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PubMed1985

Possible association of herpes simplex virus infection with demyelinating disease.

Administration of herpes simplex virus (HSV) in sublethal doses to experimental animals may cause a relapsing demyelination in the central nervous system (CNS) but will leave the peripheral myelin unimpaired. Demyelination will be followed by remyelination by oligodendroglial cells or by invading Schwann cells. Relapsing episodes of CNS demyelination seen in HSV latently infected animals may be caused either by reactivation of HSV residing in the CNS itself or virus transported to the CNS after reactivation of a latent infection in peripheral sensory or autonomic ganglia. Although HSV is not the only virus known to induce a demyelination in the CNS of experimental animals, the similarities of this HSV induced demyelination and multiple sclerosis (MS) are intriguing, albeit an association of HSV reactivation and MS has not as yet been reported. However, circumstantial evidence for HSV induction of restricted CNS demyelination in man has recently been obtained: Several laboratories have reported on association of HSV with acute idiopathic facial palsy (Bell's palsy). If HSV be the cause of this palsy, the site of a lesion giving the nerve dysfunction should be located in the brain stem of the CNS rather than in the extrapontine part of the facial nerve. Indeed, most of Bell's palsy patients studied had signs of a brain stem disorder revealed by either one or more of the following tests: auditory brain stem response test, trigeminal evoked potential test or extensive clinical neurological examination. Furthermore, 35% of patients with Bell's palsy had increased concentrations of myelin basic protein in the cerebrospinal fluid collected in the acute stage of the disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Lysolecithin-induced demyelination in primates: preliminary in vivo study with MR and magnetization transfer.

PURPOSE: To study bystander demyelination in multiple sclerosis with an experimental in vivo model of toxic demyelination. METHODS: Toxic demyelinating lesions were created in two monkeys by injection of lysophosphatidylcholine in the centrum semiovale. Follow-up was done clinically and with serial MR studies, including T2-weighted and gadolinium-enhanced T1-weighted images and measurement of magnetization transfer ratio, until the animals were killed at days 14 and 34, respectively. Light and electron microscopy analysis was compared with MR data. RESULTS: Interval measurement of magnetization transfer ratio during the course of the experiment revealed a maximum decrease at day 7 to day 8, associated with the greatest clinical manifestations. The lowest values of magnetization transfer ratio correlated with histopathologic findings of myelin and axon destruction. Magnetization transfer ratio measurements appear to be sensitive to macromolecular destruction and specifically to membrane disorganization. At no time was gadolinium enhancement observed in this model of toxic demyelination. CONCLUSION: Preliminary results of this study indicated that magnetization transfer is a good technique to follow in vivo matrix destruction in brain parenchyma lesions. The results suggest also that phases of toxic demyelination in multiple sclerosis might not show gadolinium enhancement. Differentiation between demyelinating activity and associated inflammation in multiple sclerosis lesions should be considered in further in vivo work.

Animals↗

PubMed1994

The spectrum of acquired demyelinating polyradiculoneuropathy.

Guillain-Barré Syndrome (GBS) is best viewed as a clinical syndrome which can have at least two clinical substrates: the commonest is an acquired demyelinating polyradiculoneuropathy and the other is an acute motor axonal neuropathy. An acute acquired neuropathy can also sometimes cause the Miller Fisher syndrome of ophthalmoplegia, areflexia and ataxia, and even more rarely a pure sensory neuropathy. The demyelinating form of GBS also forms one end of a spectrum which has Chronic Idiopathic Demyelinating Polyradiculoneuropathy (CIDP) at its other pole. CIDP usually produces a mixed sensory and motor, albeit predominantly motor deficit, but some patients have pure multifocal motor neuropathy (MMN) and other even less common patients have pure sensory CIDP. According to the definitions of international committees, the symptoms of GBS reach their nadir within 4 weeks and those of CIDP in not less than 8 weeks. The spectrum is completed by patients with a monophasic illness reaching its nadir in 4 to 8 weeks (subacute idiopathic demyelinating polyradiculoneuropathy (SIDP). In addition there are patients with discrete attacks of acute demyelinating neuropathy which have been called recurrent GBS. The differential diagnosis of acquired demyelinating neuropathy differs according to the position of the individual case on this spectrum. The pathogenesis of each case may depend on the nature of the autoantigen, the balance between T cell and antibody-mediated autoimmune mechanisms, and the tempo of the inflammatory process. These differences may explain the empirical observations that steroids are helpful in CIDP but not GBS. Removal of antibodies by plasma exchange or flooding the immune system with normal immunoglobulin is beneficial in GBS and some cases of CIDP.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗

PubMed1996

Adoptively transferred CD8+ T lymphocytes provide protection against TMEV-induced demyelinating disease in BALB/c mice.

