouse hepatitis virus strain JHM causes a chronic demyelinating disease in susceptible strains of rodents. Demyelination does not develop in infected RAG1-/- (recombination activation gene-deficient) mice but can be induced by several experimental interventions, including adoptive transfer of virus-specific T cells or antibodies. A common feature of demyelination in these models is extensive infiltration of macrophages/microglia into the white matter. The data obtained thus far do not indicate whether macrophage/microglia infiltration, in the absence of T cells or antibody, is sufficient to mediate demyelination. To determine whether the expression of a single macrophage chemoattractant, in the context of virus infection, could initiate the demyelinating process, we engineered a recombinant coronavirus that expressed the chemokine CCL2/monocyte chemoattractant protein-1. CCL2 has been implicated in macrophage infiltration into the central nervous system and is involved in demyelination in many experimental models of demyelination. Extensive macrophage/microglia infiltration and demyelination has developed in RAG1-/- mice infected with this recombinant virus. Thus, these results suggest that the minimal requirement for demyelination is increased expression of a single macrophage-attracting chemokine in the context of an inflammatory milieu, such as that induced by a viral infection.

Animals↗
PubMed2005

Experimental demyelination caused by primary oligodendrocyte dystrophy. Regional distribution of the lesions in the nervous system of mice [corrected].

BACKGROUND AND PURPOSE: Heterogeneity of multiple sclerosis lesions has been recently indicated: In addition to T-cell-mediated or T-cell plus antibody-mediated autoimmune mechanisms (patterns I-II) two other patterns (IIl-IV) were described. Patterns Ill-IV are characterized by primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity. It was described more than 30 years ago that dietary application of a copper-chelating agent called cuprizone results in primary oligodendrocyte degeneration which is followed by demyelination. The aim of the present study was to examine the regional distribution of cuprizone induced oligodendrocyte dystrophy and demyelination in the nervous system of mice. MATERIAL A METHODS: Demyelination was induced in male weanling Swiss-Webster mice by feeding them on a diet containing 0.6% (W/W) cuprizone bis(cyclohexanone)-oxalyldihydrazone (G. F. Smith Chemical, Columbus OH) for 8 weeks. Animals were sacrificed after 3, 7, 14, 27, 35, 56 days of cuprizone administration. Samples were taken from corpus callosum, anterior commissure, optic nerve, cervical spinal cord and sciatic nerve. Samples were examined by immunohistochemistry, in situ hybridization for myelin proteins and myelin protein mRNA-s, respectively. Conventional neuropathological stainings and electron microscopy was also performed. RESULTS: Oligodendrocyte degeneration and demyelination followed a particular standard pattern in the central nervous system. Profound myelin loss developed in the superior cerebellar peduncle, anterior commissure and corpus callosum, whereas the optic nerves, velum medullare anterior and spinal cord showed little or no demyelination. Sciatic nerves were unaffected. No infiltration by lymphocytes or blood-brain barrier damage was observed during cuprizone treatment. CONCLUSION: Cuprizone induced oligodendrocyte damage and demyelination follows a particular standard pattern in the central nervous system of mice. Cuprizone induced demyelination might be considered as a model for human demyelinating disorders with primary oligodendrocyte dystrophy and apoptosis.

Animals↗
PubMed1992

Demyelination in spinal cord injury and multiple sclerosis: what can we do to enhance functional recovery?

Demyelination in white matter tracts has been observed in experimental and human spinal cord injury. The pathophysiology of demyelinated axons depends, in part, on their ion channel organization. Myelinated axons display a complementary distribution of sodium channels (clustered in the nodal axon membrane) and fast potassium channels (in the internodal axon membrane). The low density of sodium channels in the internodal axon membrane will impede conduction after demyelination. Moreover, "unmasked" potassium channels will tend to clamp the axon membrane close to EK, interfering with conduction in demyelinated axons. Pharmacologic blockade of these potassium channels can increase the safety factor for conduction in demyelinated axons. Restoration of conduction in demyelinated axons, so that action potentials can traverse the zone without myelin, appears to underly clinical remissions in patients with multiple sclerosis and may occur in some patients with spinal cord injury. At a cellular level, conduction through demyelinated axon regions can be facilitated by several mechanisms, including remyelination, development of excitability in demyelinated regions (which requires an adequate density of sodium channels), and impedance matching. Astrocytes have been shown to establish a specific relationship with sodium channel-rich regions of the axon membrane, and may play a role in the deployment and/or maintenance of sodium channels within the demyelinated axon membrane. Calcium influx appears to play a critical role in the cascade of events leading to secondary injury after spinal cord trauma. Recent observations suggest the hypothesis that myelin damage in spinal cord trauma may be mediated, at least in part, by influx of calcium into an intracellular compartment. As the route of calcium entry is identified and characterized, it may be possible to design strategies that will limit secondary injury after CNS trauma. The deleterious effects of calcium in injured white matter accumulate gradually, which suggests the potential reversibility of dysfunction in spinal cord tracts if treated early after trauma.

