Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The association of reactive oxygen species to altered permeability of the blood-brain barrier in acute experimental encephalomyelitis was investigated by ultrastructural cytochemical localization of hydrogen peroxide (H2O2) to sites in the optic nerve previously identified by extravasation of intravascular horseradish peroxidase. Using a modified cerium method, we found electron-dense cerium-derived H2O2 reaction product was localized to the perivascular space at the lamina retinalis, lamina choroidalis, and lamina scleralis. In the optic nerve head, electron-dense reaction product was observed in the presence of intravascular leukocytes, although adjacent perivascular and interstitial inflammatory cells at this site were scant. In the myelinated retrobulbar optic nerve, cerium-derived H2O2 reaction product was seen in the intravascular space of blood vessels and surrounding perivascular and interstitial foci of inflammatory cells. Reaction product was also observed in the extracellular space adjacent to the plasmalemma of axons and glial cells in the optic nerve head and retrobulbar nerve. The perivascular and intravascular distribution of cerium-derived reaction product suggests that H2O2 may play a role in the pathogenesis of altered vascular permeability in experimental optic neuritis and supports our previous observations of suppression of blood-brain barrier permeability by detoxification of H2O2 with the exogenous administration of antioxidant enzymes.
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PMID:Hydrogen peroxide localization in experimental optic neuritis. 224 46

Detoxification of hydrogen peroxide by the antioxidant enzyme catalase suppressed the neurologic manifestations of acute experimental allergic encephalomyelitis (EAE) and prevented death of treated adult strain-13 guinea pigs. The oxygen radical scavenger superoxide dismutase (SOD) delayed the onset of paralysis by one day, but did not prevent death from encephalomyelitis common to most of this group and all untreated animals. Histopathologic analysis of the optic nerves confirmed a statistically significant reduction in demyelination with catalase treatment, but not with SOD. Hydrogen peroxide, and/or its conversion products, discharged by phagocytic mononuclear cells, may play a role in the pathogenesis of demyelination in experimental optic neuritis.
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PMID:Antioxidant enzyme suppression of demyelination in experimental optic neuritis. 273 52

The purpose of this paper was to investigate the role of deferoxamine (DFO) scavenging of hydroxyl radical (.OH) on disruption of the blood-brain barrier (BBB) and demyelination in experimental optic neuritis. Eighteen strain-13 guinea pigs were sensitized for experimental allergic encephalomyelitis. Nine animals received 100 mg/kg of hydroxyethyl starch-conjugated (HES) DFO by daily intraperitoneal injection commencing the day of antigenic sensitization. Nine paired litter mates received daily IP injections of HES. Serial fat-suppressed magnetic resonance imaging of the optic nerves was obtained with a T2 weighting (T2w) to evaluate demyelination and after intravascular administration of Gd-DTPA to evaluate BBB disruption. The intensity of Gd-DTPA enhancement and T2w signal of the optic nerves was quantitated 3, 7, 10 and 14 days after antigenic sensitization. Animals were then sacrificed and the optic nerves processed for light and transmission electron microscopy with ultracytochemical localization of endogenous hydrogen peroxide (H2O2) and immunogold colocalization of extravasated serum albumin. The area of the optic nerve head, intensity of toluidine blue staining, and the cellular infiltrate were digitized and quantitated. Administration of HES-DFO significantly reduced the intensity of Gd-DTPA enhancement in the optic nerves of HES-DFO-treated animals compared to paired control HES animals (p = 0.0236), with the mean difference between control and treated animals of 19.39. The difference in T2w signal was not significant (p = 0.39), with a mean difference between control and treated animals of -5.51. The intensity of toluidine blue staining of optic nerve specimens was slightly less with HES-DFO compared to untreated animals (mean pair difference 2.48), and the inflammatory infiltrate was reduced with HES-DFO compared to untreated animals (mean pair difference = 61.57); these differences were not statistically significant. In the optic nerve specimens of both groups cerium perhydroxide-derived H2O2 reaction product was evident in a predominantly perivascular and perineural distribution. Immunogold-labeled serum albumin showed extravasation at foci of perivascular inflammation in both the presence and absence of H2O2-derived reaction product. Conjugated DFO reduces disruption of the BBB, as measured by Gd-DTPA enhancement, suggesting the .OH radical generated from perivascular H2O2 may play a role in alterations of vascular permeability in experimental optic neuritis.
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PMID:Conjugated deferoxamine reduces blood-brain barrier disruption in experimental optic neuritis. 753 78

