Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exposure of primary cultures of neonatal rat cortical astrocytes to bacterial lipopolysaccharide (LPS) results in the appearance of nitric oxide synthase (NOS) activity. The induction of NOS, which is blocked by actinomycin D, is directly related to the duration of exposure and dose of LPS, and a 2-hr pulse can induce enzyme activity. Cytosol from LPS-treated astrocyte cultures, but not from control cultures, produces a Ca(2+)-independent conversion of L-arginine to L-citrulline that can be completely blocked by the specific NOS inhibitor NG-monomethyl-L-arginine. The induced NOS activity exhibits an apparent Km of 16.5 microM for L-arginine and is dependent on NADPH, FAD, and tetrahydrobiopterin. LPS also induces NOS in C6 glioma cells and microglial cultures but not in cultured cortical neurons. The expression of NOS in astrocytes and microglial cells has been confirmed by immunocytochemical staining using an antibody to the inducible NOS of mouse macrophages and by histochemical staining for NADPH diaphorase activity. We conclude that glial cells of the central nervous system can express an inducible form of NOS similar to the inducible NOS of macrophages. Inducible NOS in glia may, by generating nitric oxide, contribute to the neuronal damage associated with cerebral ischemia and/or demyelinating diseases.
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PMID:Induction of calcium-independent nitric oxide synthase activity in primary rat glial cultures. 127 98

We studied the effect of focal cerebral ischemia on inducible (iNOS) and constitutive (cNOS) nitric oxide synthase enzymatic activities in the affected brain. The middle cerebral artery (MCA) was occluded in spontaneously hypertensive rats. Animals were killed 1, 2, 4, and 7 days later. cNOS and iNOS enzymatic activities were determined in the infarcted cortex using the assay of Bredt and Snyder. cNOS was assayed in the presence of calcium, whereas iNOS was assayed in the absence of calcium and in the presence of tetrahydrobiopterin. The validity of the iNOS assay was verified in rats treated with bacterial lipopolysaccharide. In these animals, the magnitude of the induction of iNOS enzymatic activity in lung, spleen, and brain paralleled the expression of iNOS mRNA, assessed by reverse-transcription polymerase chain reaction. After MCA occlusion, calcium-dependent (cNOS) activity was markedly reduced only in lesioned cerebral cortex at days 1-7 (p < 0.001; analysis of variance and Tukey's test). In contrast to cNOS, calcium-independent (iNOS) activity was induced substantially in the infarct (p < 0.005) but not in the contralateral intact cortex (p > 0.05). iNOS activity peaked at day 2 and was not different from baseline at day 7 (p > 0.05). No NADPH diaphorase-positive neurons were observed in the area of the lesion at days 1-7. Macrophages appeared at day 2 and invaded the infarcted tissue by day 7. At this time, numerous glial fibrillary acidic protein-positive astrocytes were observed within the lesion. The results suggest that the decline in calcium-dependent (cNOS) activity reflects loss of NOS neurons within the lesion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Marked induction of calcium-independent nitric oxide synthase activity after focal cerebral ischemia. 752 24

Nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) exerts inhibitory and cytotoxic effects on various cells including neuronal cells. Glial NO production, mediated via induction of iNOS, is thought to facilitate neuronal damage during cerebral ischemia. Recently, interferon regulatory factor-1 (IRF-1) has been reported to be an essential transcription factor for iNOS mRNA induction in murine macrophages. However, expression of IRF-1 and its role in the central nervous system have not been examined. In the present study, by using primary glial cell cultures from mice with targeted disruption of the IRF-1 gene, we investigated whether IRF-1 is involved in iNOS mRNA induction in glial cells. After stimulation with lipopolysaccharide and interferon-gamma, IRF-1 mRNA was strongly induced in wild-type (IRF-1 +/+) glial cells. iNOS mRNA induction and nitrite production in IRF-1 -/- glial cells were reduced as compared with those observed in IRF-1 +/+ glial cells. Diethyldithiocarbamate, a selective inhibitor of nuclear transcription factor kappa B (NF-kappa B), completely inhibited iNOS mRNA induction. These results suggest that not only NF-kappa B but also IRF-1 play important roles in iNOS mRNA induction in the central nervous system.
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PMID:Attenuation of nitric oxide synthase induction in IRF-1-deficient glial cells. 922 44

Immune mechanisms contribute to cerebral ischemic injury. Therapeutic immunosuppressive options are limited due to systemic side effects. We attempted to achieve immunosuppression in the brain through oral tolerance to myelin basic protein (MBP). Lewis rats were fed low-dose bovine MBP or ovalbumin (1 mg, five times) before 3 h of middle cerebral artery occlusion (MCAO). A third group of animals was sensitized to MBP but did not survive the post-stroke period. Infarct size at 24 and 96 h after ischemia was significantly less in tolerized animals. Tolerance to MBP was confirmed in vivo by a decrease in delayed-type hypersensitivity to MBP. Systemic immune responses, characterized in vitro by spleen cell proliferation to Con A, lipopolysaccharide, and MBP, again confirmed antigen-specific immunologic tolerance. Immunohistochemistry revealed transforming growth factor beta1 production by T cells in the brains of tolerized but not control animals. Systemic transforming growth factor beta1 levels were equivalent in both groups. Corticosterone levels 24 h after surgery were elevated in all sham-operated animals and ischemic control animals but not in ischemic tolerized animals. These results demonstrate that antigen-specific modulation of the immune response decreases infarct size after focal cerebral ischemia and that sensitization to the same antigen may actually worsen outcome.
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PMID:Immunologic tolerance to myelin basic protein decreases stroke size after transient focal cerebral ischemia. 938 Jul 27

