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)

A 60-year-old woman presented with stiff-person syndrome (SPS). Treatment with diazepam controlled her painful spasms initially. Two and one-half years after the onset of SPS, new spells of paroxysmal leg jerking and apnea developed. A spell was recorded with simultaneous video and polygraphic techniques that revealed simultaneous firing of motor unit potentials in several muscles (paraspinal, internal hamstring, and abdominal muscles). Apnea was associated with arterial oxygen desaturation. An increase in the dose of diazepam decreased the number and severity of these episodes. Seventeen months later, the patient began to taper the diazepam dose. Shortly thereafter, she had a cardiorespiratory arrest and subsequently died. Autopsy showed small chronic inflammatory foci in the pancreas (some associated with islets) and findings of diffuse encephalomyelitis characterized by perivascular cuffing in the spinal cord, brainstem, thalamus, hippocampus, and amygdala and a dense mononuclear infiltrate in the anterior horns of the lumbar and cervical cord, with relative preservation of axons and myelin. Cell typing showed this infiltrate was polyclonal and reactive. There have been rare cases of SPS associated with encephalomyelitis reported previously. Although the prolonged course in our patient suggested that SPS may have preceded encephalomyelitis, the more likely explanation is that the patient had an unusually long course of encephalomyelitis alone.
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PMID:Subacute encephalomyelitis presenting as stiff-person syndrome: clinical, polygraphic, and pathologic correlations. 891 97

Breakdown of T cell tolerance to self-myelin basic protein induces an autoimmune process that leads to demyelination of the central nervous system (CNS) in multiple sclerosis (MS) patients. While the autoimmune disease is initiated by antigen-specific autoreactive T cells, there is accumulating evidence that CNS injury is essentially mediated by CNS-infiltrating inflammatory cells. In addition, it is established that activated macrophages and polymorphonuclear cells contribute to tissue damage in several inflammatory diseases by releasing highly reactive oxygen metabolites. It was therefore possible that demyelination associated with MS results from oxidative injury caused by a cascade of oxygen reactive metabolites produced by CNS-infiltrating activated macrophages and other inflammatory cells. To address this question, we tested the effect of a synthetic catalytic scavenger of oxygen radicals, EUK-8, on experimental allergic encephalomyelitis (EAE) in mice, the animal model for MS in humans. We observed that repeated injection of EUK-8 starting at the time of EAE induction delayed the onset and markedly reduced the severity of the disease. Strikingly, all EUK-8-treated mice completely recovered after 40 days. In addition, we showed that posttreatment with EUK-8 4 days after EAE induction also resulted in a significant amelioration of EAE disease. These results indicate that oxygen metabolites secreted by inflammatory cells at the site of tissue destruction play a major role in the induction and presumably the perpetuation of the autoimmune disease. This study also suggests that treatment with oxygen metabolites scavengers may represent a novel and promising strategy to prevent the onset and to block the course of ongoing autoimmune encephalomyelitis and other inflammatory autoimmune diseases.
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PMID:Prevention and suppression of autoimmune encephalomyelitis by EUK-8, a synthetic catalytic scavenger of oxygen-reactive metabolites. 914 96

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

Magnetic resonance imaging (MRI) has been performed to determine the efficacy of hyperbaric oxygen treatment (HBO) on experimental allergic encephalomyelitis (EAE) in Lewis rats. The animals were exposed for 2 x 3 h in a 24-h period at 2 ATA pure O2. Three HBO treatment protocols were used: a 10-day preventive treatment (beginning on the 1st day postimmunization), a 3-day preventive treatment (beginning on the 1st day postimmunization), and a 10-day symptomatic treatment (beginning on the 11th day postimmunization). Based on clinical and MRI observations, this study demonstrates: (i) that HBO treatment does not reduce the blood-brain barrier (BBB) disturbance and cerebral edema in EAE, (ii) that in an opposite way, it provokes reversible BBB breakdown, and (iii) that preventive HBO treatments results in modification of the course of EAE, possibly by immunosuppression effect during the initial sensitization step.
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PMID:Hyperbaric oxygen treatment in acute experimental allergic encephalomyelitis. Contribution of magnetic resonance imaging study. 934 80

