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

Altered glial function that leads to oxidative stress and excitotoxicity may contribute to the initiation or progression of neuronal death in neurodegenerative diseases. We report the pivotal role of astroglial Group II and III metabotropic glutamate receptors (mGluR) against neurotoxicity. Activation of Group II or III mGluR on astrocytes with selective agonists DCG-IV or L-AP4 respectively inhibited astroglial lipopolysaccharide (LPS)-conditioned medium induced apoptosis of primary cultured mesencephalic neurons. Specific Group II or III mGluR antagonists APICA or MSOP completely abolished the neuroprotective effects of DCG-IV and L-AP4. Morphologic analysis showed that DCG-IV or L-AP4 could also attenuate the astroglial neurotoxicity to dopaminergic neurons. Measurement of extracellular glutamate concentration and [(3)H]-glutamate uptake showed that the restoration of glutamate uptake capability in LPS-treated astrocytes might be involved in the neuroprotective effects of activating astroglial Group II or III mGluR. Furthermore, we found that the repression of astroglial uptake function could be revived by GSH, and both Group II and III mGluR agonists could recover the endogenous reduced glutathione (GSH) level in LPS-treated astrocytes. These results suggested that the possible mechanisms of neuroprotection by either Type II or Type III mGluR activation may involve restoration of endogenous GSH, in turn affording recovery of astroglial capability to take up glutamate.
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PMID:Activation of Group II/III metabotropic glutamate receptors attenuates LPS-induced astroglial neurotoxicity via promoting glutamate uptake. 1675 16

Periventricular leukomalacia (PVL), the main substrate for cerebral palsy, is characterized by diffuse injury of deep cerebral white matter, accompanied in its most severe form by focal necrosis. The classic neuropathology of PVL has given rise to several hypotheses about the pathogenesis, largely relating to hypoxia-ischemia and reperfusion in the sick premature infant. These include free radical injury, cytokine toxicity (especially given the epidemiologic association of PVL with maternofetal infection), and excitotoxicity. Among the recent findings directly in human postmortem tissue is that immunocytochemical markers of lipid peroxidation (hydroxy-nonenal and malondialdehyde) and protein nitration (nitrotyrosine) are significantly increased in PVL. Premyelinating oligodendrocytes, which predominate in periventricular regions during the window of vulnerability to PVL (24 to 34 postconceptional weeks), are the targets of this free radical injury, and suffer cell death. Susceptibility can be attributed, at least in part, to a relative deficiency of superoxide dismutases in the preterm white matter, including premyelinating oligodendrocytes. Several cytokines, including interferon-gamma (known to be directly toxic to immature oligodendroglia in vitro), as well as tumor necrosis factor-alpha and interleukins 2 and 6, have been demonstrated in PVL. Microglia, which express toll-like receptors to bacterial products such as lipopolysaccharide, are increased in PVL white matter and may contribute to the injury. Preliminary work suggests a role for glutamate receptors and glutamate transporters in PVL, as has been seen in experimental animals. These findings pave the way for eventual therapeutic or preventive strategies for PVL.
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PMID:Periventricular leukomalacia: overview and recent findings. 1680 30

Reactive astrocytes display decreased glutamate transporters, such as GLT-1, and as a result synaptic glutamate clearance is impaired. In addition, these activated astrocytes are immunocompetent and release algesic mediators that can sensitize neurons in the spinal cord. Currently, we evaluated the effect of propentofylline (PPF), an experimental antiallodynic agent, on the phenotype and glutamate transporter expression of astrocytes. Primary astrocyte cultures, which represent an activated phenotype with a polygonal morphology and low GLT-1 expression, were treated for 3 or 7 days with 10, 100, or 1,000 microM PPF or dibutyryl-cAMP (db-cAMP), a known inducer of GLT-1 expression. PPF dose-dependently induced astrocytes to display a mature phenotype, with elongated processes and a stellate shape, as well as increased GLT-1 and GLAST immunoreactivity, similar to that seen with db-cAMP. Real time RT-PCR and Western blot analysis clearly demonstrated that PPF caused a potent dose-dependent induction of GLT-1 and GLAST mRNA and protein in these astrocytes. Importantly, the observed increase in glutamate transporters was found to have a functional effect, with significantly enhanced glutamate uptake in astrocytes treated with 100 or 1,000 microM PPF that was sensitive to dihydrokainate inhibition, suggesting it is GLT-1 mediated. Finally, the effect of PPF on lipopolysaccharide-induced chemokine release was investigated. Interestingly, PPF was able to dampen both MCP-1 (CCL2) and MIP-2 (CXCL2) release from astrocytes while db-cAMP significantly enhanced this chemokine expression. These findings suggest that PPF is capable of differentiating astrocytes to a homeostatic, mature phenotype, competent for glutamate clearance and distinct from that induced by db-cAMP.
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PMID:Induction of astrocyte differentiation by propentofylline increases glutamate transporter expression in vitro: heterogeneity of the quiescent phenotype. 1681 65

