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)

Ferritin has been shown to attenuate iron-catalyzed oxidative damage in several experimental conditions. Since oxidative damage has been implicated in the pathogenesis of multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE), an animal model of MS, we tested the hypothesis that ferritin would act to attenuate disease. The experimental design was to increase plasma ferritin levels during the active stage of EAE by giving systemic injections of apoferritin and then compare disease activity between these mice and EAE mice administered vehicle. Additional mice received systemic injections of iron, which induces ferritin synthesis, in order to test the effects of exogenous iron on the disease course. Although plasma levels of ferritin were found to be elevated in both apoferritin and iron-injected EAE mice, only apoferritin treatment resulted in a reduction in disease activity compared to EAE mice given vehicle. The suppressive effects of apoferritin administration suggest that the increase in endogenous ferritin levels that have been previously observed in the cerebrospinal fluid of chronic progressive MS patients with active disease might be functioning to limit the severity and spread of tissue damage.
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PMID:Apoferritin attenuates experimental allergic encephalomyelitis in SJL mice. 1240 56

Serum levels of uric acid (UA), an inhibitor of peroxynitrite- (ONOO-) related chemical reactions, became elevated approximately 30 million years ago in hominid evolution. During a similar time frame, higher mammals lost the ability to synthesize another important radical scavenger, ascorbic acid (AA), leading to the suggestion that UA may have replaced AA as an antioxidant. However, in vivo treatment with AA does not protect against the development of experimental allergic encephalomyelitis (EAE), a disease that has been associated with the activity of ONOO- and is inhibited by UA. When compared in vitro, UA and AA were found to have similar capacities to inhibit the nitrating properties of ONOO-. However UA and AA had different capacities to prevent ONOO- -mediated oxidation, especially in the presence of iron ion (Fe3+). While UA at physiological concentrations effectively blocked dihydrorhodamine-123 oxidation in the presence of Fe3+, AA did not, regardless of whether the source of ONOO- was synthetic ONOO-, SIN-1, or RAW 264.7 cells. AA also potentiated lipid peroxidation in vivo and in vitro. In conclusion, the superior protective properties of UA in EAE may be related to its ability to neutralize the oxidative properties of ONOO- in the presence of free iron ions.
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PMID:Comparison of uric acid and ascorbic acid in protection against EAE. 1241 68

Experimental autoimmune encephalomyelitis (EAE) is a commonly used animal model that in several respects mimics human multiple sclerosis (MS), and can be used to design or validate new strategies for treatment of this disease. In the present study, different MRI techniques (macrophage tracking based on labeling cells in vivo by ultrasmall particles of iron oxide (USPIO), blood-brain barrier (BBB) breakdown, and magnetization transfer imaging (MTI)), as well as immunohistological staining were used to study the burden of disease in Lewis rats immunized by guinea pig myelin. The resulting imaging data was compared with behavioral readouts. Animals were studied during the acute phase and the first relapse. Activated monocytes were detected during both episodes in the brain stem or cortex. These areas coincided in part with areas of BBB breakdown. Significant changes of the magnetization transfer ratios (MTRs) of up to 35% were observed in areas of USPIO accumulation. This suggests that infiltrating monocytes are the major source of demyelination in EAE, but monocyte infiltration and breakdown of the BBB are temporally or spatially independent inflammatory processes.
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PMID:MRI-based monitoring of inflammation and tissue damage in acute and chronic relapsing EAE. 1287 7

Determinations of the effects of iron status on the immune system are complicated by the fact that microorganisms and immune cells both utilize iron. To determine the role of iron in immune function, we utilized a model [experimental autoimmune encephalomyelitis (EAE)] in which a strong antigen-specific CD4+ T-cell response develops in the absence of infection. EAE is an autoimmune disease frequently used as a model for the human disease multiple sclerosis (MS). EAE was induced in B10.PL mice fed low iron (1 mg/kg), normal iron (10 mg/kg) or high iron (160 mg/kg) diets that were replete in all other nutrients. Liver iron measurements verified iron status, i.e., low iron mice had 1.9 micro mol/g tissue, normal iron mice, 3.27 micro mol/g tissue and high iron mice, 5.35 micro mol/g tissue. EAE symptoms were most severe in normal iron mice, and EAE did not develop in low iron mice. The incidence of EAE was 71% in normal iron mice, 62% in iron-overloaded mice and 0% in iron-deficient mice. Two of seven mice in the normal iron group developed severe EAE and were euthanized. None of the iron-overloaded mice developed severe EAE. Other measures of EAE severity were similar in the normal and iron-overloaded mice. The data suggest that iron deficiency provides protection from the development of EAE and that iron excess with its potential contribution to free radical formation was not an important factor. The mechanism of EAE inhibition in iron-deficient mice likely involves the delivery and metabolism of iron for optimal CD4+ T-cell development.
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PMID:Iron-deficient mice fail to develop autoimmune encephalomyelitis. 1288 50