On intracerebral infection with the BeAn strain of Theiler's murine encephalomyelitis virus (TMEV), certain mouse strains develop a chronic demyelinating disease similar both clinically and pathologically to human multiple sclerosis. Other strains remain resistant. We previously established that differential susceptibility to this demyelinating disease exists among BALB/c substrains, with BALB/cAnNCr mice being susceptible while BALB/cByJ mice are resistant. BALB/cByJ mice are rendered susceptible to TMEV-induced demyelination on exposure to low dose gamma-irradiation before TMEV infection. BALB/cAnNCr and irradiated, infected BALB/cByJ animals are protected against TMEV-induced demyelination by the transfer of a splenic population from TMEV-infected BALB/cByJ donors. Resistance to demyelination appears to be mediated by a CD8+ radiosensitive population, which is induced on infection with TMEV and which must act early to establish resistance to TMEV-induced demyelination.

Animals↗

PubMed1997

Heterozygous P0 knockout mice develop a peripheral neuropathy that resembles chronic inflammatory demyelinating polyneuropathy (CIDP).

Demyelinating peripheral neuropathies are clinically divided into inherited and acquired types. Inherited demyelinating neuropathies are caused by mutations in genes expressed by myelinating Schwann cells, whereas acquired ones, including chronic inflammatory demyelinating polyneuropathy (CIDP), are probably caused by autoimmune mechanisms. We find that heterozygous P0 knockout (P0+/-) mice develop a neuropathy that resembles CIDP. By one year of age, P0+/- mice develop severe, asymmetric slowing of motor nerves, with temporal dispersion or conduction block, which are features of acquired demyelinating neuropathies including CIDP. Moreover, morphological analysis of affected nerves reveals severe and selective demyelination of motor fibers, focal regions of demyelination, and inflammatory cells. These data suggest that immune-mediated mechanisms may contribute to the pathogenesis of the neuropathy in P0+/- mice.

Action Potentials↗

PubMed1998

Dynamic regulation of alpha- and beta-chemokine expression in the central nervous system during mouse hepatitis virus-induced demyelinating disease.

Infection of C57BL/6 mice with the V5A13.1 strain of mouse hepatitis virus (MHV-V5A13.1) results in an acute encephalomyelitis and chronic demyelinating disease with features similar to the human demyelinating disease multiple sclerosis. Chemokines are a family of proinflammatory cytokines associated with inflammatory pathology in various diseases. The kinetics and histologic localization of chemokine production in the central nervous system of MHV-infected mice were examined to identify chemokines that contribute to inflammation and demyelination. Transcripts for the chemokines cytokine-response gene-2 (CRG-2), regulated on activation, normal T cell expressed and secreted (RANTES), macrophage-chemoattractant protein-1 and protein-3 (MCP-1, MCP-3), macrophage-inflammatory protein-1beta (MIP-1beta), and MIP-2 were detected in the brains of MHV-infected mice at 3 days postinfection (p.i.), and these transcripts were increased markedly in brains and spinal cords at day 7 p.i., which coincides with the occurrence of acute viral encephalomyelitis. By day 35 p.i., RANTES, CRG-2, and MIP-1beta were detected in brains and spinal cords of mice with chronic demyelination. CRG-2 mRNA expression colocalized with viral RNA and was associated with demyelinating lesions. Astrocytes were the predominant cell type expressing CRG-2 mRNA. These observations suggest a role for chemokines, notably CRG-2, in the initiation and maintenance of an inflammatory response following infection with MHV, which is important in contributing to demyelination.