Peripheral macrophages infiltrating the central nervous system and resident microglia phagocytize myelin in cell-mediated demyelinating diseases, including experimental autoimmune encephalomyelitis and multiple sclerosis. A cascade of cytokines is believed to modulate the immunological sequence of events occurring in these conditions, and several of these mediate their effects through the protein kinase C pathway. Therefore, we compared the effects of phorbol myristate acetate (PMA), an activator of protein kinase C, on various functions of cultured macrophages and microglia. PMA at moderate concentrations induced apoptosis in macrophages, and this process appeared to be increased in the presence of myelin. In contrast, microglia were activated by PMA, and greatly increased their phagocytosis of myelin. Control macrophages released a considerable amount of proteolytic activity into the medium, as measured by the breakdown of myelin basic protein, and in the process of undergoing apoptosis from PMA-treatment, even higher amounts were released. The enzyme activity in control macrophage medium was inhibited mainly by PMSF and calpain inhibitors, while that from PMA-treated macrophages was inhibited by calpain inhibitors only. An ICE inhibitor was ineffective in inhibiting activity in medium from PMA-treated cells undergoing apoptosis. Medium from microglia contained very little proteolytic activity, and this was not increased by PMA. Cultured macrophages showed little evidence of oxygen free radical release as measured by the TBARS procedure, and PMA had no effect. Microglia, on the other hand, produced higher levels of reactive oxygen species, with a further increase of 18% by PMA. Thus major functions of these phagocytic cells appear to be modulated by the protein kinase C pathway, although the two cell types show very different responses to an activator of this signal.
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PMID:Effects of phorbol myristate acetate (PMA) on functions of macrophages and microglia in vitro. 948 57

Recruitment of inflammatory cells into the CNS during pathological processes associated with neurodegeneration, trauma, autoimmune disease, and infection involves the generation of signaling molecules that are both cell-associated and soluble. Alteration in the permeability of the blood brain barrier, adhesion of blood-borne leukocytes to cerebral vessels, activation of chemoattractants and their receptors, and migration of inflammatory cells into the CNS are events that have been proposed to be regulated by cytokines and reactive oxygen and nitrogen species. In this review we propose associative connections between these events and the molecules involved as they may relate to CNS inflammation, placing illustrative emphasis on multiple sclerosis and the animal model for MS, experimental allergic encephalomyelitis.
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PMID:Inflammatory events at the blood brain barrier: regulation of adhesion molecules, cytokines, and chemokines by reactive nitrogen and oxygen species. 951 13

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

The enzyme heme oxygenase-1 (HO-1) is reducing heme to the gaseous mediator carbon monoxide, to iron and the antioxidant biliverdin. The inducible expression of HO-1 is considered a protective cellular mechanism against reactive oxygen intermediates. Further, carbon monoxide (CO) is a regulator of cGMP synthesis, of NO-synthetases and cyclooxygenases, thereby indirectly modulating reactive processes. Here we report expression of HO-1 in rat experimental autoimmune encephalomyelitis (EAE) and neuritis (EAN). With both models, similar results were obtained: HO-1 was localized predominantly to infiltrating, monocytic, but only rarely to ramified microglial cells or astrocytes surrounding the inflammatory lesions. Prominent expression by monocytic cells was seen from day 11 after immunization correlating with the development of neurologic disease. Further, local expression is persistent for long after cessation of neurologic signs. Thus, HO-1 could be considered a factor in the formation and resolution of inflammatory autoimmune lesions of the nervous system.
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PMID:Heme oxygenase-1 in lesions of rat experimental autoimmune encephalomyelitis and neuritis. 1102 40

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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