The expression of heme oxygenase-1 (HO-1) is increased in the CNS of mice and rats with experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). To investigate the role of HO-1 in EAE, a putative inhibitor [tin-protoporphyrin IX (Sn-PP IX)] of HO-1 was administered to SJL mice during active disease. Sn-PP IX (200 micromol/kg) attenuated clinical scores, weight loss, and some signs of pathology in comparison to vehicle treatment. Glutathione levels were greater in treated EAE mice than in those receiving vehicle, indicating lower oxidative stress in the former group. These data suggest that inhibition of HO-1 attenuated disease and suppressed free radical production. In the SJL model of EAE, extravasated blood is present in the CNS, and iron released by HO-1 from this heme source may not be adequately sequestered by ferritin, allowing for iron-mediated tissue damage. Thus, HO-1 may act to amplify the disease process in this model.
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PMID:Heme oxygenase-1 in SJL mice with experimental allergic encephalomyelitis. 1292 42

Fractions of bovine white matter, prepared by the methods of Folch and Lees, were studied for chemical composition and for their ability to produce experimental allergic encephalomyelitis in rabbits. Evaluation of the disease and of the lesions in animals injected with the more active fractions at several dose levels permitted comparison of the antigenic activity of these materials. When tissue was fractionated by the methods of Folch and Lees, antigenic activity was found in the chloroform-methanol extract but not in the denatured tissue residue. This activity was traced to proteolipides A and B and to the lower phase, more specifically the ether-soluble fraction of the lower phase. Proteolipide C was inactive. Correlation of the chemistry of fractions with their antigenic activity suggested two possibilities: (a) that there might be two antigens, one proteolipide and the other non-proteolipide; or (b) that a small specific proteolipide is responsible for all the observed activity. The high concentration of acetal phosphatide in the ether-soluble lower phase suggested that compounds of this type might be the hypothetical non-proteolipide antigen, but this hypothesis was disproved by analytic study of active and inactive materials. The possibility that proteolipide might account for all the antigenic activity was strongly supported by the experimental finding that total lipide and proteolipide progressively lost activity as proteolipide was degraded by adequate processing. The use of an entirely different method for preparing total lipides free of proteolipide (the colloidal iron technique) indicated that this loss of activity did not result from incidental removal of some non-proteolipide antigen. These tentative conclusions are in agreement with those of Tal and Olitsky and provide a satisfactory interpretation of the findings of Goldstein et al. The very fact, however, that the suggested proteolipide antigen would amount to no more than 1 per cent of the total chloroform-methanol extractives leaves open the possibility that some unrecognized trace substance may be the antigen. Skin tests with the various fractions indicated some cross-reactivity between proteolipides A and B and the ether-soluble lower phase fraction and a fair correlation of positive skin reactions with disease. This finding is compatible with the suggestion that the same antigen is present in both of these types of material. When the disease produced by whole tissue or fractions was evaluated by the use of the proportion of animals developing disease, the day of onset, and the severity of the histologic lesions, it was found that fractions produced milder disease of later onset than intact tissue at all dose levels. The disease-producing activity was not enhanced by increasing the dose; i.e., it appeared to reach an asymptotic maximum below that obtainable with whole fresh tissue. This finding suggests both a quantitative loss of activity and a qualitative change during the initial chloroform-methanol extraction, a procedure which denatures all proteins in the tissue residue. A comparable change appeared to occur in whole white matter stored at -15 degrees C. for 15 months and thawed and refrozen several times during this period. The later fractionation steps resulted in no apparent loss of antigenic activity. A scoring method employing the same type of data to estimate the actual relative antigen contents of different preparations is presented in the Appendix.
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PMID:A study of the chemical nature of components of bovine white matter effective in producing allergic encephalomyelitis in the rabbit. 1321 7

The present study investigates the immunological effects of a combination treatment of mitoxantrone and the cardioprotector dexrazoxane in experimental autoimmune encephalomyelitis (EAE). Mitoxantrone, an anthracycline-derived immunosuppressive drug has been approved recently for treatment of very active multiple sclerosis (MS). Its prolonged use is limited due to its cardiotoxic properties. Dexrazoxane (DZR (S)-(+)-1,2-bis (3,5.dioxopiperazinyl)propane, ICRF-187) is an iron III chelator which in animal models and in cancer patients reduces anthracycline and mitoxantrone induced cardiotoxicity when given immediately before these agents. We examined the immunological effects of dexrazoxane in combination with mitoxantrone in experimental autoimmune encephalomyelitis (EAE) in Lewis rats. EAE was induced by active immunization with myelin basic protein (MBP) or by adoptive transfer of MBP specific T cells (AT-EAE). The clinical course, spinal cord pathology, activity of metalloproteinases (MMP-2 and MMP-9) and T cell apoptosis were assessed. Monotherapy with DZR ameliorated slightly the course of actively induced EAE and AT-EAE. The combination of DZR and mitoxantrone was superior to mitoxantrone given alone. Clinical amelioration ran in parallel with the marked reduction of inflammatory infiltration which was nearly abolished by the combination treatment. DZR did not affect the activity of metalloproteinase 9 and did not increase the proportion of apoptotic lymph node cells ex vivo or T cells in situ. We conclude that in addition to its cardioprotective role, DZR augments mitoxantrone-mediated immunosuppressive effects in animal models of human central nervous system (CNS) autoimmune disease. Clinical trials in MS patients are warranted to evaluate the unexpected immunosuppressive efficacy of DZR as add-on treatment.
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PMID:The cardioprotector dexrazoxane augments therapeutic efficacy of mitoxantrone in experimental autoimmune encephalomyelitis. 1467 64