During experimental allergic encephalomyelitis (EAE), both blood-borne macrophages as well as activated, resident microglial cells are considered to be involved in inflammatory reactions in the central nervous system (CNS), resulting in the neurological deficits common to EAE. Both cell types can produce multiple mediators of tissue damage, among which are the reactive oxygen species (ROS). In this study we show that macrophages and microglial cells, isolated from the CNS of Lewis rats with clinical signs of EAE, exhibited significantly elevated spontaneous and phorbol myristate acetate (PMA)-inducible levels of ROS compared to similar cells isolated from healthy controls, sham (complete Freund's adjuvant, CFA)-immunized rats as well as rats sacrificed before the manifestation of clinical signs of EAE. However, during clinical EAE, peripheral blood mononuclear cells (PBMC) did not show increased spontaneous nor PMA-inducible ROS production compared to controls. In vivo treatment of EAE with catalase, which scavenges the ROS H2O2, markedly suppressed the severity of the disease as compared to sham (albumin)-treated controls. In contrast, superoxide dismutase had no effect on clinical signs. Our studies point at a putative functional role for ROS, and in particular H2O2, in the pathogenesis of EAE.
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PMID:Reactive oxygen species are involved in the pathogenesis of experimental allergic encephalomyelitis in Lewis rats. 786 Jul 16

In order to determine the role of H2O2 in demyelination of the optic nerve, serial quantitative analysis of H2O2-derived cerium perhydroxide reaction product particles was obtained by computerized digitization of electron micrographs of the myelinated retrobulbar optic nerve, unmyelinated optic nerve head, and the optic nerve sheath of guinea pigs sensitized for experimental allergic encephalomyelitis (EAE) and euthanized 3-14 days later. We found that cerium perhydroxide reaction product particles were greatest in the myelinated optic nerve 3 days after antigenic sensitization, but at this focus decreased 7-14 days after antigenic sensitization. Reaction product accumulated in the unmyelinated optic nerve head and optic nerve sheath 3-14 days after sensitization. These results in the myelinated optic nerve suggest H2O2 consumption results in peroxidation of myelin lipid as demyelination proceeds 7-14 days after antigenic sensitization. Hydrogen peroxide accumulation in the optic nerve head and the optic nerve sheath appears to provide a reservoir for diffusion of H2O2 into the retrobulbar optic nerve and adjacent perineural nerve, contributing to the frequent predilection for optic nerve involvement in EAE and perhaps in multiple sclerosis.
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PMID:Role of hydrogen peroxide in experimental optic neuritis. A serial quantitative ultrastructural study. 823 51

Apoptosis is a major mechanism of T cell elimination during ontogeny and tolerance induction as well as in autoimmunity. To assess the possible involvement of reactive oxygen and nitrogen intermediates (ROI and NO.) in T-cell apoptosis during autoimmune demyelination we investigated the effects of H2O2 and NO. in vitro on activated autoreactive CD4+ T cell lines capable of transferring experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune neuritis (EAN). For detection and quantitation of apoptotic cells, DNA fragmentation was assessed by in situ tailing with fluorescein-ddUTP and subsequent flow cytometric analysis. H2O2 applied directly to the cell cultures for 6 to 18 hr at concentrations of 10 to 300 microM and ROI released by combination of hypoxanthine and xanthine oxidase (HX/XO) caused apoptosis in a dose-dependent manner in 13-33% of T cells of neuritogenic and encephalitogenic T cell lines. Apoptosis induction could be suppressed by the H2O2-neutralizing enzyme catalase. NO. released by the penicillamine derivative SNAP induced apoptosis to a similar extent as ROI. Maximum values were 38% in an encephalitogenic V beta 8.2-T cell receptor-bearing T cell line and 26% in a neuritogenic T cell line. T cell lines with specificity to ovalbumin revealed slightly lower susceptibility to apoptosis induction by all three kinds of trigger, which is, however, most probably not due to the different antigen specificity, but rather a result of fewer in vitro restimulation cycles of these cells. In neuritogenic cells high-dose (100 units/ml) exogenous interleukin-2 (IL-2) prevents H2O2-induced apoptosis. In conclusion, macrophage-derived reactive oxygen and nitrogen intermediates have the potency to limit inflammatory demyelination by elimination of autoreactive and bystander T cells via apoptotic cell death, and IL-2 is a rescue factor.
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PMID:Apoptosis of myelin-reactive T cells induced by reactive oxygen and nitrogen intermediates in vitro. 918 92

Suppression of oxidative injury by viral-mediated transfer of the human catalase gene was tested in the optic nerves of animals with experimental allergic encephalomyelitis (EAE). EAE is an inflammatory autoimmune disorder of primary central nervous system demyelination that has been frequently used as an animal model for the human disease multiple sclerosis (MS). The optic nerve is a frequent site of involvement common to both EAE and MS. Recombinant adeno-associated virus containing the human gene for catalase was injected over the right optic nerve heads of SJL/J mice that were simultaneously sensitized for EAE. After 1 month, cell-specific catalase activity, evaluated by quantitation of catalase immunogold, was increased approximately 2-fold each in endothelia, oligodendroglia, astrocytes, and axons of the optic nerve. Effects of catalase on the histologic lesions of EAE were measured by computerized analysis of the myelin sheath area (for demyelination), optic disc area (for optic nerve head swelling), extent of the cellular infiltrate, extravasated serum albumin labeled by immunogold (for blood-brain barrier disruption), and in vivo H2O2 reaction product. Relative to control, contralateral optic nerves injected with the recombinant virus without a therapeutic gene, catalase gene inoculation reduced demyelination by 38%, optic nerve head swelling by 29%, cellular infiltration by 34%, disruption of the blood-brain barrier by 64%, and in vivo levels of H2O2 by 61%. Because the efficacy of potential treatments for MS are usually initially tested in the EAE animal model, this study suggests that catalase gene delivery by using viral vectors may be a therapeutic strategy for suppression of MS.
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PMID:Adeno-associated viral-mediated catalase expression suppresses optic neuritis in experimental allergic encephalomyelitis. 981 89

