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)

1. In the presence of genotoxic stress poly(ADP-ribose) polymerase-1 (PARP-1) leads to NAD(+) and ATP depletion, participating in the pathogenesis of several disorders including inflammation. Accordingly, chemical inhibitors of PARP-1 are efficacious anti-inflammatories, albeit the underlying molecular mechanisms are still under debate. 2. This study investigated the effect of the PARP-1 inhibitors 6(5H)-phenanthridinone and benzamide as well as that of benzoic acid, an inactive analogue of benzamide, on development of experimental allergic encephalomyelitis (EAE) in rats. Both 6(5H)-phenanthridinone and benzamide attenuated development of EAE, reducing clinical score, neuroimmune infiltration and expression of inflammatory mediators such as inducible nitric oxide synthase, interleukin-1beta and -2, cyclooxygenase-2, tumour necrosis factor-alpha and interferon-gamma in the spinal cord of myelin-immunized rats. Importantly, no evidence of NAD(+) and ATP depletion as well as poly(ADP-ribose) formation was detected in the spinal cord. 3. By contrast, a robust formation of poly(ADP-ribose) occurred in B- and T-cell areas in lymph nodes of myelin-immunized rats and was suppressed by the treatment with 6(5H)-phenanthridinone and benzamide. In cultures of activated rat lymphocytes, 6(5H)-phenanthridinone and benzamide reduced the DNA-binding activity of NF-kappaB and AP-1 and transcription of pro-inflammatory cytokines such as interleukin-2, interferon-gamma and tumour necrosis factor-alpha. 4. Notably, benzoic acid did not reproduce the in vivo and in vitro effects of its parent compound. 5. These findings indicate that PARP-1 promotes transcriptional activation in lymphocytes and inhibitors of its enzymatic activity are useful for the treatment of autoimmune disorders of the central nervous system.
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PMID:Inhibitors of poly(ADP-ribose) polymerase-1 suppress transcriptional activation in lymphocytes and ameliorate autoimmune encephalomyelitis in rats. 1241 6

Alphaviruses are mosquito-borne, enveloped, plus-strand RNA viruses that cause a spectrum of diseases in humans that include fever, rash, arthritis, meningitis, and encephalomyelitis. Sindbis virus (SINV) is the prototype alphavirus, causes encephalomyelitis in mice, and provides a model system for studying the pathogenesis of alphavirus-induced neurological disease. Major target cells for SINV infection in the central nervous system (CNS) are neurons, and both host and viral factors determine the fate of infected neurons. Young animals are most susceptible to fatal disease. This correlates with the ability of SINV to induce apoptosis in immature neurons. In vitro, apoptotic death of neuroblastoma cells can be induced by fusion of the virus envelope with the endosomal membrane and does not require infectious virus. This fusion process activates acid sphingomyelinase that cleaves sphingomyelin to release ceramide, an initiator of apoptosis. Within an hour, poly(ADP-ribose) polymerase is activated, and this is followed by release of cytochrome c and activation of effector caspases. SINV-induced cell death can be delayed or prevented by treatment with antioxidants or caspase inhibitors and by intracellular expression of Bcl-2, Beclin-1, or protease inhibitors. Older animals survive infection unless infected with a neurovirulent strain of SINV. In these mice, anterior horn motor neurons die by a primarily necrotic process that is influenced by excitotoxic amino acids and inflammation, whereas hippocampal neurons can be either apoptotic or necrotic. Death also occurs in uninfected neurons in the vicinity of infected neurons and can be delayed or prevented by treatment with glutamate receptor antagonists.
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PMID:Neuronal cell death in alphavirus encephalomyelitis. 1579 51

Glutamate excitotoxicity and complement attack have both been implicated separately in the generation of tissue damage in multiple sclerosis and in its animal model, experimental autoimmune encephalomyelitis. Here, we investigated whether glutamate receptor activation sensitizes oligodendrocytes to complement attack. We found that a brief incubation with glutamate followed by exposure to complement was lethal to oligodendrocytes in vitro and in freshly isolated optic nerves. Complement toxicity was induced by activation of kainate but not of AMPA receptors and was abolished by removing calcium from the medium during glutamate priming. Dose-response studies showed that sensitization to complement attack is induced by two distinct kainate receptor populations displaying high and low affinities for glutamate. Oligodendrocyte death by complement required the formation of the membrane attack complex, which in turn increased membrane conductance and induced calcium overload and mitochondrial depolarization as well as a rise in the level of reactive oxygen species. Treatment with the antioxidant Trolox and inhibition of poly(ADP-ribose) polymerase-1, but not of caspases, protected oligodendrocytes against damage induced by complement. These findings indicate that glutamate sensitization of oligodendrocytes to complement attack may contribute to white matter damage in acute and chronic neurological disorders.
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PMID:Activation of kainate receptors sensitizes oligodendrocytes to complement attack. 1655 73

