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

We studied the role of 15-deoxy-delta (12,14)-PGJ2 (15d-PGJ2), a macrophage inhibitor with reported therapeutic effects on experimental allergic encephalomyelitis, in human astrocyte activation in vitro. 15d-PGJ2 inhibited a broad range of astrocyte inflammatory gene expression induced by IL-1, including cytokines (TNFalpha and IL-6), chemokines (RANTES/CCL5 and IP-10/CXCL10) and inducible nitric oxide synthase. 15d-PGJ2 inhibited transactivation of NF-kappaB-dependent promoters, as well as p38 and JNK MAPK phosphorylation induced by IL-1, while having no inhibitory effect on IFN-induced Stat signaling pathways. Our results demonstrating 15d-PGJ2-mediated astrocyte deactivation through inhibition of NF-kappaB are similar to those described for macrophages, and add astrocytes as additional targets for this prostaglandin (PG).
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PMID:15-deoxy-delta (12,14)-PGJ2 inhibits astrocyte IL-1 signaling: inhibition of NF-kappaB and MAP kinase pathways and suppression of cytokine and chemokine expression. 1526 71

Experimental autoimmune encephalomyelitis (EAE) disease was accelerated iNOS-deficient (KO) mice: coinciding with greatly increased numbers of Ag-specific Th1 cells in the periphery that appeared to rapidly shift from the spleen to the CNS during onset of disease symptoms. iNOS KO mice had significantly increased Th1 cells in the CNS versus wild-type mice. Apoptosis of CNS-infiltrating CD4(+) T cells was impaired in iNOS KO mice at peak of disease; consequently, these mice had more CNS-infiltrating CD4(+) T cells. Subsequently, iNOS KO mice up-regulated apoptosis of CNS-CD4(+) T cells. During chronic EAE, CNS macrophages were greatly decreased, suggesting elimination of CNS-infiltrating CD4(+) T cells and activated macrophages by iNOS-independent mechanisms. INOS is not only required for apoptosis of CNS-CD4(+) T cells but also prevents overexpansion of autoreactive Th1 cells in the periphery and the CNS.
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PMID:Nitric-oxide-dependent and independent mechanisms of protection from CNS inflammation during Th1-mediated autoimmunity: evidence from EAE in iNOS KO mice. 1571 Apr 64

As with other major autoimmune diseases, susceptibility to multiple sclerosis (MS) is believed to result from the complex interaction of a number of genes, each with modest effect. Extensive research of experimental autoimmune encephalomyelitis in mice and several direct MS studies have implicated NOS2A, which encodes the inducible form of nitric oxide synthase, and the genetic region encoding NOS2A, 17q11.2, has been identified in a number of genome wide screens as being potentially associated with MS. We investigated four single nucleotide polymorphisms in the proximal promoter region of NOS2A, in a case-control group of 100 Australian MS patients and 100 controls and in 203 MS patients and their unaffected parents. We found a trend toward excess transmission of the -277A allele (tag for the AGCC haplotype) to HLA-DRB1*1501-positive MS patients (P (uncorrected)=0.05). We initially discovered a trend toward over-representation of the AGCC haplotype in HLA-DRB1*1501-positive compared to HLA-DRB1*1501-negative MS patients in the case-control cohort. However, when combined with the probands from the transmission disequilibrium analysis, this trend was nullified. Nonetheless, despite the lack of significant evidence of association for the NOS2A promoter polymorphisms with MS, the gene remains an interesting candidate for MS susceptibility, particularly with regard to the HLA-DRB1*1501 haplotype.
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PMID:An investigation of NOS2A promoter polymorphisms in Australian multiple sclerosis patients. 1585 71

We report that N-acetyl-L-cysteine (NAC) treatment blocked induction of TNF-alpha, IL-1beta, IFN-gamma and iNOS in the CNS and attenuated clinical disease in the myelin basic protein induced model of experimental allergic encephalomyelitis (EAE) in Lewis rats. Infiltration of mononuclear cells into the CNS and induction of inflammatory cytokines and iNOS in multiple sclerosis (MS) and EAE have been implicated in subsequent disease progression and pathogenesis. To understand the mechanism of efficacy of NAC against EAE, we examined its effect on the production of cytokines and the infiltration of inflammatory cells into the CNS. NAC treatment attenuated the transmigration of mononuclear cells thereby lessening the neuroinflammatory disease. Splenocytes from NAC-treated EAE animals showed reduced IFN-gamma production, a Th1 cytokine and increased IL-10 production, an anti-inflammatory cytokine. Further, splenocytes from NAC-treated EAE animals also showed decreased nitrite production when stimulated in vitro by LPS. These observations indicate that NAC treatment may be of therapeutic value in MS against the inflammatory disease process associated with the infiltration of activated mononuclear cells into the CNS.
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PMID:N-acetyl-L-cysteine ameliorates the inflammatory disease process in experimental autoimmune encephalomyelitis in Lewis rats. 1586 13

