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)

Astrogliosis and microglial activation are associated with many neurodegenerative disorders including multiple sclerosis, its animal model experimental allergic encephalomyelitis, and Alzheimer's disease. To address the hypothesis that chronic astroglial or microglial activation could be contributing factors to neuronal death or injury, the immunostimulant lipopolysaccharide was infused into the hippocampus for 16 days using Alzet mini-osmotic pumps attached to a cannula. Placement of the cannula and infusion of vehicle for 16 days caused a hippocampal lesion with a volume of 0.5 +/- 0.1 mm3. Infusion of lipopolysaccharide at the dose of 2.0 micrograms/day produced a lesion of 4.9 +/- 1.3 mm3 (P < 0.01, Newman-Keuls), whereas, a lower dose of 0.2 microgram/day caused a lesion of 1.3 +/- 0.3 mm3 (P < 0.05). The lesion was defined as a focal necrotic reaction with fibrin deposits outlining an area at an early stage of encapsulation. No apparent neuronal loss was observed by Cresyl Violet staining outside the encapsulated necrotic area. There was a pronounced astrogliosis and an increase in activated macrophages throughout the lipopolysaccharide-infused hippocampus as determined by glial fibrillary acidic protein and ED-1 immunohistochemistry, respectively. Choline acetyltransferase and glutamic acid decarboxylase enzyme activities, used as functional measures of neuronal viability for cholinergic and GABAergic neurons, respectively, were unaffected in the hippocampus following a 16 day infusion of lipopolysaccharide at the doses of 0.2, 0.6 and 2.0 micrograms/day. In addition, unilateral infusion of lipopolysaccharide into the hippocampus did not affect 24 h locomotion when tested on day 13, body temperature or weight gain. Under the experimental conditions employed in the present study, chronic infusion of lipopolysaccharide into the hippocampus resulted in a dose-dependent focal necrotic lesion at the site of infusion. In tissue surrounding the encapsulated lesion, neurons were present among the reactive astrocytes and increased number of macrophages suggesting that astrocytes and macrophages can be activated without causing neuronal loss.
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PMID:Effects of chronic intrahippocampal infusion of lipopolysaccharide in the rat. 884 36

In neurodegenerative disease or after brain injury, parenchymal cells in the central nervous system are activated to produce inflammatory mediators, mainly consisting of cytokine-induced factors, in a manner similar to, but clearly different from a peripheral inflammatory response. The upregulated expression of several extracellular matrix proteins in astrocytes located surrounding a neuritic plaque in Alzheimer's disease is a good example of such a response. A family of mediators which is cytokine-induced during an inflammatory response in the periphery are the matrix metalloproteinases. Matrix metalloproteinases are calcium-requiring, zinc-containing endopeptidases that constitute a major component of the enzyme cascade responsible for degradation of extracellular matrix proteins such as collagen, proteoglycan and laminin. Little is known about the cellular source or the function of matrix metalloproteinases in the central nervous system or how their expression is regulated in brain. Thus, it was of interest to determine which factors of the so-called 'brain inflammatory response' regulate the expression of these proteases in the nervous system. To this end, we measured the expression of matrix metalloproteinases in cultured rat astrocytes and microglia after treatment with various cytokines. Interleukin-1 beta, tumor necrosis factor-alpha and lipopolysaccharide were potent stimulators of matrix metalloproteinase-2 (gelatinase A) and matrix metalloproteinase-9 (gelatinase B) in cultured rat astrocytes; the effect of each secretagogue was inhibited in the presence of glucocorticoid. Interleukin-1 beta and lipopolysaccharide also stimulated the production of matrix metalloproteinase-3 (stromelysin-1) in astrocytes. In addition, activated microglia release matrix metalloproteinase-9. The 'coactivator' of monocytic phagocytes, interferon-gamma, rather than augmenting the response to lipopolysaccharide, inhibited it. Thus, cytokines appear to be potent regulators of matrix metalloproteinase production in astrocytes and microglia. The presence of these enzymes in 'inflamed' central nervous system may suggest their involvement in the pathogenesis or progression of neurodegenerative diseases which are associated with an inflammatory component. Much remains to be learned about the potential substrates for these enzymes and the mechanism of their activation in the central nervous system.
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PMID:Regulation of matrix metalloproteinase expressions in astrocytes, microglia and neurons. 894 20

