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PubMed1986

Chronic demyelination in mouse peripheral nerve produced by lysophosphatidyl choline and X-irradiation: ultrastructural observations.

The effects of X-irradiation on demyelination and remyelination were studied in the peripheral nerve of the mouse. Three days after injection of lysophosphatidyl choline into one sciatic nerve, a 20 Gy dose of X-rays was administered to the hind limb. At survival times ranging from 4 days to 6 months after injection, the nerves were examined by light and electron microscopy. Removal of myelin debris was retarded and remyelination delayed or prevented. The myelin sheaths which did form were thin and the configuration of Schmidt-Lanterman incisures and nodes of Ranvier was abnormal. Some of the chronically demyelinated fibres formed focal node-like complexes: patches of finely granular material coated the inner aspect of the axolemma, the external surface was covered by slender processes of Schwann cell cytoplasm, and an electron-dense lamina was present in the enlarged periaxonal space. Elsewhere demyelinated axons and their ensheathing Schwann cells were separated by gap junctions or transverse bands. The present findings indicate that the morphological differentiation of structures thought to be characteristic of nodes of Ranvier can take place in the absence of remyelination.

Animals↗
PubMed1996

Primary demyelination and regeneration of ascending axons in the dorsal funiculus of the rat spinal cord following photochemically induced injury.

The extent of primary demyelination and regeneration of ascending axons in the dorsal funiculus of the rat spinal cord was investigated following photochemically-induced ischaemic injury. Groups of rats were killed at intervals from 48h to 1 month after injury and a combination of light and electron microscopy and counting of axons in specific sites was used to study the axonal changes. Unmyelinated axons were noted in the dorsal rim of the lesion at its centre and at the centre of the gracile fasciculus at the caudal end of the lesion 7 days after injury. By 1 month, axons in these sites were thinly myelinated by Schwann cells or oligodendrocytes. In order to differentiate between remyelination of demyelinated axons and myelination of regenerated axons, axon counts were performed. The number of sub-pial axons present at the lesion centre did not change significantly from 48h to 1 month after injury, whereas the number of axons at the caudal end of the lesion increased significantly from 4 to 10 days after injury. We therefore conclude that sub-pial axons at the lesion centre are demyelinated between 4 and 7 days after injury and subsequently remyelinated by Schwann cells. At the caudal end of the lesion, a specific population of small diameter axons located at the centre of the gracile fasciculus regenerates for a distance of approximately 1 mm between 4 and 10 days after injury; these axons are then myelinated by oligodendrocytes or Schwann cells. In contrast, larger diameter axons of the gracile fasciculus do not show a regenerative response, demonstrating the variability of axonal responses to injury.

Animals↗
PubMed2003

Phase-dependent expression of matrix metalloproteinases and their inhibitors in demyelinating canine distemper encephalitis.

Matrix metalloproteinases (MMPs) are zinc- and calcium-dependent enzymes that cleave molecules of the extracellular matrix, and thus are able to open the blood-brain-barrier and affect myelin. Their inhibitors (TIMPs) are important candidates for the therapy of demyelinating diseases. To establish an immunohistochemical profile of MMP and TIMP expression in plaque variants in dogs with spontaneous demyelinating distemper encephalitis, paraffin-embedded cerebella were studied employing the avidin-biotin-peroxidase complex method with a panel of nine polyclonal (anti-MMP-1, -3, -7, -9, -12, -13, -14, -TIMP-1, and -2) and two monoclonal antibodies (anti-latent MMP-2, and -MMP-11). All MMPs and TIMPs were prominently up-regulated in acute and subacute non-inflammatory lesions, and double-labeling techniques showed that they were mainly expressed by astrocytes and brain macrophages/microglia. In subacute inflammatory and chronic plaques, a moderate to strong decrease of MMP and TIMP expression compared to acute lesions was observed. In these phases MMP-11, -12, and -13 were still moderately present. In addition to astro- and microglia, invading perivascular mononuclear cells were positive for MMPs and TIMPs. In summary, there seems to be a phase-dependent expression of MMPs and TIMPs in demyelinating canine distemper encephalitis, and an MMP-TIMP imbalance might account for the lesion progression in this disease.

