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)

The activity and expression of nitric oxide synthase (NOS) isoforms and protein nitrotyrosine (NT) residues were investigated in whole encephalic mass (WEM) homogenates during the development of experimental allergic encephalomyelitis (EAE) in Lewis rats. EAE stages (0-III) were daily defined by clinical evaluation, and in the end of each stage, WEMs were removed for analysis of NOS activity, protein NT residues and mRNA for the different NOS isoforms. In the presence of NADPH, WEMs from EAE-III rats showed lower Ca2+-dependent NOS activity than those from control group. These differences disappeared in the presence of exogenous calmodulin, flavin adenine dinucleotide (FAD), tetrahydrobiopterin (BH4) and NADPH. Of all the cofactors, just the omission of FAD caused comparable decrease of Ca2+-dependent NOS activity from both groups. Ca2+-independent NOS activity from EAE-III animals was insensitive to the omission of any of the cofactors, while in control animals this activity was significantly inhibited by the omission of either FAD or BH4. Increased levels of both iNOS mRNA and protein NT expression were observed in animals with EAE, which also showed lower levels of a thermolabile NOS inhibitor in WEM homogenates and sera than controls. In conclusion, during late EAE stages, constitutive Ca2+-dependent NOS activity decreases concomitantly with iNOS upregulation, which could be responsible for the high protein NT levels. The differential dependence of iNOS activity on cofactors and the absence of an endogenous thermolabile NOS inhibitor in animals with EAE could reflect additional control mechanisms of NOS activity in this model of multiple sclerosis.
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PMID:Expression and activity of nitric oxide synthase isoforms in rat brain during the development of experimental allergic encephalomyelitis. 1186 4

Free radical nitric oxide (NO), generated by inducible nitric oxide synthase (iNOS) in astrocytes and macrophages, has been implicated in CNS inflammatory disorders such as multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). Mycophenolic acid (MPA), a selective inhibitor of inosine monophosphate dehydrogenase (IMPDH), inhibited interferon-gamma (IFN-gamma) + lipopolysaccharide (LPS)-induced NO production dose-dependently in astrocytes, but not in macrophages. The effect of MPA was not mediated through interference with IMPDH-dependent synthesis of iNOS cofactor BH4 and subsequent suppression of iNOS enzymatic activity, as direct BH4 precursor sepiapterin failed to block the action of the drug. However, MPA markedly inhibited IFN-gamma + LPS-triggered astrocyte expression of mRNA for iNOS and its transcription factor IRF-1, while the expression of tumor necrosis factor-alpha (TNF-alpha) gene was not altered. The observed MPA suppression of NO release and iNOS and IRF-1 induction in astrocytes were efficiently prevented by exogenous guanosine, indicating that the drug acted through reduction of IMPDH-dependent synthesis of guanosine nucleotides. This IRF-1-dependent inhibition of iNOS activation might be partly responsible for the protective effect of MPA in EAE, prompting investigation of its potential use in multiple sclerosis.
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PMID:Mycophenolic acid downregulates inducible nitric oxide synthase induction in astrocytes. 1220 91