Animals↗
PubMed1990

The relationship between viral RNA, myelin-specific mRNAs, and demyelination in central nervous system disease during Theiler's virus infection.

The DA strain of Theiler's murine encephalomyelitis virus (DAV) causes a chronic demyelinating disease in susceptible mouse strains. To elucidate the pathogenesis of DAV-induced demyelination, the authors investigated the spatial and chronologic relationship between virus (antigen and RNA), myelin-specific mRNAs, and demyelination in DAV-infected mice using immunohistochemistry, in situ hybridization, and slot blot hybridization analyses. In spinal cord white matter, viral RNA was detected easily in ventral root entry zones 1 to 2 weeks after infection. Viral RNA increased to maximum levels by 4 weeks after infection, which was associated with inflammation and mild demyelination. At 8 to 12 weeks after infection, when demyelination became most extensive, viral RNA was significantly decreased. Demyelination did not chronologically or spatially parallel the presence of viral RNA within the spinal cord. Decrease of myelin-specific mRNAs, including myelin-basic protein and proteolipid protein mRNAs, was observed within the demyelinating lesions with or without detectable viral RNA. These results indicate that a viral infection of white matter in the early phase of the infection initiates spinal cord disease leading to demyelination, but later an ongoing immunopathologic process contributes to the presence of extensive demyelination.

Animals↗
PubMed1993

Abrogation of resistance to Theiler's virus-induced demyelination in H-2b mice deficient in beta 2-microglobulin.

Intracerebral infection of susceptible strains of mice with Theiler's virus, a picornavirus, results in central nervous system demyelination, which is similar to multiple sclerosis. Immunogenetic experiments indicate that the MHC (H-2) and, in particular, the D region that controls class I-restricted immune responses, is an important determinant to development of demyelination. We tested whether disruption of beta 2-microglobulin (beta 2-m) would abrogate resistance to demyelinating disease normally observed in H-2b mice. All (C57BI/6 x 129)F3 mice transgenic for homozygous beta 2-m gene disruption (-/-) developed chronic demyelination after Theiler's murine encephalomyelitis virus infection, whereas none of the infected littermates with normal expression of class I MHC (beta 2-m, +/+) developed demyelination. Demyelinated lesions showed class II MHC expression, macrophages, and TNF but no class I MHC expression or CD8+ T cells. No correlation was observed between development of demyelination and delayed-type hypersensitivity responses to virus Ag. Despite the presence of demyelinating lesions, none of the infected beta 2-m (-/-) mice developed neurologic deficits. Infectious virus and virus Ag persisted in the central nervous systems of infected beta 2-m (-/-) mice but not in beta 2-m (+/+) mice. These experiments support the hypothesis that a class I immune response mediated by CD8+ T cells is important in resistance to Theiler's murine encephalomyelitis virus-induced demyelination. Development of chronic neurologic deficits as observed in immunocompetent susceptible strains of mice may be dependent on the presence of class I MHC and CD8+ T cells.

Animals↗
PubMed1979

Multiple sclerosis: immunochemical studies on the demyelinating serum factor.

Sera from patients with multiple sclerosis (MS) frequently produce demyelination of central nervous system tissue cultures. The nature of the factors responsible for demyelination is not as yet clearly established. However, several authors previously reported, in in vivo and in vitro models, demyelinating activity in IgG fractions isolated from sera and cerebrospinal fluid of MS patients14,42,48. We found the demyelinating activity of MS sera to be extremely labile to conventional biochemical treatments. Therefore, we isolated IgG from MS sera by absorption with staphylococcal protein A. Protein A binds specifically IgG1. IgG2 and IgG4. With this method we were able to remove most of the IgG, leaving only a small percentage, most probably IgG3, in the sera. Isolated IgG fractions from several sera of MS patients in the presence of human complement actively demyelinated central nervous system tissue cultures. Although a small, but significant, decrease in demyelinating activity could be observed in most of the sera absorbed in most of the sera absorbed with protein A, the majority of the demyelinating activity could not be removed by this treatment. From these studies, it appears that at least the majority of demyelinating activity in MS sera is not associated with IgG1, IgG2 or IgG4. If IgG is responsible for demyelination, IgG3 will most likely be the active factor.