Between one-third and one-half of all cases of sepsis are known to be caused by gram-positive microorganisms through the cell wall component, e.g. lipoteichoic acid (LTA). Gram-positive bacteria are also known to induce encephalomyelitis and meningeal inflammation, and enhance the production of nitric oxide (NO) via expression of inducible nitric oxide synthase (iNOS) in murine tissue macrophages. It remains to be explored if LTA could activate microglia considered to be resident brain macrophages. We report here that LTA derived from gram-positive bacteria (Staphylococcus aureus) significantly induces NO release and iNOS expression in primary microglia. LTA-induced NO accumulation was detected at 2 h in microglial culture and was significantly attenuated by pretreatment with anti-CD14, complement receptor type 3 (CR3) or scavenger receptor (SR) antibodies. LTA activated mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase, p38 MAPK or c-Jun N-terminal kinase in cultured microglia. LTA-elicited microglial NO production was also drastically suppressed by SB203580 (p38 MAPK inhibitor) or pyrrolidine dithiocarbamate (an inhibitor of nuclear factor kappaB), indicating that p38 MAPK and nuclear factor kappaB were involved in microglial NO release after LTA challenge. These results suggest that gram-positive bacterial product such as LTA can activate microglia to release NO via the signal transduction pathway involving multiple LTA receptors (e.g. CD14, CR3 or SR), p38 MAPK and nuclear factor kappaB. The in vivo study further confirmed that administered intracerebrally LTA induced considerable noticeable iNOS, phospho-IkappaB and phospho-p38 MAPK expression in microglia/macrophages.
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PMID:Signal transduction pathways of nitric oxide release in primary microglial culture challenged with gram-positive bacterial constituent, lipoteichoic acid. 1587 5

Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) is a well-characterized murine model of human multiple sclerosis (MS) that closely resembles the chronic and progressive clinical form of the disease. Recent studies have described the involvement of the cannabinoid system in the progression of the disease and the benefits associated with the administration of cannabinoid agonists. With the objective to study whether "indirect" agonists, that is, compounds able to reinforce the physiological endocannabinoid transmission and, therefore, devoid of the psychotropic effects of "direct" agonists, could be suitable agents for the amelioration of MS neurological deficits, we administered the potent and selective anandamide uptake inhibitor UCM707 to TMEV-infected mice. Our results indicate that treatment during established disease significantly improves the motor function of the diseased mice. At the histological level, UCM707 is able to reduce microglial activation, diminish major histocompatibility complex class II antigen expression, and decrease cellular infiltrates in the spinal cord. Additionally, in microglial cells, UCM707 decreases the production of the proinflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6; reduces nitric oxide levels and inducible nitric oxide synthase expression; and is able to potentiate the action of a subeffective dose of the endocannabinoid anandamide. Overall, these results suggest that agents able to activate the endocannabinoid system could constitute a new series of drugs for the treatment of MS.
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PMID:Activation of the endocannabinoid system as therapeutic approach in a murine model of multiple sclerosis. 1594 68

Vitamin K2 (VK2), which has been in wide use for the management of hypoprothrombinemia and osteoporosis in Japan, was tested for its efficacy on experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). The severity of EAE was significantly ameliorated by the prophylactic administration of VK2, though it was not effective when given after the onset. Inflammatory cellular infiltration and the expression of both MHC class II and inducible nitric oxide synthase (iNOS) were reduced in the spinal cords of VK2-treated rats with EAE. The inhibitory effect of VK2 on the iNOS expression in glial cells was also observed in vitro. Considering the long use of VK2 without noticeable untoward effects, it may be applicable to the patients with MS.
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PMID:Vitamin K2 ameliorates experimental autoimmune encephalomyelitis in Lewis rats. 1614 54