Macrophages have been shown to produce endothelin and to play a role in the pathogenesis of neural damage after cerebral ischemia or vasospasm after subarachnoid hemorrhage. Cyclooxygenase 2 is induced during inflammation following brain insult and participates in inflammation-mediated neurotoxicity. However, it has not yet been established how endothelin-1 acts on cyclooxygenase 2 expression in macrophages. In the present study, we examined the effects of endothelin-1 on cyclooxygenase 2 expression and prostaglandin E2 production, and the effects of endothelin ET(A) and ET(B) receptor antagonists. Stimulation by endothelin-1 ranging from 10(-11) to 10(-9) M time and dose dependently increased the production of prostaglandin E2 and the expression of cyclooxygenase 2 protein without changing that of cyclooxygenase 1 protein, an effect which was inhibited by dexamethasone, nonsteroidal anti-inflammatory drugs and the selective endothelin ET(B) receptor antagonist, BQ788 (N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma-methyl-leucyl-D-L-me thoxycarbonyl-tryptophanyl-D-norleucine). The selective endothelin ET(A) receptor antagonist, BQ123 [cyclo (D-Trp-D-Asp-Pro-D-Val-Leu)] also inhibited these reactions, but its potency was less than that of the selective endothelin ET(B) receptor antagonist. Endothelin ET(A) and ET(B) receptor antagonists had no effects on cyclooxygenase 2 protein expression and prostaglandin E2 production in lipopolysaccharide-stimulated macrophages. We conclude that endothelin-1 increases cyclooxygenase 2 protein expression and prostaglandin E2 production via mainly endothelin ET(B) receptors and partly endothelin ET(A) receptors in macrophages; however, lipopolysaccharide increases both cyclooxygenase 2 protein expression and prostaglandin E2 production in pacrophages without involving endothelin ET(A) or ET(B) receptor-mediated processes.
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PMID:Cyclooxygenase 2 expression by endothelin-1-stimulated mouse resident peritoneal macrophages in vitro. 976 26

Nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit prostaglandin (PG) synthesis, augment production of tumor necrosis factor (TNF) in most experimental models. We investigated the effect of two NSAIDs, indomethacin and ibuprofen, on the production of TNF in the CNS induced by intracerebroventricular injection of lipopolysaccharide (LPS). Indomethacin and ibuprofen, administered intraperitoneally, augmented (three- to ninefold) the levels of TNF in serum and peripheral organs of mice injected intraperitoneally with LPS and in rats with adjuvant arthritis (up to a sevenfold increase). However, NSAIDs (intraperitoneally or intracerebroventricularly) did not increase brain TNF production induced by intravenous LPS. In fact, indomethacin decreased (1.4-1.8-fold) TNF levels in the spinal cord of rats with experimental autoimmune encephalomyelitis and in the cortex of rats with focal cerebral ischemia. Systemic administration of iloprost inhibited serum TNF levels after intraperitoneal LPS, whereas intracerebroventricular injection of iloprost or PGE2 did not inhibit brain TNF induced by intracerebroventricular LPS. Both peripheral and central TNF productions were inhibited by cyclic AMP level-elevating agents or dexamethasone. Thus, a PG-driven negative feedback controls TNF production in the periphery but not in the CNS.
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PMID:Nonsteroidal anti-inflammatory drugs increase tumor necrosis factor production in the periphery but not in the central nervous system in mice and rats. 979 31

The effect of nimodipine on nitric oxide synthase (NOS) activities in brains in transient focal cerebral ischemia rats, in cultured mouse neurons and astroglial cells and bovine brain capillary endothelial cells (BCECs) was investigated. The administration of nimodipine (3 mg.kg(-1), p.o., twice a day, for 3 days) before middle cerebral artery (MCA) occlusion significantly reduced infarct size, decreased nitrite/nitrate (NOx) content and inhibited Ca2+-independent NOS activity in the infarct area. Nimodipine inhibited the Ca2+-independent NOS activity induced by lipopolysaccharide (LPS) + tumor necrosis factor alpha (TNF alpha) in mouse astroglial cells with an IC50 value of 0.036+/-0.003 mM and Ca2+-dependent NOS activity in mouse neurons with an IC50 value of 0.047+/-0.003 mM, but did not affect Ca2+-dependent NOS activity in BCECs. The inhibition of Ca2+-independent NOS activity by nimodipine in astroglial cells was competitive with respect to L-arginine. Nimodipine also inhibited the induction of Ca2+-independent NOS activity in vitro. These results suggest that nimodipine in addition to its cerebral vasodilating effect may protect brain from ischemic neuronal damage through modifying NOS activity.
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PMID:Nimodipine inhibits calcium-independent nitric oxide synthase activity in transient focal cerebral ischemia rats and cultured mouse astroglial cells. 1057 30