Animals↗
PubMed2005

Up-regulation of mRNA for matrix metalloproteinases-9 and -14 in advanced lesions of demyelinating canine distemper leukoencephalitis.

Matrix metalloproteinases (MMPs) comprise a family of proteolytic zinc- and calcium-dependent enzymes that are capable of disrupting the blood-brain barrier and mediating the destruction of extracellular matrix and myelin components. MMPs are also involved in facilitating leukocyte migration into inflammatory sites of the central nervous system. To determine the cellular localization and the amount of mRNA for MMP-9, MMP-14 and a tissue inhibitor of metalloproteinases (TIMP-1) in dogs with spontaneous demyelinating distemper encephalitis, formalin-fixed paraffin-embedded cerebella were investigated by in situ hybridization using specific digoxigenin-labeled RNA probes. Additionally, immunohistochemistry was performed to characterize the different types of plaques of demyelinating leukoencephalitis. Furthermore, virus antigen and mRNA were detected by immunohistochemistry and in situ hybridization. Healthy control dogs revealed a weak signal for mRNA for MMP-9, MMP-14, and TIMP-1 in various numbers of neurons, astrocytes, microglial cells and oligodendrocytes. In the cerebella of dogs with distemper, a strong increase of both number and staining intensity of MMP-9, MMP-14, and TIMP-1 mRNA-expressing cells, mainly in subacute inflammatory lesions and chronic plaques, was observed. The number of cells expressing mRNA for MMP-9 and MMP-14 increased about two- to threefold compared to TIMP-1 mRNA-expressing cells, whereas staining intensity of individual cells was similar. In early lesions, especially astrocytes and activated macrophages/microglial cells displayed a positive signal for MMPs and TIMP-1, whereas in older lesions activated microglia/macrophages and infiltrating lymphocytes represented the main source for MMP-9, MMP-14, and TIMP-1 mRNA synthesis as revealed by double-labeling techniques. In summary, the proportionally higher increase of MMP mRNA-expressing cells might indicate an MMP/TIMP imbalance as a cause for lesion initiation and progression in demyelinating canine distemper leukoencephalitis.

Animals↗
PubMed2001

The range of chronic demyelinating neuropathy of infancy: a clinico-pathological and genetic study of 15 unrelated cases.

The concept of Dejerine-Sottas disease, which corresponds to presumed recessive demyelinating neuropathies with onset in infancy, remains controversial. To learn more on the subject, we performed a clinico-pathological and molecular genetic study in 15 unrelated patients with the Dejerine-Sottas phenotype seen over a 16 year period. There were 12 females and 3 males, born to asymptomatic parents. Study of the PMP22, P0 and Egr2 genes was performed in all cases and 14 underwent a nerve biopsy. First manifestations of neuropathy occurred before 3 years of age in all patients. An inherited disorder was suspected in 10 patients, because of their family history and/or disclosure of a molecular genetic defect in 4 of them. One patient had a recessively transmitted homozygous point mutation (Arg157Trp) of the PMP22 gene. A heterozygous duplication of the 17p11.2-12 segment was detected in one offspring of a consanguineous marriage. One patient carried a "de novo" heterozygous Ser72Leu substitution in the PMP22. A heterozygous double mutation of the P0 gene including a "de novo" Val42 deletion and an Ala221Thr substitution, maternally inherited, were found in an apparently sporadic case. No mutation of the Egr2 gene was identified. A neuropathy with focally folded myelin sheaths (CMT4B) was diagnosed in the nerve biopsy specimens of two patients. In five patients, the clinico-pathological findings along with the absence of an identified mutation suggested the diagnosis of chronic inflammatory demyelinating polyneuropathy of infantile onset. Our findings illustrate the genetic heterogeneity of cases with identified mutations, the scarcity of cases with "demonstrated" recessive transmission and the likelihood of early acquired chronic inflammatory demyelinating polyneuropathy in several patients.