The heat-shock response (HSR), a highly conserved cellular response, is characterized by rapid expression of heat-shock proteins (HSPs), and inhibition of other synthetic activities. The HSR can attenuate inflammatory responses, via suppression of transcription factor activation. A HSR can be induced pharmacologically by HSP90 inhibitors, through activation of the transcription factor Heat Shock Factor 1 (HSF1). In the present study we characterized the effects of 17-allylamino-17-demethoxygeldanamycin (17-AAG), a less toxic derivative of the naturally occurring HSP90 inhibitor geldanamycin, on glial inflammatory responses and the development of experimental autoimmune encephalomyelitis. In primary enriched glial cultures, 17-AAG dose dependently reduced lipopolysaccharide-dependent expression and activity of inducible nitric oxide synthase, attenuated interleukin (IL)-1beta expression and release, increased inhibitor of kappaB protein levels, and induced HSP70 expression. 17-AAG administration to mice immunized with myelin oligodendrocyte glycoprotein peptide prevented disease onset when given at an early time, and reduced clinical symptoms when given during ongoing disease. T cells from treated mice showed a reduced response to immunogen re-stimulation, and 17-AAG reduced CD3- and CD28-dependent IL-2 production. Together, these data suggest that HSP90 inhibitors could represent a new approach for therapeutic intervention in autoimmune diseases such as multiple sclerosis.
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PMID:The heat-shock protein 90 inhibitor 17-allylamino-17-demethoxygeldanamycin suppresses glial inflammatory responses and ameliorates experimental autoimmune encephalomyelitis. 1706 48

Experimental allergic encephalomyelitis (EAE) is an inflammatory demyelinating disease of the CNS that is used to model certain parameters of multiple sclerosis. To establish the relative contributions of T cell reactivity, the loss of blood-brain barrier (BBB) integrity, CNS inflammation, and lesion formation toward the pathogenesis of EAE, we assessed the incidence of EAE and these parameters in mice lacking NF-kappaB, TNF-alpha, IFN-alphabeta receptors, IFN-gamma receptors, and inducible nitric oxide synthase. Although increased myelin oligodendrocyte glycoprotein-specific T cell reactivity was generally associated with a more rapid onset or increased disease severity, the loss of BBB integrity and cell accumulation in spinal cord tissues was invariably associated with the development of neurological disease signs. Histological and real-time RT-PCR analyses revealed differences in the nature of immune/inflammatory cell accumulation in the spinal cord tissues of the different mouse strains. On the other hand, disease severity during the acute phase of EAE directly correlated with the extent of BBB permeability. Thus, the loss of BBB integrity seems to be a requisite event in the development of EAE and can occur in the absence of important inflammatory mediators.
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PMID:Loss of blood-brain barrier integrity in the spinal cord is common to experimental allergic encephalomyelitis in knockout mouse models. 1737 91

Multiple sclerosis (MS) is a complex neurodegenerative disease whose pathogenesis involves genetic and environmental risk factors leading to an aberrant, neuroantigen-specific, CD4+ T cell-mediated autoimmune response. In support of the hypothesis that vitamin D3 may reduce MS risk and severity, we found that vitamin D3 and 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) inhibited induction of experimental autoimmune encephalomyelitis (EAE), an MS model. To investigate how 1,25-(OH)2D3 could carry out anti-inflammatory functions, we administered 1,25-(OH)2D3 or a placebo to mice with EAE, and subsequently analyzed clinical disease, chemokines, inducible nitric oxide synthase (iNOS), and recruitment of dye-labeled monocytes. The 1,25-(OH)2D3 treatment significantly reduced clinical EAE severity within 3 days. Sharp declines in chemokines, inducible iNOS, and CD11b+ monocyte recruitment into the central nervous system (CNS) preceded this clinical disease abatement in the 1,25-(OH)2D3-treated animals. The 1,25-(OH)2D3 did not directly and rapidly inhibit chemokine synthesis in vivo or in vitro. Rather, the 1,25-(OH)2D3 rapidly stimulated activated CD4+ T cell apoptosis in the CNS and spleen. Collectively, these results support a model wherein inflammation stimulates a natural anti-inflammatory feedback loop. The activated inflammatory cells produce 1,25-(OH)2D3, and this hormone subsequently enhances the apoptotic death of inflammatory CD4+ T cells, removing the driving force for continued inflammation. In this way, the sunlight-derived hormone could reduce the risk of chronic CNS inflammation and autoimmune-mediated neurodegenerative disease.
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PMID:1,25-dihydroxyvitamin D3 reverses experimental autoimmune encephalomyelitis by inhibiting chemokine synthesis and monocyte trafficking. 1760 Mar 74


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