Resveratrol (trans-3,5,4'-trihydroxystilbene), a polyphenolic compound found in plant products, including red grapes, exhibits anticancer, antioxidant, and anti-inflammatory properties. Using an animal model of multiple sclerosis (MS), we investigated the use of resveratrol for the treatment of autoimmune diseases. We observed that resveratrol treatment decreased the clinical symptoms and inflammatory responses in experimental allergic encephalomyelitis (EAE)-induced mice. Furthermore, we observed significant apoptosis in inflammatory cells in spinal cord of EAE-induced mice treated with resveratrol compared with the control mice. Resveratrol administration also led to significant down-regulation of certain cytokines and chemokines in EAE-induced mice including tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-2, IL-9, IL-12, IL-17, macrophage inflammatory protein-1alpha (MIP-1alpha), monocyte chemoattractant protein-1 (MCP-1), regulated on activation normal T-cell expressed and secreted (RANTES), and Eotaxin. In vitro studies on the mechanism of action revealed that resveratrol triggered high levels of apoptosis in activated T cells and to a lesser extent in unactivated T cells. Moreover, resveratrol-induced apoptosis was mediated through activation of aryl hydrocarbon receptor (AhR) and estrogen receptor (ER) and correlated with up-regulation of AhR, Fas, and FasL expression. In addition, resveratrol-induced apoptosis in primary T cells correlated with cleavage of caspase-8, caspase-9, caspase-3, poly(ADP-ribose) polymerase, and release of cytochrome c. Data from the present study demonstrate, for the first time, the ability of resveratrol to trigger apoptosis in activated T cells and its potential use in the treatment of inflammatory and autoimmune diseases including, MS.
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PMID:Resveratrol (trans-3,5,4'-trihydroxystilbene) ameliorates experimental allergic encephalomyelitis, primarily via induction of apoptosis in T cells involving activation of aryl hydrocarbon receptor and estrogen receptor. 1787 69

Theiler's murine encephalomyelitis virus (TMEV) induces two distinct cell death programs, necrosis and apoptosis. The apoptotic pathway is of particular interest because TMEV persists in the central nervous system of mice, largely in infiltrating macrophages, which undergo apoptosis. Infection of murine macrophages in culture induces apoptosis that is Bax dependent through the intrinsic or mitochondrial pathway, restricting infectious-virus yields and raising the possibility that apoptosis represents a mechanism to attenuate TMEV yet promote macrophage-to-macrophage spread during persistent infection. To help define the cellular stressors and upstream signaling events leading to apoptosis during TMEV infection, we screened baby hamster kidney (BHK-21) cells transfected to express individual nonstructural genes (except 3B) of the low-neurovirulence BeAn virus strain for cell death. Only expression of the leader protein led to apoptosis, as assessed by fluorescence-activated cell sorting analysis of propidium iodide- and annexin V-stained transfected cells, immunoblot analysis of poly(ADP-ribose) polymerase and caspase cleavages, electron microscopy, and inhibition of apoptosis by the pancaspase inhibitor qVD-OPh. After transfection, Bak and not Bax expression increased, suggesting that the apical pathway leading to activation of these Bcl-2 multi-BH-domain proapoptotic proteins differs in BeAn virus infection versus L transfection. Mutation to remove the CHCC Zn finger motif from L, a motif required by L to mediate inhibition of nucleocytoplasmic trafficking, significantly reduced L-protein-induced apoptosis in both BHK-21 and M1-D macrophages.
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PMID:Theiler's murine encephalomyelitis virus leader protein is the only nonstructural protein tested that induces apoptosis when transfected into mammalian cells. 1940 76

Experimental autoimmune encephalomyelitis (EAE), an animal model for human multiple sclerosis, is characterized by demyelination, inflammation and neurodegeneration of CNS in which free radicals play a role. Recently, the efficacy of murine mesenchimal stem cells (MSCs) as treatment of EAE induced in mice by the encephalitogenic peptide MOG(35-55) was demonstrated. The present study analyzed some markers of oxidative stress, inflammation/degeneration and apoptosis such as metallothioneins (MTs), antioxidant enzymes (superoxide dismutase, catalase and glutathione-S-transferase), poly(ADP-ribose) polymerase-1 and p53 during EAE progression and following MSC treatment. Expression of the three brain MT isoforms increased significantly in EAE mice compared with healthy controls, but while expression of MT-1 and MT-3 increased along EAE course, MT-2 was up-regulated at the onset, but returned to levels similar to those of controls in chronic phase. The changes in the transcription and activity of the antioxidant enzymes and in expression of poly(ADP-ribose) polymerase-1 and p53 showed the same kinetics observed for MT-1 and MT-3 during EAE. Interestingly, i.v. administration of MSCs reduced the EAE-induced increases in levels/activities of all these proteins. These results support an antioxidant and neuroprotective activity for MSCs that was also confirmed in vitro on neuroblastoma cells exposed to an oxidative insult.
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PMID:Neuroprotective mesenchymal stem cells are endowed with a potent antioxidant effect in vivo. 1961 33

Multiple sclerosis is an inflammatory disease of the central nervous system that begins as a relapsing-remitting disease (RRMS) and is followed by a progressive phase (SPMS). The progressive phase causes the greatest disability and has no effective therapy, but the processes that drive SPMS are mostly unknown. Here we found higher serum concentrations of 15alpha-hydroxicholestene (15-HC) in patients with SPMS and in mice with secondary progressive experimental autoimmune encephalomyelitis (EAE) but not in patients with RRMS. In mice, 15-HC activated microglia, macrophages and astrocytes through a pathway involving Toll-like receptor 2 (TLR2) and poly(ADP-ribose) polymerase 1 (PARP-1). PARP-1 activity was higher in monocytes of patients with SPMS, and PARP-1 inhibition suppressed the progression of EAE. Thus, the TLR2-PARP-1 pathway is a potential new therapeutic target in SPMS.
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PMID:Toll-like receptor 2 and poly(ADP-ribose) polymerase 1 promote central nervous system neuroinflammation in progressive EAE. 2168 47