Evidence has accumulated to indicate that systemic administration of lipopolysaccharide (LPS), in addition to elevating tumor necrosis factor-alpha (TNF-alpha) as well as fever, induces overproduction of both glutamate and hydroxyl radicals in the rabbit's hypothalamus. Current investigation was attempted to determine whether baicalin exerts its antipyresis by suppressing overproduction of circulating TNF-alpha and hypothalamic glutamate and hydroxyl radicals in rabbits. The microdialysis probes were stereotaxically and chronically implanted into the preoptic anterior hypothalamus of rabbit brain for determination of both glutamate and hydroxyl radicals in situ. It was found that systemic administration of LPS (0.5-10 microg/kg) induced dose-related increased levels of both core temperature and hypothalamic levels of both glutamate and hydroxyl radicals accompanied by increased plasma levels of TNF-alpha. The rise in both the core temperature and hypothalamic glutamate and hydroxyl radicals could also be induced by direct injection of TNF-alpha (1-20 ng) into the lateral ventricle of rabbit brain. Pretreatment with baicalin (2-20 mg/kg, i.v.) one hour before an i.v. dose of LPS significantly reduced the LPS-induced overproduction of circulating TNF-alpha and brain glutamate and hydroxyl radicals. Both the febrile response and overproduction of both glutamate and hydroxyl radicals in the hypothalamus caused by central administration of TNF-alpha could be suppressed by baicalin. These findings suggest that systemic administration of baicalin may exert its antipyresis by inhibiting the N-methyl-D-aspartate receptor-dependent hydroxyl radicals pathways in the hypothalamus and circulating TNF-alpha accumulation during LPS-fever.
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PMID:The antipyretic effects of baicalin in lipopolysaccharide-evoked fever in rabbits. 1684 51

Kynurenic acid (KYNA) is an endogenous antagonist of alpha7 nicotinic receptors and all ionotropic glutamate receptors. Its neuroprotective activity has been suggested. In this study, the presence of KYNAin human saliva and its potential bactericidal role was investigated. KYNAwas found in all samples of human saliva with mean concentration of 3.4 nM. The concentration of KYNA in saliva obtained from patients with odontogenic abscesses was 3.5 times higher than in healthy subjects. We have shown that the human gingival fibroblasts produce KYNAand an inflammatory stimulant, lipopolysaccharide, enhanced its synthesis in vitro. The bactericidal effect of KYNA was also presented. We hypothesize that KYNA may contribute to the control of oral microflora.
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PMID:Kynurenic acid in human saliva--does it influence oral microflora? 1684 13

The physiological function of microglial glutamate uptake has been debated as it is about 10% of that measured for astrocytes. This study addresses how glutamate, taken up from the extracellular space, is utilized by microglia. It was found that purified rat microglia incubated for 60 min with (3)H-glutamate had an increased intracellular accumulation of (3)H-glutamate after 12 h incubation with tumour necrosis factor alpha (TNF-alpha) but not after incubation with lipopolysaccharide (LPS). Furthermore, LPS- but not TNF-alpha-treated cells showed an increased efflux of (3)H-labelled compounds, presumably glutamate through the X(C) (-) system and treatment with LPS or TNF-alpha increased the microglial glutathione concentrations and led to an increased incorporation of (3)H-glutamate into glutathione. Depending on the stimuli, 3-6% of the total labelled contents were found in the form of glutathione and 25-35% in the form of glutamate. These results show that microglial glutamate uptake is directly coupled to glutathione synthesis and release of glutamate and/or glutamate metabolites. Additionally, the increased glutathione contents after LPS or TNF-alpha treatment were able to reduce microglial cell death after H(2)O(2) challenge, showing a potential (self)-protective function for microglial glutamate transporter expression and glutathione synthesis.
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PMID:Microglial glutamate uptake is coupled to glutathione synthesis and glutamate release. 1692 88

Neuroinflammation is reliably associated with the pathogenesis of a number of neurodegenerative diseases, and can be detected by the presence of activated microglia. Neuroinflammation can be induced by chronic lipopolysaccharide (LPS) infusion into the 4th ventricle of the rat resulting in region-selective microglia activation and impaired hippocampal-dependent memory. Furthermore, this treatment results in altered behaviorally-induced expression of the immediate early gene Arc, indicating altered network activity. LPS is known to activate microglia directly, leading to increased glutamate release, and in enhanced N-methyl-d-aspartate (NMDA) -dependent signaling. Taken together, the foregoing suggests that decreasing NMDA receptor activation during early stages of chronic neuroinflammation should reduce a) microglia activation, b) overexpression of Arc, and c) spatial memory deficits. Memantine, a low to moderate affinity open channel uncompetitive NMDA receptor antagonist, at low doses was used here to test these hypotheses. Rats were chronically infused into the 4th ventricle for 28 days with LPS alone, vehicle alone (via osmotic minipump) or LPS and memantine (10 mg/kg/day memantine s.c.). The results reported here demonstrate that memantine reduces OX6-immunolabeling for activated microglia, spares resident microglia, returns Arc (activity-regulated cytoskeletal associated protein, protein) -expressing neuronal populations to control levels (as revealed by Arc immunolabeling and fluorescence in situ hybridization), and ameliorates the spatial memory impairments produced by LPS alone. These data indicate that memantine therapy at low doses, recreating plasma levels similar to those of therapeutic doses in human, acts in part through its ability to reduce the effects of neuroinflammation, resulting in normal gene expression patterns and spatial learning. Combined, these findings suggest that low, therapeutically relevant doses of memantine delivered early in the development of neuroinflammation-influenced diseases may confer neural and cognitive protection.
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PMID:Memantine protects against LPS-induced neuroinflammation, restores behaviorally-induced gene expression and spatial learning in the rat. 1698 56