Enhanced cerebrovascular permeability and cellular infiltration mark the onset of early multiple sclerosis lesions. So far, the precise sequence of these events and their role in lesion formation and disease progression remain unknown. Here we provide quantitative evidence that blood-brain barrier leakage is an early event and precedes massive cellular infiltration in the development of acute experimental allergic encephalomyelitis (EAE), the animal correlate of multiple sclerosis. Cerebrovascular leakage and monocytes infiltrates were separately monitored by quantitative in vivo MRI during the course of the disease. Magnetic resonance enhancement of the contrast agent gadolinium diethylenetriaminepentaacetate (Gd-DTPA), reflecting vascular leakage, occurred concomitantly with the onset of neurological signs and was already at a maximal level at this stage of the disease. Immunohistochemical analysis also confirmed the presence of the serum-derived proteins such as fibrinogen around the brain vessels early in the disease, whereas no cellular infiltrates could be detected. MRI further demonstrated that Gd-DTPA leakage clearly preceded monocyte infiltration as imaged by the contrast agent based on ultra small particles of iron oxide (USPIO), which was maximal only during full-blown EAE. Ultrastructural and immunohistochemical investigation revealed that USPIOs were present in newly infiltrated macrophages within the inflammatory lesions. To validate the use of USPIOs as a non-invasive tool to evaluate therapeutic strategies, EAE animals were treated with the immunomodulator 3-hydroxy-3-methylglutaryl Coenzyme A reductase inhibitor, lovastatin, which ameliorated clinical scores. MRI showed that the USPIO load in the brain was significantly diminished in lovastatin-treated animals. Data indicate that cerebrovascular leakage and monocytic trafficking into the brain are two distinct processes in the development of inflammatory lesions during multiple sclerosis, which can be monitored on-line with MRI using USPIOs and Gd-DTPA as contrast agents. These studies also implicate that USPIOs are a valuable tool to visualize monocyte infiltration in vivo and quantitatively assess the efficacy of new therapeutics like lovastatin.
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PMID:Blood-brain barrier permeability and monocyte infiltration in experimental allergic encephalomyelitis: a quantitative MRI study. 1578 47

Multiple sclerosis (MS) and its animal model, experimental allergic encephalomyelitis (EAE), are autoimmune disorders resulting in demyelination in the central nervous system (CNS). Pathologically, the blood-brain barrier becomes damaged, macrophages and T cells enter into the CNS, oligodendrocytes and myelin are destroyed, astrocytes and microglia undergo gliosis, and axons become transected. Data from several biochemical and pharmacological studies indicate that free radicals participate in the pathogenesis of EAE, and iron has been implicated as the catalyst leading to their formation. The primary focus of this article is the examination of the role of iron in the pathogenesis of MS and EAE. Particular attention will be paid to the role and distribution of iron and proteins involved with iron metabolism (e.g., transferrin, ferritin, heme oxygenase-1, etc.) in normal and disease states of myelin. Furthermore, therapeutic interventions aimed at iron, iron-binding proteins, and substrates or products of iron-catalyzed reactions leading to free radical production will be discussed.
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PMID:The role of iron in the pathogenesis of experimental allergic encephalomyelitis and multiple sclerosis. 1510 71

Multiple sclerosis (MS) is a T cell-mediated autoimmune disease with early lesions characterized by mononuclear cellular infiltrate, edema, demyelination, and axonal loss that contribute to the clinical course of the disease. Experimental autoimmune encephalomyelitis (EAE) in the mouse is a valuable model with a similar disease course to relapsing-remitting MS. The ability to detect the migration of encephalitogenic T cells into the central nervous system in EAE and MS would provide key information on these cells role in the development of lesions observed on magnetic resonance imaging (MRI). T cells were labeled for detection by magnetic resonance imaging using Food and Drug Administration-approved, superparamagnetic iron oxide nanoparticles (Ferumoxides) complexed to poly-L-Lysine (FE-PLL). EAE was induced by adoptive transfer of either labeled or unlabeled T cells. After disease onset, FE-PLL-labeled T cells were detected in the mouse spinal cord using in vivo and ex vivo cellular MRI. Excellent correlation was seen between MRI-visible lesions in the spinal cord and histopathology. The results demonstrate that T cells labeled with FE-PLL can induce EAE disease and can be detected in vivo in the mouse model. The magnetic labeling of cells opens the possibility of monitoring specific cellular phenotypes or pharmacologically or genetically engineered cells by MRI.
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PMID:Magnetic resonance imaging of labeled T-cells in a mouse model of multiple sclerosis. 1512 5


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