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)

The potential role(s) of cytokines in the reduction of infectious virus and persistent viral infection in the central nervous system was examined by determining the kinetics of cytokine mRNA expression following infection with the neurotropic JHM strain of mouse hepatitis virus. Mice were infected with an antibody escape variant which produces a nonlethal encephalomyelitis and compared to a clonal virus population which produces a fulminant fatal encephalomyelitis. Infection with both viruses induced the accumulation of mRNAs associated with Th1- and Th2-type cytokines, including IFN-gamma, IL-4, and IL-10. Peak mRNA accumulations were coincident with the clearance of virus and there was no obvious differences between lethally and nonlethally infected mice. TNF-alpha mRNA was induced more rapidly in lethally infected mice compared to mice undergoing a nonfatal encephalomyelitis. Rapid transient increases in the mRNAs encoding IL-12, iNOS, IL-1alpha, IL-1beta, and IL-6 occurred following infection. Nonlethal infections were associated with increased IL-12, IL-1beta, and earlier expression of IL-6, while lethal infections were associated with increased iNOS and IL-1alpha mRNA. These data suggest a rapid but differential response within the central nervous system cells to infection by different JHMV variants. However, neither the accumulation nor kinetics of induction provide evidence to distinguish lethal infections from nonlethal infections leading to a persistent infection. Accumulation of both Th1 and Th2 cytokines in the central nervous system of JHMV-infected mice is consistent with the participation of both cytokines and cell immune effectors during resolution of acute viral-induced encephalomyelitis.
 ...
PMID:Kinetics of cytokine mRNA expression in the central nervous system following lethal and nonlethal coronavirus-induced acute encephalomyelitis. 921 50

Interleukin 12 (IL-12), a novel heterodimeric protein produced primarily by antigen-presenting cells, serves as a key regulator of innate and adaptive immune responses. In addition to being a potent inducer of IFN-gamma, IL-12 is widely considered to be the principal cytokine that regulates the generation of Th1 type effector cells. As the successful induction of experimental autoimmune encephalomyelitis (EAE) is associated with a strong Th1 type cellular response, we have evaluated the role of IL-12 in regulating the pathogenesis of EAE in SJL/J mice and Lewis rats. In both settings, treatment with IL-12 was found to accelerate the onset and increase the severity and duration of clinical disease. More importantly, administration of IL-12 to Lewis rats that had recovered from primary disease was found to trigger clinical relapse. In all instances, IL-12-induced exacerbation was associated with a profound increase in iNOS positive macrophages within the perivascular lesions. Although IL-12-induced IFN-gamma does not appear to be required for exacerbation of disease, neutralizing antibodies against murine IL-12 delay the onset and reduce the severity of adoptively transferred EAE, indicating a role for endogenous IL-12 as regulator of disease. Based on the above findings, effective inhibition of IL-12 in vivo may have great therapeutic value in the treatment of MS and other Th1-associated inflammatory disorders.
 ...
PMID:Regulation of the inflammatory response in animal models of multiple sclerosis by interleukin-12. 941 42

We used an antisense oligodeoxynucleotide (ODN) complementary to inducible nitric oxide synthase (iNOS) to inhibit experimental autoimmune encephalomyelitis (EAE) in female SJL/J mice, an animal model for multiple sclerosis. The antisense ODN was administered intraventricularly to mice daily for 10 days beginning at the time of adoptive transfer of myelin basic protein-specific T lymphocytes. The antisense ODN treatment significantly reduced the clinical score of EAE and blocked iNOS mRNA and protein synthesis, as well as iNOS enzyme activity within the central nervous system. The levels of nitric oxide and cyclic guanosine monophosphate were also significantly reduced by the antisense ODN treatment. Neither sense nor random ODN affected clinical EAE or iNOS expression. Moreover, the protein and enzyme activity level of constitutive neuronal nitric oxide synthase was not affected by the antisense ODN. Thus, we have shown that the iNOS antisense ODN specifically blocked iNOS expression and ameliorated the induction of EAE.
 ...
PMID:Antisense knockdown of inducible nitric oxide synthase inhibits induction of experimental autoimmune encephalomyelitis in SJL/J mice. 951 Jan 51