Recent findings have suggested that the N-methyl-D-aspartate (NMDA) receptor-dependent hydroxyl radical pathway in the hypothalamus of rabbit brain may mediate the fever induced by lipopolysaccharide (LPS). The aim of this study was to investigate whether aspirin exerts its antipyresis by suppressing hypothalamic glutamate and hydroxyl radicals in rabbits. The microdialysis probes were stereotaxically and chronically implanted into the preoptic anterior hypothalamus of rabbit brain for determination of both glutamate and hydroxyl radicals in situ. It was found that intravenous (i.v.) injection of LPS, in addition to inducing fever, caused increased levels of both glutamate and hydroxyl radicals in the hypothalamus. Pretreatment with aspirin (10 - 60 mg/kg, i.v.) one hour before an i.v. dose of LPS significantly reduced the febrile response and attenuated the LPS-induced increased levels of both glutamate and hydroxyl radicals in the hypothalamus. The increased levels of prostaglandin E(2) (PGE(2)) in the hypothalamus induced by LPS could be suppressed by aspirin pretreatment. The data indicate that systemic administration of aspirin, in addition to suppressing PGE(2) production, may exert its antipyresis by inhibiting the NMDA receptor-dependent hydroxyl radical pathways in the hypothalamus during LPS fever.
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PMID:Aspirin may exert its antipyresis by inhibiting the N-methyl-D-aspartate receptor-dependent hydroxyl radical pathways in the hypothalamus. 1734 44

When activated by proinflammatory stimuli, microglia release substantial levels of glutamate, and mounting evidence suggests this contributes to neuronal damage during neuroinflammation. Prior studies indicated a role for the Xc exchange system, an amino acid transporter that antiports glutamate for cystine. Because cystine is used for synthesis of glutathione (GSH) synthesis, we hypothesized that glutamate release is an indirect consequence of GSH depletion by the respiratory burst, which produces superoxide from NADPH oxidase. Microglial glutamate release triggered by lipopolysaccharide was blocked by diphenylene iodonium chloride and apocynin, inhibitors of NADPH oxidase. This glutamate release was also blocked by vitamin E and elicited by lipid peroxidation products 4-hydroxynonenal and acrolein, suggesting that lipid peroxidation makes crucial demands on GSH. Although NADPH oxidase inhibitors also suppressed nitrite accumulation, vitamin E did not; moreover, glutamate release was largely unaffected by nitric oxide donors, inhibitors of nitric oxide synthase, or changes in gene expression. These findings indicate that a considerable degree of the neurodegenerative consequences of neuroinflammation may result from conversion of oxidative stress to excitotoxic stress. This phenomenon entails a biochemical chain of events initiated by a programmed oxidative stress and resultant mass-action amino acid transport. Indeed, some of the neuroprotective effects of antioxidants may be due to interference with these events rather than direct protection against neuronal oxidation.
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PMID:Glutamate release from activated microglia requires the oxidative burst and lipid peroxidation. 1740 30

The purpose of the current study was to explore the effects of N-methyl-D-aspartate (NMDA)-receptor antagonists (MK-801 and LY235959) administered intracerebroventricularly on the changes of both core temperature and hypothalamic levels of 2,3-dihydroxybenzoic acid (2,3-DHBA) induced by intracerebroventricular injection of glutamate (100 - 400 microg at 10 microl/rabbit) or intravenous administration of lipopolysaccharide (LPS) (2 microg/kg) in rabbits. The measurements of 2,3-DHBA were used as an index of the intrahypothalamic levels of hydroxyl radicals. The rise in both the core temperature and hypothalamic 2,3-DHBA could be induced by intracerebroventricular injection of glutamate or intravenous administration of LPS. The glutamate- or LPS-induced fever and increased hypothalamic levels of 2,3-DHBA were significantly antagonized by pretreatment with injection of MK-801 or LY235959 1 h before glutamate or LPS injection. The increased levels of prostaglandin E2 in the hypothalamus induced by glutamate or LPS could be suppressed by MK-801 or LY235959. The data demonstrate that prior antagonism of NMDA receptors in the brain, in addition to reducing prostaglandin E2 production in the hypothalamus, suppresses both the glutamate- and LPS-induced fever and increased hypothalamic hydroxyl radicals.
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PMID:Lipopolysaccharide- and glutamate-induced hypothalamic hydroxyl radical elevation and fever can be suppressed by N-methyl-D-aspartate-receptor antagonists. 1753 30


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