Autoimmune Diseases↗
PubMed1989

Demyelination and early remyelination in experimental allergic encephalomyelitis passively transferred with myelin basic protein-sensitized lymphocytes in the Lewis rat.

Histological studies were performed on Lewis rats with experimental allergic encephalomyelitis (EAE) passively transferred by myelin basic protein (MBP)-sensitized syngeneic spleen cells in order to determine the relationship between demyelination and neurological signs. Neither inflammation nor demyelination was present on the day prior to the onset of neurological signs but both were present in the spinal roots and spinal cord on the day of onset of tail weakness (4 days after passive transfer). Demyelination and the neurological signs both increased over the next 48 h. There was evidence that the caudal roots were more severely affected than the rostral roots. The peripheral nerves were spared. Demyelination in the spinal cord was concentrated in the dorsal root entry and ventral root exit zones. The initial stages of repair of demyelinated spinal root fibres by Schwann cells were observed on the earliest day that clinical recovery commenced (day 7). At this time some demyelinated fibres were closely associated with debris-free Schwann cells, and occasional fibres were completely invested by 1-2 layers of Schwann cell cytoplasm. Remyelination (compact myelin lamellae formation) by Schwann cells was first observed in the spinal roots on day 9. By the time of complete clinical recovery (day 11) the majority of affected spinal root cores had thin new myelin sheaths. Repair of central nervous system myelin by oligodendrocytes was slower than peripheral nervous system myelin repair. Investment of demyelinated spinal cord axons by oligodendrocytes was observed on day 9, and remyelination by these cells was seen on day 10. We conclude that the neurological signs of passively induced MBP-EAE can be accounted for by demyelination of the lumbar, sacral and coccygeal spinal roots and spinal cord root entry and exit zones, and that the subsequent clinical recovery can be explained by investment and remyelination of demyelinated peripheral and central nervous system fibres by Schwann cells and oligodendrocytes respectively.

Animals↗
PubMed2005

Inflammation stimulates remyelination in areas of chronic demyelination.

A major challenge in multiple sclerosis research is to understand the cause or causes of remyelination failure and to devise ways of ameliorating its consequences. This requires appropriate experimental models. Although there are many models of acute demyelination, at present there are few suitable models of chronic demyelination. The taiep rat is a myelin mutant that shows progressive myelin loss and, by 1 year of age, its CNS tissue has many features of chronic areas of demyelination in multiple sclerosis: chronically demyelinated axons present in an astrocytic environment in the absence of acute inflammation. Using the taiep rat and a combination of X-irradiation and cell transplantation, it has been possible to address a number of questions concerning remyelination failure in chronic multiple sclerosis lesions, such as whether chronically demyelinated axons have undergone changes that render them refractory to remyelination and why remyelination is absent when oligodendrocyte progenitor cells (OPCs) are present. Our experiments show that (i) transplanted OPCs will not populate OPC-containing areas of chronic demyelination; (ii) myelination competent OPCs can repopulate OPC-depleted chronically demyelinated astrocytosed tissue, but this repopulation does not result in remyelination--closely resembling the situation found in some multiple sclerosis plaques; and (iii) the induction of acute inflammation in this non-remyelinating situation results in remyelination. Thus, we can conclude that axonal changes induced by chronic demyelination are unlikely to contribute to remyelination failure in multiple sclerosis. Rather, remyelination fails either because OPCs fail to repopulate areas of demyelination or because if OPCs are present they are unable to generate remyelinating oligodendrocytes owing to the presence of inhibitory factors and/or a lack of the stimuli required to activate these cells to generate remyelinating oligodendrocytes. This non-remyelinating situation can be transformed to a remyelinating one by the induction of acute inflammation.

Acute Disease↗
PubMed2006

Endogenous cell repair of chronic demyelination.