Adolescent↗
PubMed1975

Anti-synaptic antibody in allergic encephalomyelitis. II. The synapse-blocking effects in tissue culture of demyelinating sera from experimental allergic encephalomyelitis.

It has been suggested that demyelination cannot account for all of the observed clinical symptoms of multiple sclerosis (MS), in particular the rapidity of onset and remission of the disease, and attention has been focussed on the role of the synapse in 'demyelinating diseases'. In the present paper we have attempted to resolve the fundamental question of the site of action of a demyelinating disease, experimental allergic encephalomyelitis (EAE), by the use of cultures of neonatal rat cerebellum. Electrophysiological and morphological development in these cultures run hand-in-hand, and in the first few days in vitro there is a 4-5 day period when synapses are both seen ultrastructurally and known to be functioning but before the onset of myelination. The serum from guinea pigs with EAE was added to these cultures at different stages during their development and the morphological and electrophysiological effects observed. An abolitionary effect on the bioelectric activity of the culture was only observed when the serum was added to mature, myelinated cultures. Also the same active sera had no effect on synaptic activity before myelination had occurred. We conclude that the synaptic blocking effect occurs only when myelin is destroyed.

Animals↗
PubMed1983

Demyelinating and myelination-inhibiting factors induced by chloroform-methanol insoluble proteins of myelin.

A host of proteins was seen when the chloroform-methanol insoluble protein (CMIP) fraction of bovine brain myelin was transferred from polyacrylamide gels to cellulose nitrate sheets. Inoculation of rabbits with the CMIP fraction generated a number of antibodies which were demonstrated by the immunoblot technique. These antisera against CMIP contained antibodies which induced demyelination and inhibited myelin formation in central nervous system cultures. The demyelinating factor was specific for centrally myelinated fibers, and did not demyelinate peripherally myelinated axons.

Animals↗
PubMed1984

Impulse conduction in inhomogeneous axons: effects of variation in voltage-sensitive ionic conductances on invasion of demyelinated axon segments and preterminal fibers.

Conduction in inhomogeneous axons may be blocked by several mechanisms. Conduction in demyelinated axons may fail since normal internodal membrane is inexcitable, because values of sodium conductance are too low to support impulse conduction. In addition, focal loss of myelin causes increased current leakage which slows or blocks invasion of impulses into the demyelinated zone due to inadequate current density. Similar considerations apply to the invasion of non-myelinated preterminal axons from myelinated parent fibers, where conduction can be blocked as a result of inadequate current density. A cable model of an axon is presented which allows myelinated regions, regions without myelin, and variable length transition zones of redistributed channel densities, to be studied. Action potentials and membrane currents were studied. Computer simulations using this model show that the safety factor for invasion is dependent on temperature. These studies also show that small changes in axon membrane properties, at the transition region between the myelinated zone and the region without myelin, may promote invasion of the region without myelin. In particular, increasing sodium conductance (gNa) or decreasing potassium conductance (gK) promotes invasion. Because of the non-linear behavior of excitable membranes the spatial distribution of channels is shown also to have significant effects on invasion. Thus, relatively small degrees of membrane reorganization may lead to functional changes with respect to the invasion of demyelinated axon regions. Similarly, the properties of the heminode at the distal part of the parent myelinated fiber may determine the invasion characteristics of non-myelinated terminal axons.

Axons↗
PubMed1991

Increase of sodium channels in demyelinated lesions of multiple sclerosis.

Redistribution of sodium channels along demyelinated pathways in multiple sclerosis (MS) could be an important event in restoring conduction prior to other reparative mechanisms such as remyelination. Sodium channels in human multiple sclerosis lesions were identified by quantitative light microscopic autoradiography using tritiated saxitoxin (STX), a highly specific sodium channel ligand. Demyelinated areas in various central nervous system regions containing denuded but vital axons exhibited a high increase of STX-binding sites by up to a factor of 4 as compared to normal human white matter. This important finding could explain aspects of fast clinical remissions and 'silent' MS lesions on functional and morphological properties. Demyelinated axons may functionally reorganize their membranes and adapt properties similar to those of slow conducting unmyelinated nerve fibres which have a higher amount and a more diffuse distribution of STX binding sites. This report is the first description of an altered distribution of voltage-sensitive sodium channels in human multiple sclerosis lesions.