Animals↗

PubMed1998

Coronavirus infection and demyelination. Development of inflammatory lesions in Lewis rats.

Coronavirus infections of rodents can cause diseases of the central nervous system characterised by inflammatory demyelination. The lesions mimick in many aspects the pathology of multiple sclerosis in humans and of other neurological diseases. As an animal model for demyelination, we studied the MHV-JHM induced encephalomyelitis of Lewis rats. The pathomorphological analysis revealed patterns of lesions which developed in stages. Infected oligodendrocytes were first destroyed by necrosis. Later stages were characterized by demyelinated plaques. In the center of plaques, no virus antigen was found and oligodendrocytes were mainly destroyed by apoptosis. At the edge of plaques, virus antigen was expressed in parallel to infiltrations consisting of lymphocytes and macrophages. The prevailing mechanisms leading to demyelination may change individually and during defined stages of the disease. The transcriptional expression of chemoattractants and other mediators of inflammation was studied by semiquantitative RT-PCR. Virus induced inflammatory demyelination was accompanied by high expression of a relatively novel cytokine, the endothelial monocyte activating polypeptide II (EMAP II). By immunocytochemistry, EMAP II was detected in parenchymal microglia located both within the lesions and in unaffected areas. Furthermore, the level of transcriptional expression of the regulatory calcium binding S100 proteins MRP8, MRP14 and CP10 was associated with inflammatory demyelination and expression of IFN gamma, IL-2, TNF alpha, and iNOS.

Animals↗

PubMed1996

Immunocytochemical investigations of sodium channels along nodal and internodal portions of demyelinated axons.

Voltage-gated sodium channels are largely localized to the nodes of Ranvier in myelinated axons, providing the physiological basis for saltatory conduction. Studies using antisodium channel antibodies have shown that along demyelinated axons sodium channels form new distributions. The nature of this changed distribution appears to vary with the time course and mechanism of demyelination. In chronic demyelination, sodium channels increase in number and redistribute along previously internodal axon segments. In chronic demyelination produced by doxorubicin, the increase in sodium channels appeared independently of Schwann cells, suggesting increased neuronal synthesis. In acute demyelination produced by lysolecithin new clusters of sodium channels developed but only in association with the edges of remyelinating Schwann cells, which appeared to control the distribution and mobility of the channels. These findings affirm the plasticity of sodium channels in demyelinated axons and are relevant to understanding how these axons recover conduction.

Animals↗

PubMed1989

Model investigations of the temperature dependence of demyelinated and reorganized axonal membrane.

The temperature dependence (from 10 degrees to 50 degrees C) of the intracellular action potentials' parameters in a fiber with a simulated reorganization of the axonal membrane against the background of a systematic paranodal demyelination of the fiber was investigated. The temporal and spatial distribution of the potential as well as the ionic currents' kinetics have been represented. The reorganization of the axonal membrane was achieved by means of potassium channels blocking and increase of the sodium-channel permeability, while the demyelination was achieved by means of elongation of the nodes of Ranvier. In order to account for the temperature dependence of the rate constants and of the maximal sodium and potassium permeabilities, the temperature coefficients (Q10) have been used. It has been shown for the demyelinated and reorganized membrane that increased temperature blocks the conduction at temperatures much higher than the blocking temperature for the demyelinated fiber only. When temperature increases the amplitude of the potential decreases while the velocity increases up to temperatures approaching the blocking temperature after which it abruptly drops. The dependence of the asymmetry and the wavelength of the potential on temperature is complex and nonmonotonic. For the reorganized membrane at the background of a given degree of demyelination with increasing temperature the ionic currents' flow and the membrane conduction respectively increase, but, at lower temperatures, when the temperature increase is combined with the increased degree of the fiber demyelination, the conduction is blocked.

Action Potentials↗

PubMed1986

Detection of sodium channel distribution in rat sciatic nerve following lysophosphatidylcholine-induced demyelination.