The purposes of this study were to investigate the role of nitric oxide (NO), nitric oxide synthase (NOS), and 70 kDa heat shock protein in brain ischemic tolerance induced by ischemic preconditioning and lipopolysaccharide. Focal cerebral ischemia was induced in rats by intraluminal middle cerebral artery occlusion. Infarct volume was significantly reduced (1) in rats subjected to 3 min ischemia 72 h prior to 60 min ischemia; (2) in rats administered lipopolysaccharide (0.5 mg/kg; i.p.) 72 h prior to 60 min ischemia compared with controls. The beneficial effect of ischemic preconditioning was unchanged despite prior administration of nitro-L-arginine methyl ester (L-NAME), a NOS inhibitor. Conversely, the protective effect of lipopolysaccharide was nullified by L-NAME. Using immunohistochemical techniques, we observed that (1) ischemic preconditioning but not lipopolysaccharide induces the expression of 70 kDa heat shock protein in cerebral cortex and (2) lipopolysaccharide induces early increased expression of endothelial NOS in cerebral blood vessels. The results suggest that (1) endothelium-derived NO plays a role of a trigger in the brain tolerance induced by lipopolysaccharide, and (2) 70 kDa heat shock protein is involved in the protection afforded by ischemic preconditioning but not by lipopolysaccharide.
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PMID:Differential role of nitric oxide pathway and heat shock protein in preconditioning and lipopolysaccharide-induced brain ischemic tolerance. 1068 98

Microglia as the first line of defensive cells in the brain produce free radicals including superoxide and nitric oxide (NO), contributing to neurodegeneration. An opioid receptor antagonist, naloxone, has been considered pharmacologically beneficial to endotoxin shock, experimental cerebral ischemia, and spinal cord injury. However, the mechanisms underlying these beneficial effects of naloxone are still not clear. This study explores the effects of naloxone on the production of superoxide and NO by the murine microglial cell line, BV2, stimulated with lipopolysaccharide (LPS) as measured by electron paramagnetic resonance (EPR). The production of superoxide triggered by phobol-12-myristate-13-acetate (PMA) resulted in superoxide dismutase (SOD)-inhibitable, catalase-uninhibitable 5,5-dimethyl-1-pyrroline N-oxide (DMPO) hydroxyl radical adduct formation. LPS enhanced the production of superoxide and triggered the formation of non-heme iron-nitrosyl complex. Cells pre-treated with naloxone showed significant reduction of superoxide production by 35%. However, it could not significantly reduce the formation of non-heme iron-nitrosyl complex and nitrite. Taken together, the results expand our understanding of the neuroprotective effects of naloxone as it decreases superoxide production by microglia.
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PMID:A novel effect of an opioid receptor antagonist, naloxone, on the production of reactive oxygen species by microglia: a study by electron paramagnetic resonance spectroscopy. 1078 26

A sudden increase in extracellular potassium ions (K(+)) often occurs in cerebral ischemia and after brain trauma. This increase of extracellular K(+) constitutes the basis for spreading depression across the cerebral cortex, resulting in the expansion of neuronal death after ischemic and traumatic brain injuries. Besides spreading depression, it has become clear that cerebral inflammation also is a key factor contributing to secondary brain injury in acute neurological disorders. Experiments to validate the relationship between elevated levels of extracellular K(+) and inflammation have not been studied. This study aims to elucidate the roles of high concentrations of extracellular K(+) in bacterial endotoxin lipopolysaccharide-induced production of inflammatory factors. Increased concentration of KCl in the medium (20mM) significantly enhanced neurotoxicity by lipopolysaccharide in glia-neuron mixed cultures. To delineate the underlying mechanisms of increased neurotoxicity, the effects of high extracellular K(+) were examined by using mixed glial cultures. KCl at 20mM significantly enhanced nitrite, an index for nitric oxide, production by about twofold, and was pronounced from 24 to 48h, depending on the concentration of KCl. Besides nitric oxide production of tumor necrosis factor-alpha was also enhanced. The augmentative effects of high KCl on the production of inflammatory factors were probably due to the further activation of microglia, since high KCl also enhanced the production of tumor necrosis factor-alpha in microglia-enriched cultures. The increased production of nitrite by high K(+) was eliminated through use of a K(+)-blocker. Taken together, the results show that increases of extracellular K(+) concentrations in spreading depression augment lipopolysaccharide-elicited neurotoxicity, because production of inflammatory factors such as nitric oxide and tumor necrosis factor-alpha are potentiated. Since spreading depression and cerebral inflammation are important in acute neurological disorders, the present results suggest a biochemical mechanism: elevated extracellular K(+) concentrations augment glial inflammatory responses, and thus the neurotoxicity.
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PMID:High concentrations of extracellular potassium enhance bacterial endotoxin lipopolysaccharide-induced neurotoxicity in glia-neuron mixed cultures. 1084 21


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