Aged↗
PubMed1991

Increased numbers of sodium channels form along demyelinated axons.

Sodium channels, which are largely localized to the nodes of Ranvier in myelinated axons, appear to form new distributions along demyelinated axons. In this study a sensitive radioimmunoassay (RIA) was used to examine the changes in the total number of sodium channels that occur in nerves experimentally demyelinated in vivo with doxorubicin (adriamycin). The results clearly illustrate the development of an increased number of sodium channels during demyelination, suggesting that this process is associated with the formation of new sodium channels.

Animals↗
PubMed1993

Axonal coding of action potentials in demyelinated nerve fibers.

Conduction in individual axons of Xenopus has been measured optically in response to short trains of stimuli, following demyelination of the sciatic nerve. In many cases the initial action potential in a burst is absent. Failure may also occur later in the train, resulting in a profound alteration of signal coding by the axon. Integration leading to delayed transmission occurred at the heminode forming the proximal border of the demyelinated zone, as well as at new nodes of Ranvier forming in remyelinating axons. This process appeared to involve a depolarizing afterpotential and seemed to be analogous to the threshold changes involved in superexcitability. Axonal coding was very sensitive to small changes in the stimulus pattern. Neither 1 mM tetraethylammonium ion, which blocks nodal and Ca2+ activated K+ channels, nor 1 mM 4-aminopyridine, which blocks fast internodal K+ channels, prevented loss of the initial spike in a burst. Similarly, neither block of Ca2+ channels by Cd2+ nor lowering of Cl- had a notable effect. Ouabain, on the other hand, had small but possibly significant effects on responses to repetitive stimuli. A computational model was used to test mechanisms involving passive cable properties. Lowering the myelin resistance and the nodal leakage conductance, in accord with recent evidence from intracellular recordings, reproduced many of the results and was accurate with respect to stimulus frequency, temperature and sensitivity to average potential. The coding of action potentials observed here may have clinical consequences in demyelinating diseases such as multiple sclerosis.

Action Potentials↗
PubMed1981

Histogenesis of demyelinating lesions in the spinal cord of guinea pigs with chronic relapsing experimental allergic encephalomyelitis.

Spinal cord lesions in Hartley guinea pigs with chronic relapsing experimental allergic encephalomyelitis (EAE) were studied by light, transmission and scanning electron microscopy at different stages of the formation of demyelinated plaques. In addition the inflammatory response in the meninges was studied in isolated pia mater preparations separated from the spinal cord surface. In initial chronic lesions in the spinal cord, inflammation was restricted to penetrating parenchymal veins of the spinal cord and meninges. With the formation of large demyelinated plaques in the spinal cord, massive fibrosis of the meninges with infiltration by inflammatory cells was noted in an area covering the surface of the lesion. In plaques which reach the spinal cord surface, inflammatory cells could be seen passing between the pia and the spinal cord substance. In chronic remyelinated lesions, adhesions between meningeal fibroblasts and the astroglial limiting membrane were seen. In addition a topographical correlation between the distribution of spinal cord veins and venules and demyelinated plaques was found. These observations indicate that spinal cord lesions in chronic relapsing EAE are initiated by perivenous inflammation in the parenchyma and the meninges. Plaque formation, especially in spinal cord surface lesions, is additionally enhanced by the entrapment of inflammatory cells in the fibrosed meninges. The exchange of macrophages through the glia-limiting membrane may be responsible for the more rapid debris removal in the spinal cord in comparison with brain lesions in chronic relapsing EAE.

Animals↗
PubMed1988

Peripheral demyelination and remyelination initiated by the calcium-selective ionophore ionomycin: in vivo observations.