In vivo application of lysophosphatidylcholine (LPC) to rat sciatic nerve induces impaired hind leg movement within 2 days which is recovered by 6 days. Segmental demyelination was seen at 2 days after LPC application, and remyelination had barely started in a few axons by 6 days. Using sodium channel-specific monoclonal antibodies and immunofluorescence microscopy, we observed altered distribution of sodium channels in demyelinated axons. Bright fluorescent labeling was found along the segmentally demyelinated axolemma at 6 days in contrast to the dim staining of the demyelinated nerve found at 2 days. In addition, radioimmunoassays detected an elevated number of antibody binding sites on sciatic nerve trunk from the sixth day. Our data provide the immunocytochemical evidence for the assumption that recruitment of sodium channels into demyelinated axolemma contributes to the recovery of function following axon demyelination by LPC.

Action Potentials↗

PubMed1983

Structural specificity in demyelination induced by lysophospholipids.

The demyelinating activity of lysophosphatidylcholine (lysoPC) and various structural analogs in rat sciatic nerve was evaluated by following electrophysiologic changes within the first hour and 1 week after intraneural injection. The lysophospholipids tested included 1-O-hexadecanoyl-sn-glycero-3-phosphocholine (1-acyl-GPC), 3-O-hexadecanoyl-sn-glycero-1-phosphocholine (3-acyl-GPC), 1-O-hexadecanoylpropanediol-3-phosphocholine (acyl-PPC), 1-O-hexadecylpropanediol-3-phosphocholine (alkyl-PPC) and 1-acyl-sn-glycero-3-phosphoethanolamine (1-acyl-GPE). Changes in conduction velocity, width, amplitude and time integral percentage were measured. Within 1 hour, the highest demyelinating activity was observed for alkyl-PPC, followed by 3-acyl-GPC, 1-acyl-GPC and acyl-PPC. Hydrolysis products of lysoPC (glycerophosphocholine, fatty acid), lysophosphatidylethanolamine (1-acyl-GPE), biradyl choline phospholipids (1,2-di-O-alkyl-rac-glycero-3-phosphocholine, dialkyl-GPC) or sodium deoxycholate proved ineffective in these short-term experiments. One week after intraneural injection, all lysophospholipids tested caused severe electrophysiologic changes, although dialkyl-GPC and sodium deoxycholate did not. Our data suggest (i) that differences in early demyelinating activity by the choline lysophospholipids are related to their rate of turnover, as highest activity was associated with the agents that are not metabolized by lysophospholipase (e.g., alkyl-PPC) or lysolecithin acyltransferase (e.g., 3-acyl-GPC), (ii) that the lysoPC molecule as such and not its products of catabolism causes demyelination, and (iii) that demyelinating activity is not due to the general detergent action of lysoPC, but rather that specific interactions appear to trigger the processes of demyelination induced by lysophospholipids.

Action Potentials↗

PubMed1991

Distribution of sodium channels in chronically demyelinated spinal cord axons: immuno-ultrastructural localization and electrophysiological observations.

The immuno-ultrastructural localization of voltage-sensitive sodium channels was demonstrated within a central demyelinating lesion induced in the rat spinal cord by ethidium bromide/irradiation using polyclonal antibody 7493. Antibody 7493 has previously been shown to immunostain intensely axon membrane at nodes of Ranvier, and also perinodal astrocyte processes. At 25-35 days post injection/irradiation, the central portion of the demyelinating lesion is populated with chronically demyelinated axons and there is an absence of glial processes. Sodium channel immunoreactivity was not observed on the chronically demyelinated axolemma within this central portion of the lesion. Within the peripheral portion of the lesion demyelinated axons were occasionally abutted by astrocyte and Schwann cell processes. At these focal sites of apposition, the axon membrane displayed intense sodium channel immunoreactivity, while the abutting astrocyte and Schwann cell processes did not exhibit immunostaining. Also in the periphery of the lesion, some axons become ensheathed and myelinated by oligodendrocytes and Schwann cells. The axon membrane of circumferentially ensheathed axons displayed antibody 7493 immunostaining, and this immunoreactivity persisted on the axolemma until the ensheathing cytoplasmic processes compacted into myelin. Internodal axon membrane beneath the myelin sheath did not display sodium channel immunoreactivity, though (putative) developing nodal axon membrane adjacent to terminal paranodal loops exhibited robust sodium channel staining. Electrophysiological recordings within the ethidium bromide/irradiation lesion demonstrated that at least some axons conducted action potentials within the lesion, while others exhibited conduction block. These results indicate that there is a reorganization of sodium channels within the axon membrane of chronically demyelinated central axons.

