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)

Lewis rats that are primed with guinea pig spinal cord homogenized in complete Freund's adjuvant (GPSCH-CFA) develop overt symptoms of experimental allergic encephalomyelitis (EAE). Treatment with the iron-chelating agent, desferrioxamine B mesylate (DFOM), at various times before the onset of EAE, dramatically suppressed both the severity and duration of disease. When DFOM was administered to rats soon after the development of neurological signs, a rapid recovery occurred, though mild, transient symptoms could be seen approximately 1 wk after withdrawal of the drug. Treatment with DFOM was always accompanied by a diminution of T cell responsiveness on the part of the delayed-type hypersensitivity/helper subset and, on histological examination, an absence of inflammatory cells from lesions. Iron is believed to influence both the migration and function of immune effector cells. It can also act as a catalyst in the formation of free radicals, which are highly toxic agents causing tissue damage in sites of inflammation. The mechanisms underlying the effect of DFOM on the severity of EAE, and the possible implications for treatment of multiple sclerosis are discussed.
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PMID:Inhibition of autoimmune neuropathological process by treatment with an iron-chelating agent. 633 85

Experimental allergic encephalomyelitis (EAE) is a demyelinating autoimmune disorder that can be induced in susceptible mice by T lymphocytes sensitized to central nervous system (CNS) myelin components and is a prime animal model for the human CNS demyelinating disorder, multiple sclerosis (MS). Although CNS inflammation in which T lymphocytes and activated macrophages are the predominant cell types is observed in mice with EAE and in humans with MS, the exact mechanisms underlying the CNS damage and demyelination are not understood. Nitric oxide (NO), a gaseous free radical, has recently been shown to be a cytolytic product of activated macrophages. Using electron paramagnetic resonance spectroscopy, the nitric oxide free radical complexed with iron-sulfur proteins has been identified in affected spinal cords of mice with EAE, concurrent with the diminution of iron-sulfur proteins. These results indicate NO may play a role in the disease process of EAE, and perhaps MS.
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PMID:Nitric oxide localized to spinal cords of mice with experimental allergic encephalomyelitis: an electron paramagnetic resonance study. 839 79

Data from several studies indicate that free radicals have a pathogenic role in experimental allergic encephalomyelitis (EAE). Iron can contribute to free radical damage by catalyzing the formation of hydroxyl radical, inducing secondary initiation of lipid peroxidation and by promoting the oxidation of proteins. The iron chelator, desferrioxamine, can limit these oxidative reactions and it can scavenge peroxynitrite independent of iron chelation. Two previous studies have examined the therapeutic value of desferrioxamine in EAE. One study observed an effect when disease was induced by spinal cord homogenates (J. Exp. Med. 160, p. 1532, 1984), but a second study found no therapeutic value of desferrioxamine for myelin basic protein (MBP)-induced EAE (J. Neuroimmunol. 17, p. 127, 1988). In the second study, the drug was only administered during the preclinical stages of disease. Since desferrioxamine scavenges free radicals and prevents their formation, we hypothesized that the drug should be given during the active stage of disease to have therapeutic value. We first demonstrated that the drug enters the CNS around inflammatory cells in EAE animals. In animals treated during the active stage of MBP-induced EAE, the clinical signs were significantly reduced compared to vehicle-treated animals. The iron-bound form of this drug, ferrioxamine, was without therapeutic value. A derivative of desferrioxamine, hydroxylethyl starch (HES)-desferrioxamine, has a greater plasma half-life than desferrioxamine and it was also tested. Although there was a suggestion of improvement in these animals, the effects were less than that observed for desferrioxamine which may be related to the greater molecular size of HES-desferrioxamine. In summary, these data suggest that chelation of iron is an effective therapeutic target for EAE.
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PMID:Desferrioxamine suppresses experimental allergic encephalomyelitis induced by MBP in SJL mice. 962 62