Incubation of nerve with Ca2+ and the divalent cation ionophores A23187 or ionomycin, causes a prompt vesiculation of the myelin at the paranodes and Schmidt-Lanterman incisures. The vesiculation appears to be dependent upon a rise in the intracellular calcium concentration of the affected Schwann cells. To determine whether a similar vesiculation might occur in vivo, and to examine the long term consequences of ionophore exposure, the sciatic nerves of rats and mice were injected with ionomycin and examined histologically after intervals of 1 h to 75 days. A prompt myelin vesiculation was again observed, and this spread from the paranodes and incisures to invade regions of formerly compact myelin: segmentally demyelinated axons were common 7 days post-injection. The lesions were large, and involved up to 95% of the fibres in the mouse. There was little evidence of either Schwann cell necrosis, or axonal degeneration in either species. The appearance and spatio-temporal progression of the lesion was strikingly similar to that seen after the intraneural injection of lysophosphatidylcholine or phospholipase A2. However, in the ionophore lesion, not all the demyelination was effected by myelin vesiculation, for up to 30% of the affected fibres showed evidence of macrophage-mediated stripping. Macrophage stripping was confined to internodes already affected by vesiculation. Most of the myelin debris was removed by macrophages, and myelin debris was only rarely observed within Schwann cells. Remyelination was initiated in nearly all the affected fibres by 21 days, and by 2 months all affected fibres were invested with thin, new myelin sheaths. These findings may be relevant to immune-mediated demyelination in the peripheral nervous system.

Animals↗
PubMed1992

Phospholipids in X-linked adrenoleukodystrophy white matter: fatty acid abnormalities before the onset of demyelination.

Changes in fatty acid composition of complex lipids were analyzed in postmortem white matter from a patient with late onset adrenoleukodystrophy (ALD). The specimen showed three regions with progressive myelin breakdown: morphologically normal white matter; areas with active demyelination and perivascular lymphocyte and macrophage infiltration; and areas with marked gliosis. In the morphologically intact region, cholesterol esters were similar in amount and fatty acid composition to those in control tissue, although marked changes were observed in the actively demyelinating area. Galactolipids in these areas were also similar to those in controls. In contrast, glycerophospholipids were increased in amount and in very long chain fatty acids (VLCFA), which are the hallmark of ALD, at the active edge of the demyelinative lesion and even in the apparently intact sample. Further fractionation of the glycerophospholipids by high performance liquid chromatography showed a significant (up to 39-fold) accumulation of hexacosanoic acid (C26:0) in phosphatidylcholine, but not in other phosphatidyl derivatives. The consistent increases in phosphatidylcholine VLCFA in all samples from the ALD brain, which are postulated to represent progressive stages in the development of the disorder, suggest that phosphatidylcholine may be involved in antigen formation and may underlie an immunological basis for the pathogenesis of ALD.

Adrenoleukodystrophy↗
PubMed1992

Early morphological features in dominantly inherited demyelinating motor and sensory neuropathy (HMSN type I).

Seventeen cases of dominantly inherited demyelinating motor and sensory neuropathy (HMSN type I) with infantile onset were studied. Not only clinical and electrophysiological data, but also the g ratio (axon diameter to fibre diameter), considered to be a distinguishing feature between HMSN type I and HMSN type III, showed overlap. Morphological and morphometrical investigations already revealed a lack of small and large diameter myelinated axons at an early stage, and a demyelinating process most active in early childhood followed later by axonal loss. It was concluded that the histopathology of HMSN type I cannot be sufficiently explained by axonal atrophy with secondary demyelination.

Action Potentials↗
PubMed1988

Demyelination of sciatic nerve in acute experimental allergic neuritis of the rat. A gel electrophoresis investigation.