Nitric oxide is believed to be a prominent mediator of inflammation based in part on the correlative expression of the inducible nitric oxide synthase (iNOS) gene in various pathologies. The resulting high output of the highly reactive molecule nitric oxide is then believed to play an important role in the evolving inflammatory response. Studies have shown that iNOS and nitric oxide are present in the tissues of patients with multiple sclerosis (MS). In rodent models of MS, experimental autoimmune encephalomyelitis (EAE), it has been shown that nonspecific NOS inhibitors partially ameliorate the disease. To determine the importance of iNOS in this model of MS, we induced EAE in mice containing a disrupted iNOS (NOS2) gene. Surprisingly, by day 24, the NOS2 knockout mice had a greater incidence of EAE than wild-type control mice (75 vs 12%), and had a higher average severity score (2.42 vs 0.44). These differences appear to result largely from the failure of the disease to remit in NOS2 KO mice. Wild-type mice have a profound ability to reverse EAE (82%) compared with the knockout mice (19%). This result implies that iNOS may in some instances play a protective role in autoimmune-mediated tissue destruction.
 ...
PMID:Experimental autoimmune encephalomyelitis is exacerbated in mice lacking the NOS2 gene. 951 Jan 98

This study evaluated effects of the inducible nitric oxide synthase (iNOS) inhibitor, aminoguanidine (AG), on the neuropathology and clinical disease produced by Theiler's murine encephalomyelitis virus (TMEV) DA strain infection. Treatment with AG was started on day 7, 14, 28 or 66 post-inoculation and continued for a minimum of 21 days. Inflammation, demyelination and axonal necrosis were scored in a blinded fashion on spinal cord sections from each mouse. Reduction in inflammation, demyelination and axonal necrosis was observed in mice treated with AG. Apoptosis within the spinal cord parenchyma and perivascular cuffs was significantly decreased. AG treatment resulted in delayed onset of clinical disease.
 ...
PMID:Nitric oxide synthase inhibitor, aminoguanidine, reduces inflammation and demyelination produced by Theiler's virus infection. 952 9

To elucidate the role of excessive nitric oxide (NO) via the inducible nitric oxide synthase (iNOS) in experimental allergic encephalomyelitis (EAE), the effect of a selective iNOS inhibitor, aminoguanidine, was investigated using mice with actively induced EAE. Administration of aminoguanidine by intraperitoneal or intracisternal injection from day 2 to day 12 after immunization produced a significant delay in the onset of EAE. On the other hand, administration of aminoguanidine by intraperitoneal or intracisternal injection for 10 days after the onset of EAE enhanced the clinical severity and mortality rate and hastened the onset of relapse significantly. The histological study at day 11 after the onset revealed that more inflammatory cells were present in the central nervous system of mice treated with aminoguanidine as compared with mice without aminoguanidine treatment. These results suggested that NO via iNOS was a pathogenetic factor in the induction phase of EAE, but had an inhibitory role in the progression phase of EAE. Although the effect of NO synthase inhibitors on EAE has been controversial, the present study suggested that the timing of administration might be an important consideration and might explain the previous contradictory reports.
 ...
PMID:Aminoguanidine, a selective inhibitor of the inducible nitric oxide synthase, has different effects on experimental allergic encephalomyelitis in the induction and progression phase. 952 23

Nitric oxide (NO) generated by the inducible nitric oxide synthase (iNOS) has been implicated in the pathogenesis of experimental autoimmune encephalomyelitis (EAE). In this study mice genetically deficient for iNOS are shown to be susceptible to EAE induced by immunization with myelin oligodendrocyte glycoprotein (MOG). In iNOS (-/-) mice the course of disease was earlier in onset and more aggressive compared to control animals. A disease-relevant compensatory up-regulation of neuronal (n)NOS and endothelial (e)NOS with increased production of NO in iNOS (-/-) mice is excluded by 1) the failure to detect increased nNOS and eNOS mRNA, 2) the absence of detection of nitrosylated tyrosine residues in EAE tissue indicating absence of NO-derived peroxynitrite, and 3) the lack of disease-preventing effects of NG-nitro-L-arginine methyl ester. In conclusion, these results do not support the hypothesis that NO is crucial for the development of EAE.
 ...
PMID:Mice with an inactivation of the inducible nitric oxide synthase gene are susceptible to experimental autoimmune encephalomyelitis. 956 73