MION-46L, a superparamagnetic iron oxide contrast agent, was investigated for its ability to increase the sensitivity of in vivo 3D MRI in the detection of brain lesions in a chronic experimental allergic encephalomyelitis (crEAE) mouse model. Lesion conspicuity on postcontrast 3D MRI was dramatically enhanced as compared to precontrast images corresponding to areas of inflammatory and demyelinating lesions. MION-46L could be detected on Prussian blue iron stain in the vascular endothelium, the perivascular space, and in macrophages within perivascular cuffs and areas of inflammation and demyelination. By taking advantage of the MION-46L induced macroscopic susceptibility effect, acute early lesions measuring only 100 microm in diameter could be detected. MION-46L enhanced MRI may be used to 1) provide a unique sensitivity in EAE lesion detection and correlate imaging to histopathology; 2) help to understand EAE lesion development and its underlying pathophysiology; and 3) eventually assist in preclinical screening of new experimental therapies directed at patients with multiple sclerosis (MS).
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PMID:Study of relapsing remitting experimental allergic encephalomyelitis SJL mouse model using MION-46L enhanced in vivo MRI: early histopathological correlation. 963 11

Iron has been proposed to promote oxidative tissue damage in multiple sclerosis (MS). In order to gain insights about how iron gets processed during MS, the deposition of iron was investigated in the CNS of mice with experimental allergic encephalomyelitis (EAE), which is a commonly used animal model of MS. Control mice (adjuvant only) and EAE mice (myelin basic protein plus adjuvant), were sacrificed at 4-8 days (preclinical phase), 10-13 days (clinical phase), or 18 days (recovery phase) post injection. Sections from the cerebrum, hindbrain, and cervical, thoracic and lumbar spinal cord were stained as previously described (J. Neurosci. Res. 29:413, 1991), and scored blindly for histopathological staining. There was minimal histopathological staining at any age in control animals or during the preclinical stage in EAE animals. At the clinical stage of EAE, stained pathological features (macrophages, extravasated RBC and granular staining) were significantly increased compared to the preclinical stage. In the recovery phase, macrophage and granular staining persisted but there was loss of extravasated RBC. Dual labeling studies revealed that granular deposits were present in astrocytes and in locations that appeared to be extracellular. In order to gain insights about the origin of iron deposits in EAE mice, additional studies were performed on brains of mice with extravasated blood lesions. These brains had granular, macrophage and RBC staining. Thus, each of the stained features in EAE animals could be due to the extravasation of blood which occurs in the SJL model of EAE, although some of the iron could have originated from myelin and oligodendrocytes damaged during EAE.
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PMID:Iron deposits in the central nervous system of SJL mice with experimental allergic encephalomyelitis. 987 Jul 13

Nitric oxide (NO) produced in inflammatory lesions may play a major role in the destruction of oligodendrocytes in multiple sclerosis and experimental allergic encephalomyelitis. The transformed murine oligodendroglial line N20.1 is much more resistant than primary oligodendrocytes to killing by the NO generator S-nitroso-N-acetyl-DL-penicillamine (SNAP). This observation prompted investigation of the mechanisms leading to cell death in the N20.1 cells and comparison of SNAP with another NO donor, sodium nitroprusside (SNP). We observed that N20.1 cells were 30 times more sensitive to SNP than to SNAP. The specific NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO) protected against SNP only, not against SNAP. However, dithiothreitol protected against both SNAP and SNP, indicating that S-nitrosylation of cysteines plays a major role in the cytotoxicity of both NO donors. We did not observe any formation of peroxynitrite or increase of Ca2+ concentration with either SNAP or SNP, thus excluding their involvement in the mechanisms leading to N20.1 cell death. Based on two observations, (a) potentiation of the cytotoxic effect of SNP when coincubated with ferricyanide or ferrocyanide, but not sodium cyanide, and (b) protection by deferoxamine, an iron cyanide chelator, we conclude that the greater sensitivity of N20.1 cells to SNP compared with SNAP is due to synergism between NO released and the iron cyanide portion of SNP, with the cyanide accounting for very little of the cytotoxicity. Finally, SNP but not SNAP induces some apoptosis, as shown by DNA laddering and protection by a caspase-3 inhibitor. These results suggest that low levels of NO in combination with increased iron content lead to apoptotic cell death rather than the necrotic cell death seen with higher levels of NO generated by SNAP.
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PMID:Synergism of nitric oxide and iron in killing the transformed murine oligodendrocyte cell line N20.1. 1003 76