4-Aminopyridine↗

PubMed1984

Quantitative chemical analysis of demyelination in cultured mouse spinal cord.

These studies were designed to determine whether chemical parameters can be used to quantify the demyelinative potency of anti-CNS sera or other demyelinating factors as revealed by cultured nerve tissue. The activity of 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNPase) and the amount of some major myelin lipids were measured in cultured embryonic mouse spinal cord during different stages of demyelination. Cultures exposed to anti-white matter serum for various times (6-60 h) or various concentrations (2.5-25%) showed a decrease (up to -70%) in CNPase activity. This change paralleled the degree of demyelination as evaluated by light microscopic examination. Cultures exposed to normal rabbit serum under the same conditions did not show changes in the amount of myelin or in the activity of CNPase. Conversely, changes in the lipid content did not correlate with the morphologic evaluation of demyelination. Glycolipids were found to decrease in cultures exposed to anti-white matter as well as in those exposed to normal rabbit sera. The decrease in cerebrosides was higher with anti-white matter serum than with normal serum, but sulfatides were altered in similar amounts in both groups. In contrast, under the same conditions, the amount of total protein or other lipid such as total cholesterol is not altered. Therefore, biochemical analysis of some myelin components could constitute a more sensitive and reliable quantitative method for early evaluation of the time course of demyelination in cultured nerve tissues.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗

PubMed2006

Mechanisms and therapy of osmotic demyelination.

Central pontine myelinolysis (CPM) is a rare but serious demyelinative disease that is associated with rapid correction of chronic hyponatremia. Disruption of the blood-brain barrier (BBB) following a rapid increase in serum sodium concentration is considered to play a critical role in the pathogenesis of osmotic demyelination. We investigated the protective effect of dexamethasone (DEX) on osmotic demyelination in rats. After rapid correction of chronic hyponatremia, rats displayed serious neurologic impairments and demyelinative lesions were observed in various brain regions. Conversely, DEX-treated rats exhibited minimal neurologic impairments and demyelinative lesions were rarely seen in the brain. A marked extravasation of endogenous immunoglobulin G and Evans blue dye were observed in the brains of rats that did not receive DEX, indicating disruption of the BBB, but this was not observed in DEX-treated rats. These results indicate that DEX is effective in preventing osmotic demyelination by inhibiting BBB disruption, and suggest that DEX might be useful for the prevention of CPM in clinical practice.

Animals↗

PubMed2005

Protective effect of dexamethasone on osmotic-induced demyelination in rats.

Central pontine myelinolysis (CPM) is a serious demyelination disease commonly associated with the rapid correction of hyponatremia. Although its pathogenesis remains unclear, the disruption of the blood-brain barrier (BBB) as a consequence of a rapid increase in serum sodium concentration is considered to play a critical role. Since glucocorticoids are known to influence BBB permeability and prevent its disruption as a result of hypertension or hyperosmolarity, we investigated whether dexamethasone (DEX) could protect against osmotic demyelination in an animal model of CPM. Hyponatremia was induced in rats by liquid diet feeding and dDAVP infusion. Seven days later, the animals' hyponatremia was rapidly corrected by injecting a bolus of hypertonic saline intraperitoneally. Rats subjected to this treatment displayed serious neurological impairment and 77% died within 5 days of rapid correction of their hyponatremia; demyelinative lesions were observed in various brain regions in these animals. On the other hand, rats that were treated with DEX (2 mg/kg, 0 and 6 h after hypertonic saline injection) exhibited minimal neurological impairment and all were alive after 5 days. Demyelinative lesions were rarely seen in the brains of DEX-treated rats. A marked extravasation of endogenous IgG was observed in the demyelinative lesions in the brains of rats that did not receive DEX, indicating disruption of the BBB, but was not observed in DEX-treated rats. Furthermore, Evans blue injection revealed a significant reduction in staining in the brains of DEX-treated rats (P < 0.05). These results indicate that early DEX treatment can prevent the BBB disruption that is caused by the rapid correction of hyponatremia and its associative demyelinative changes, and suggest that DEX might be effective in preventing CPM.