Reactive oxygen species (ROS) are thought to be involved in the pathogenesis of multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). In this study we showed that the phagocytosis of myelin by macrophages triggers the production of ROS. We also demonstrated that ROS play a crucial role in the myelin phagocytosis. Blocking the ROS production with NADPH oxidase inhibitors (100 microM DPI or 10 mM Apocynin) essentially prevented the phagocytosis of myelin. Furthermore, scavenging of ROS with catalase (H2O2) or mannitol (OH-) decreased the phagocytosis of myelin by macrophages, whereas superoxide dismutase (O2-) did not show this effect. In addition, Lipoic acid (LA), a non-specific scavenger of ROS, also decreased the phagocytosis of myelin by macrophages. In our results, we demonstrate for the first time that ROS appear to play a regulatory role in the phagocytosis of myelin.
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PMID:Reactive oxygen species are required for the phagocytosis of myelin by macrophages. 991 81

Nuclear factor kappa B (NF-kappa B) is a transcription factor crucially involved in glial and neuronal function. NF-kappa B is ubiquitously distributed within the nervous system, and its inducible activity can be discerned from constitutive activity. Prototypic inducible NF-kappa B in the nervous system is composed of the DNA-binding subunits p50 and p65 complexed with an inhibitory I kappa B-alpha molecule. A number of signals from the cell surface can lead to rapid activation of NK-kappa B, thus releasing the inhibition by I kappa B. This activates translocation of NF-kappa B to the nucleus, where it binds to kappa B motifs of target genes and activates transcription. Previous findings have identified reactive oxygen intermediates (ROI) as a common denominator of NF-kappa B activating signals. More specifically, hydrogen peroxide (H2O2) might be used as second messenger in the NF-kappa B system, despite its cytotoxicity. Analysis of pathways leading to NF-kappa B activation in the nervous system has identified a number of ROI-dependent pathways such as cytokine- and neurotrophin-mediated activation, glutamatergic signal transduction, and various diseases with crucial ROI involvement (e.g., Alzheimer's disease, Parkinson's disease, experimental autoimmune encephalomyelitis, multiple sclerosis, amyotrophic lateral sclerosis, and injury). A number of NF-kappa B-specific target genes contribute to the production of ROI or are involved in detoxification of ROIs. In this review, possible mechanisms and regulatory pathways of ROI-mediated NF-kappa B activation are discussed.
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PMID:Activation of NF-kappa B by reactive oxygen intermediates in the nervous system. 1122 42

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by destruction of myelin. Recent studies have indicated that axonal damage is involved in the pathogenesis of the progressive disability of this disease. To study the role of axonal damage in the pathogenesis of MS-like disease induced by myelin oligodendrocyte glycoprotein (MOG), we compared experimental autoimmune encephalomyelitis (EAE) in wild-type (WT) and transgenic mice expressing the human bcl-2 gene exclusively in neurons under the control of the neuron-specific enolase (NSE) promoter. Our study shows that, following EAE induction with pMOG 35-55, the WT mice developed significant clinical manifestations with complete hind-limb paralysis. In contrast, most of the NSE-bcl-2 mice (16/27) were completely resistant, whereas the others showed only mild clinical signs. Histological examination of CNS tissue sections showed multifocal areas of perivascular lymphohistiocytic inflammation with loss of myelin and axons in the WT mice, whereas only focal inflammation and minimal axonal damage were demonstrated in NSE-bcl-2 mice. No difference could be detected in the immune potency as indicated by delayed-type hypersensitivity (DTH) and T-cell proliferative responses to MOG. We also demonstrated that purified synaptosomes from the NSE-bcl-2 mice produce significantly lower level of reactive oxygen species (ROS) following exposure to H2O2 and nitric oxide (NO) than WT mice. In conclusion, we demonstrated that the expression of the antiapoptotic gene, bcl-2, reduces axonal damage and attenuates the severity of MOG-induced EAE. Our results emphasize the importance of developing neuroprotective therapies, in addition to immune-specific approaches, for treatment of MS.
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PMID:Mice overexpressing Bcl-2 in their neurons are resistant to myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). 1130 81


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