In multiple sclerosis lesions, remyelination typically fails with repeated or chronic demyelinating episodes and results in neurologic disability. Acute demyelination models in rodents typically exhibit robust spontaneous remyelination that prevents appropriate evaluation of strategies for improving conditions of insufficient remyelination. In the current study, we used a mouse model of chronic demyelination induced by continuous ingestion of 0.2% cuprizone for 12 weeks. This chronic process depleted the oligodendrocyte progenitor population and impaired oligodendrocyte regeneration. Remyelination remained limited after removal of cuprizone from the diet. Fibroblast growth factor 2 (FGF2) expression was persistently increased in the corpus callosum of chronically demyelinated mice as compared with nonlesioned mice. We used FGF2 mice to determine whether removal of endogenous FGF2 promoted remyelination of chronically demyelinated areas. Wild-type and FGF2 mice exhibited similar demyelination during chronic cuprizone treatment. Importantly, in contrast to wild-type mice, the FGF2 mice spontaneously remyelinated completely during the recovery period after chronic demyelination. Increased remyelination in FGF2 mice correlated with enhanced oligodendroglial regeneration. FGF2 genotype did not alter the density of oligodendrocyte progenitor cells or proliferating cells after chronic demyelination. These findings indicate that attenuating FGF2 created a sufficiently permissive lesion environment for endogenous cells to effectively remyelinate viable axons even after chronic demyelination.

Animals↗
PubMed1987

Schwann cell proliferation and migration during paranodal demyelination.

This study examined Schwann cell behavior during paranodal demyelination induced by beta,beta'-iminodipropionitrile (IDPN). The stimuli for Schwann cell proliferation, extensively studied in vitro, are less well understood in vivo. Most in vivo systems previously used to examine Schwann cell proliferation in disease are dominated by loss of internodal myelin sheaths. As used in this study, IDPN administration produces neurofilamentous axonal swellings and paranodal demyelination, without segmental demyelination or fiber degeneration. We asked whether Schwann cells would proliferate following the restricted paranodal demyelination that accompanies the axonal swellings, and if so what the sources and distributions of new Schwann cells might be. IDPN was given as a single large dose (2 ml/kg) to 21-d-old rats. Neurofilamentous axonal swellings formed in the proximal regions of motor axons, reaching their greatest enlargement in the root exit zone 8 d after IDPN administration. These swellings subsequently migrated distally down the nerves at rates approaching 1 mm/d. The axonal enlargement was consistently associated with displacement of the myelin sheath attachment sites into internodal regions, and consequent paranodal demyelination. This stage was associated with perikaryal changes, including nucleolar enlargement, "girdling" of the perikaryon, and formation of attenuated stalks separating the perinuclear region from the external cytoplasmic collar. Schwann cells proliferated abundantly during this stage. Daughter Schwann cells migrated within the endoneurial space (outside the nerve fiber basal laminae) to overlie the demyelinated paranodes of swollen nerve fibers. In these regions, local proliferation of Schwann cells continued, resulting in large paranodal clusters of Schwann cells. As the axonal calibers subsequently returned to normal, the outermost myelin lamellae of the original internodes returned to their paranodal attachment sites and the supernumerary Schwann cells disappeared. Formation of short internodes, segmental demyelination, and nerve fiber loss were rare phenomena. These results indicate that paranodal demyelination is a sufficient stimulus to excite abundant Schwann cell proliferation; neither internodal demyelination nor myelin breakdown is a necessary stimulus for mitosis. The 3H-thymidine incorporation studies indicated that the sources of new Schwann cells included markedly increased division of the Schwann cells of unmyelinated fibers and, as they formed, supernumerary Schwann cells. In addition, there were rare examples of 3H-thymidine incorporation by Schwann cells associated with myelinated nerve fibers.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1983

Studies on demyelination in vitro: the requirement of membrane attack components of the complement system.

Anti-spinal cord antibodies (anti-SC) cause demyelination of well myelinated mouse cerebellum cultures in the presence of fresh serum. Heating the serum for 30 min at 56 degrees C abolishes the demyelinating activity. We studied the role of complement (c) in demyelination initiated by anti-SC in well myelinated mouse cerebellum cultures. Demyelination was assessed morphologically. The extent of demyelination was correlated to the dose of whole serum C as well as the dose of antibody. To evaluate the requirement of membrane attack components of C, C5b-C9, sister cultures were treated with antibody + C8 deficient human serum (C8D-HS) with and without purified human C8. Extensive demyelination was observed in C8-reconstituted cultures whereas antibody + C8D-HS did not demyelinate, indicating the essential requirement of C5b-8, and/or C5b-9. Extensively demyelinated cultures remyelinated when fresh medium was supplied, suggesting that the process of antibody and C-mediated demyelination is selective for myelin membrane in this system.

Animals↗