Cell-specific imaging has been proposed to increase the potential of magnetic resonance imaging (MRI) for tissue analysis. The hypothezis of the present work was that following intravenous injection of ultra-small particle iron oxide, a contrast agent that accumulates in mononuclear phagocyte cells, macrophages with iron burden would be detectable by MRI within the central nervous system at sites of inflammatory cellular activity. In experimental autoimmune encephalomyelitis in Lewis rats (in which intense macrophage activity results from both hematogenous macrophages and activated microglia), lesions have been seen by MRI as low signal intensities related to magnetic susceptibility effects induced by iron particles. Electron microscopy has revealed the presence of such particles within the cytoplasm of cells that had the morphological aspect of macrophages. Macrophage activity imaging might increase MRI capability with regard to the in vivo pathophysiological aspects of central nervous system (CNS) diseases and might help in therapeutic trials in the numerous CNS diseases in which macrophages are involved.
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PMID:In vivo macrophage activity imaging in the central nervous system detected by magnetic resonance. 1008 Feb 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

Active nitrogen species are overproduced in inflammatory brain lesions in multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). NO has been shown to mediate the death of oligodendrocytes (OLs), a primary target of damage in MS. To develop strategies to protect OLs, we examined the mechanisms of cytotoxicity of two NO donors, S-nitroso-N-acetyl-penicillamine (SNAP) and sodium nitroprusside (SNP) on mature mouse OLs. Nitrosonium ion (NO+) rather than NO. mediates damage with both SNAP and SNP, as shown by significant protection with hemoglobin (HbO2), but not with the NO. scavenger PTIO. SNAP and SNP differ in time course and mechanisms of killing OLs. With SNAP, OL death is delayed for at least 6 hr, but with SNP, OL death is continuous over 18 hr with no delay. Relative to NO release, SNP is more toxic than SNAP, due to synergism of NO with cyanide released by SNP. SNAP elicits a Ca2+ influx in over half of the OLs within min. Further, OL death due to NO release from SNAP is Ca2+-dependent, because the Ca2+ chelator EGTA protects OLs from killing by SNAP, and also from killing by the NONOates NOC-9 and NOC-18, which spontaneously release NO. SNP does not elicit a Ca2+ influx, and EGTA is not protective. In comparison to the N20.1 OL cell line (Boullerne et al., [1999] J. Neurochem. 72:1050-1060), mature OLs are (1) more sensitive to SNAP, (2) much more resistant to SNP, (3) sensitive to cyanide, but not iron, and (4) exhibit a Ca2+ influx and EGTA protection in response to NO generated by SNAP.
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PMID:Role of calcium in nitric oxide-induced cytotoxicity: EGTA protects mouse oligodendrocytes. 1116 22

Proinflammatory cytokines, pathological iron deposition, and oxidative stress have been implicated in the pathogenesis of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). HO-1 mRNA levels and mitochondrial uptake of [(55)Fe]Cl(3)-derived iron were measured in rat astroglial cultures exposed to interleukin-1beta (IL-1beta) or tumor necrosis factor-alpha (TNF-alpha) alone or in combination with the heme oxygenase-1 (HO-1) inhibitors, tin mesoporphyrin (SnMP) or dexamthasone (DEX), or interferon beta1b (INF-beta). HO-1 expression in astrocytes was evaluated by immunohistochemical staining of spinal cord tissue derived from MS and control subjects. IL-1beta or TNF-alpha promoted sequestration of non-transferrin-derived (55)Fe by astroglial mitochondria. HO-1 inhibitors, mitochondrial permeability transition pore (MTP) blockers and antioxidants significantly attenuated cytokine-related mitochondrial iron sequestration in these cells. IFN-beta decreased HO-1 expression and mitochondrial iron sequestration in IL-1beta- and TNF-alpha-challenged astroglia. The percentage of astrocytes coexpressing HO-1 in affected spinal cord from MS patients (57.3% +/- 12.8%) was significantly greater (p < 0.05) than in normal spinal cord derived from controls subjects (15.4% +/- 8.4%). HO-1 is over-expressed in MS spinal cord astroglia and may promote mitochondrial iron deposition in MS plaques. In MS, IFN-beta may attenuate glial HO-1 gene induction and aberrant mitochondrial iron deposition accruing from exposure to proinflammatory cytokines.
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PMID:Proinflammatory cytokines promote glial heme oxygenase-1 expression and mitochondrial iron deposition: implications for multiple sclerosis. 1138 89


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