Interleukin 10 (IL-10) is an important anti-inflammatory cytokine. To examine its role in virus-induced encephalomyelitis, IL-10-deficient (IL-10 -/-) mice were infected with a neurotropic strain of mouse hepatitis virus (JHMV). JHMV-infected IL-10 -/- mice, compared to IL-4 -/- and syngeneic C57BL/6 mice, exhibited increased morbidity and mortality. Virus was cleared from the CNS of all groups of mice with equal kinetics by day 9 postinfection and the lack of either IL-4 or IL-10 did not alter the distribution of viral antigen, suggesting a lack of correlation between viral replication and the increased clinical disease in IL-10 -/- mice. In moribund IL-10 -/- mice, a moderate increase in mononuclear cell infiltration was correlated with increased expression of tumor necrosis factor-alpha, interferon-gamma, and inducible nitric oxide synthase mRNAs. In the small percentage of IL-10 -/- mice that survived, no differences in either demyelination or inflammation were observed. Together, these results suggest that IL-10 is not required for viral clearance, and although it appears to be one of the mechanisms responsible for inhibiting the extent of inflammation in the CNS during acute JHMV infection, it has little role in the eventual resolution of CNS inflammatory responses.
 ...
PMID:The role of IL-10 in mouse hepatitis virus-induced demyelinating encephalomyelitis. 963 66

Peroxynitrite and hydroxyl radicals are potent initiators of DNA single strand breakage, which is an obligatory stimulus for the activation of the nuclear enzyme poly(ADP-ribose)synthetase (PARS). Rapid activation of PARS depletes the intracellular concentration of its substrate, NAD+, slowing the rate of glycolysis, electron transport and ATP formation. This process can result in acute cell dysfunction and cell necrosis. Accordingly, inhibitors of PARS protect against cell death under these conditions. In addition to the direct cytotoxic pathway regulated by DNA injury and PARS activation, PARS also appears to modulate the course of inflammation by regulating the expression of a number of genes, including the gene for intercellular adhesion molecule 1, collagenase and the inducible nitric oxide synthase. The research into the role of PARS in inflammatory conditions is now supported by novel tools, such as novel, potent inhibitors of PARS, and genetically engineered animals lacking the gene for PARS. In vivo data demonstrate that inhibition of PARS protects against various forms of inflammation, including zymosan or endotoxin induced multiple organ failure, arthritis, allergic encephalomyelitis, and diabetic islet cell destruction. Pharmacological inhibition of PARS may be a promising novel approach for the experimental therapy of various forms of inflammation.
 ...
PMID:Role of poly(ADP-ribose)synthetase in inflammation. 968 9

Organ-specific autoimmune diseases are characterized by infiltrates, including T lymphocytes and activated macrophages. Macrophages and secondarily activated tissue resident counterparts can both present Ag to and contribute to cytokine secretion by T lymphocytes. We have previously shown a crucial role of peripheral macrophages in experimental allergic encephalomyelitis (EAE), a Th1-mediated demyelinating disease that serves as a an animal model for multiple sclerosis (MS), by their depletion using mannosylated liposome-encapsulated dichloromethylene diphosphonate (Cl2MDP). Here we describe studies to investigate the mechanisms by which macrophages contribute to the lesion formation in EAE, by studying the effect of Cl2MDP-containing mannosylated liposomes (Cl2MDP-mnL) on adoptively transferred EAE in SJL/J mice. Adoptive transfer of EAE with myelin basic protein-reactive CD4+ T cells to SJL/J mice was abrogated by Cl2MDP-mnL treatment. CD4+ T cell and MHC II+ B220+ B cell extravasation from blood vessels and Th1 cytokine production were not inhibited. However, invasion of the central nervous system intraparenchymal tissues by lymphocytes, F4/80+, Mac-1+, and MOMA-1+ macrophages was almost completely blocked after treatment with Cl2MDP-mnL. Furthermore, in Cl2MDP-mnL-treated mice, the myelin sheaths appeared completely normal, whereas, in the control groups, marked demyelination occurred. Production of TNF-alpha and inducible nitric oxide synthase, both associated with macrophage/microglial activation, was inhibited. This intervention reveals a role for macrophages in regulating the invasion of autoreactive T cells and secondary glial recruitment that ordinarily lead to demyelinating pathology in EAE and multiple sclerosis.
 ...
PMID:Immune invasion of the central nervous system parenchyma and experimental allergic encephalomyelitis, but not leukocyte extravasation from blood, are prevented in macrophage-depleted mice. 975 3


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>