Animals↗

PubMed1998

Failure of treatment with Linomide or oral myelin tolerization to ameliorate demyelination in a viral model of multiple sclerosis.

Both Linomide (quinoline-3-carboxamide) and tolerization with self-antigens have been demonstrated to successfully ameliorate demyelinating disease in experimental autoimmune encephalomyelitis (EAE). Based on the autoimmune hypothesis of multiple sclerosis (MS), both agents have been tested in clinical trials but have been found to be toxic or not efficacious. We investigated the efficacy of these immunomodulators in an alternative experimental model of MS, a virus-induced demyelinating disease. Oral administration of Linomide to Theiler's virus-infected mice beginning either at time of infection or at day 15 post-infection (p.i.) resulted in an increased percentage of spinal cord quadrants with demyelination. Administration of Linomide beginning at day 15 p.i. increased lesion size as compared to infected control-treated mice. Treatment with 80 mg kg(-1) day(-1) of Linomide beginning at the time of infection significantly increased the number of Theiler's murine encephalomyelitis virus (TMEV)-positive cells mm(-2) of spinal cord white matter. There were no differences in the amount of remyelination between mice treated with Linomide or water. However, chronically infected mice treated with Linomide had severely reduced spontaneous vertical activity as measured using a activity wheel. Oral tolerization of mice with mouse or bovine myelin had no effect on virus-induced demyelination or virus antigen expression. The contrasting results obtained between the TMEV model and the autoimmune model of demyelination do not support recent reports suggesting that the underlying mechanism of demyelination in the Theiler's model is autoimmune.

Adjuvants, Immunologic↗

PubMed2003

Outcome of axonal and demyelinating forms of Guillain-Barré syndrome in children.

Previous reports have suggested that outcome is worse in the axonal compared with the demyelinating form of Guillain-Barré syndrome (GBS). We performed a retrospective study of 23 children with electrophysiologically confirmed cases of predominant subtypes of GBS to investigate this issue. The patients were classified based on the electrodiagnostic features: Ten (44%) had acute inflammatory demyelinating polyradiculoneuropathy, eight (35%) had acute motor axonal neuropathy, and five (21%) had acute motor-sensory axonal neuropathy. All patients received a standard intravenous immunoglobulin therapy (0.4 g /kg /day for 5 consecutive days). In the acute phase of the disease, patients with the axonal forms of GBS were more disabled than were those with the demyelinating GBS, as measured by GBS scores. Mechanical ventilation was required in five (38%) patients in the axonal group compared with one (10%) patient in the demyelinating group. There was no significant difference at 6 months in GBS scores between demyelinating and axonal forms of GBS. All 20 survivors recovered completely by 12 months. After standard intravenous immunoglobulin therapy, children with axonal forms of GBS recover more slowly than those with the demyelinating form, but outcome at 12 months appears to be equally favorable in two groups.

Adolescent↗

PubMed2000

Axonal loss results in spinal cord atrophy, electrophysiological abnormalities and neurological deficits following demyelination in a chronic inflammatory model of multiple sclerosis.

Recent pathological studies have re-emphasized that axonal injury is present in patients with multiple sclerosis, the most common demyelinating disease of the CNS in humans. However, the temporal profile of demyelination and axonal loss in multiple sclerosis patients and their independent contributions to clinical and electrophysiological abnormalities are not completely understood. In this study, we used the Theiler's murine encephalomyelitis virus model of progressive CNS inflammatory demyelination to demonstrate that demyelination in the spinal cord is followed by a loss of medium to large myelinated fibres. By measuring spinal cord areas, motor-evoked potentials, and motor coordination and balance, we determined that axonal loss following demyelination was associated with electrophysiological abnormalities and correlated strongly with reduced motor coordination and spinal cord atrophy. These findings demonstrate that axonal loss can follow primary, immune-mediated demyelination in the CNS and that the severity of axonal loss correlates almost perfectly with the degree of spinal cord atrophy and neurological deficits.

Animals↗