Acute experimental allergic neuritis (EAN) of Lewis rats was monitored by clinical and electrophysiological tests for 60 days. Sciatic nerve myelin proteins were analyzed by quantitative microgel electrophoresis and electroimmunoblotting at different clinical stages of the disease. The clinical severity of EAN and the demyelination as measured by electrophysiological tests and myelin protein concentrations in sciatic nerve did not correspond during the course of the disease. Demyelination reached its peak after partial clinical recovery and was still present on day 60. The major peripheral nervous system (PNS) myelin proteins P0, P1 and P2 decreased at different rates during the course of the disease, indicating possible differences in their proteolytic degradation. Treatment with Freund's complete adjuvant (CFA) alone resulted in alterations of membrane and myelin protein patterns challenging the widely held belief that pure CFA is inert with regard to demyelination.

Animals↗
PubMed1988

Ibotenic acid induced demyelination in the central nervous system: a consequence of a local inflammatory response.

We examined the effects of injections of ibotenic acid into the medial septum (MS), dorsal lateral geniculate nucleus (dLGN), caudate-putamen (CP) or fornix-fimbria (FF) on fibres close to the injection site. Injections into the MS and dLGN resulted in demyelination. The area of demyelination correlated with the area of maximal gliosis. The major cell type in the area of gliosis were cells of haemopoietic origin, as revealed by using monoclonal antibodies (Mabs). Demyelination was not observed in the CP or FF. Axonal transport in fibres en passage through the dLGN lesion was also disrupted following injections of horseradish peroxidase (HRP) into the eye contralateral to the lesion. These results show that when ibotenic acid induces cell death it can secondarily damage myelin sheaths and disrupt axonal transport in areas containing diffuse fibre systems. We suggest that this is due to a non-specific effect of the inflammatory response.

Animals↗
PubMed1992

Demyelination, and remyelination by Schwann cells and oligodendrocytes after kainate-induced neuronal depletion in the central nervous system.

Excitotoxins are thought to kill neurons while sparing afferent fibers and axons of passage. The validity of this classical conclusion has recently been questioned by the demonstration of axonal demyelination. In addition, axons are submitted to a profound alteration of their glial environment. This work was, therefore, undertaken to reassess axonoglial interactions over time after an excitotoxic lesion in the rat. Ultrastructural studies were carried out in the ventrobasal thalamus two days to 18 months after neuronal depletion by in situ injections of kainic acid. In some cases, lemniscal afferents were identified by using anterograde transport of wheatgerm agglutinin conjugated to horseradish peroxidase from the dorsal column nuclei. Two and four days after kainate injection, numerous dying axons displaying typical signs of Wallerian degeneration were observed in a neuropile characterized by the loss of neuronal somata and dendrites, an increase in number of microglia/macrophages and the disappearance of astrocytes. Ten and 12 days after kainate injection, degenerating axons were no longer observed although myelin degeneration of otherwise unaltered axons was ongoing with an accumulation of myelin remnants in the neuropile. At 16 and 20 days, the demyelination process was apparently complete and axons of different diameters were sometimes packed together. One and two months after kainate injection, the axonal environment changed again: remyelination of large-caliber axons occurred at the same time as reactive astrocytes, oligodendrocytes and numerous Schwann cells appeared in the tissue. Schwann cell processes surrounded aggregates of axons of diverse calibers, ensheathed small ones and myelinated larger ones. Axons were also remyelinated by oligodendrocytes. Horseradish peroxidase-labeled lemniscal afferents could be myelinated by either of the two cell types. After three months, the neuropile exhibited an increase in number of hypertrophied astrocytes and the progressive loss of any other cellular or axonal element. At this stage, remaining Schwann cells were surrounded by a glia limitans formed by astrocytic processes. These data indicate that although excitotoxins are sparing the axons, they are having a profound and complex effect on the axonal environment. Demyelination occurs over the first weeks, accompanying the loss of astrocytes and oligodendrocytes. Axonal ensheathment and remyelination takes place in a second period, associated with the reappearance of oligodendrocytes and recruitment of numerous Schwann cells, while reactive astrocytes appear in the tissue at a slightly later time. Over the following months, astrocytes occupy a greater proportion of the neuron-depleted territory and other elements decrease in number.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