Immunological mechanisms, including stimulation of brain microglia and elevation of various inflammatory cytokines, have been implicated in the pathogenesis of Alzheimer's disease, where accumulation of beta-amyloid peptide (A beta) is one of its main pathological features. In this study we investigated the interaction of human monocyte-like cells with synthetic beta-amyloid peptide A beta (1-40) and its subfragment A beta (25-35). THP-1 cells (a transformed human monocyte cell line) were used with or without prior differentiation by phorbol myristate acetate (PMA), and cell activation was assessed by the secretion of tumor necrosis factor-alpha (TNF-alpha). First, it was shown that THP-1 cells could be induced to secrete significant amounts of TNF-alpha by interleukin-1, lipopolysaccharide, interferon-gamma (IFN-gamma) and PMA alone or in combination with each other. Next it was shown that A beta (1-40) could also induce secretion of TNF-alpha by THP-1 cells, but the effect was diminished when this peptide was applied in combination with IFN-gamma. The A beta subfragment A beta (25-35) was ineffective in inducing TNF-alpha production. The cellular action of A beta (1-40) appears to involve protein kinase C since pretreatment of THP-1 cells by PMA or the protein kinase C inhibitor H-7 diminished the cellular response to A beta (1-40). Identification of the pathway by which extracellular A beta activates the intracellular PKC-dependent secretion of TNF-alpha may help in developing new therapeutic strategies for Alzheimer's disease.
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PMID:Interaction of Alzheimer beta-amyloid peptide with the human monocytic cell line THP-1 results in a protein kinase C-dependent secretion of tumor necrosis factor-alpha. 904 34

The proinflammatory cytokine, interleukin-1 (IL-1) is elevated in the Alzheimer's disease (AD) brain. Studies from our laboratory have demonstrated that beta-amyloid (A beta) 1-42, fibrillar A beta 1-40 and A beta 25-35 induce the release of IL-1 beta from activated THP-1 cells, a human monocyte cell line. A beta also is chemotactic for primary rodent microglia and peritoneal macrophages. We hypothesize that A beta is a chemokine and induces these responses by interaction with chemotactic receptors. If this is true, then these A beta-induced responses should be calcium-dependent and require activation of pertussis toxin-sensitive G-proteins. To test this hypothesis, THP-1 cells were grown in culture with lipopolysaccharide (LPS) and incubated with A beta 1-42 (5 muM) in the presence and absence of a calcium chelator, an inhibitor of intracellular calcium mobilization, a calcium channel blocker, or pertussis toxin, a bacterial endotoxin which uncouples G proteins from receptors by catalyzing the ADP ribosylation of cysteine near the carboxy-terminus of the alpha subunit. The media was collected and IL-1 beta present in the media was measured using an ELISA. Treatment of LPS-activated THP-1 cells with A beta 1-42 significantly elevated IL-1 beta released into the media as previously shown. Addition or ethylene glycol-bis (beta-aminothyl ether) N,N,N'N'-tetraacetic acid (EGTA) (0.5 mM), a calcium chelator, to the media blocked A beta-induced IL-1 beta release, but had no effect on LPS-activated THP-1 cell release of IL-1 beta. The presence of 3,4,5-trimethoxybenzoic acid 8-(diethyl amino)-octyl ester (TMB-8), an inhibitor of intracellular calcium mobilization, as well as nickel chloride, a non-specific calcium channel blocker, in the media also inhibited A beta-induced IL-1 release from LPS-activated THP-1 cells. IL- 1 beta release from activated THP-1 monocytes incubated with TMB-8 and nickel chloride without A beta remained at baseline values. Pretreatment of THP-1 monocytes with pertussis toxin for 4 h, followed by LPS activation and incubation with A beta, antagonized the release of IL-1 beta from these cells, but did not alter IL-1 beta release from activated THP-1 monocytes. These data suggest that A beta-induced IL-1 beta release from these cells is calcium-dependent and requires the activation of specific G-proteins. These findings are consistent with known second messengers that are activated following stimulation of chemotactic receptors.
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PMID:beta-Amyloid-induced IL-1 beta release from an activated human monocyte cell line is calcium- and G-protein-dependent. 914 72

Alzheimer's disease is characterized by the development of a degenerative condition in the elderly, associated with dementia. Upon pathological examination, cerebral amyloid plaques are found which contain denatured protein or peptide material. The process of denaturation of protein requires the presence of excessive heat, organic solvents, or oxidizing acids (OA). It seems that only OA could produce these effects since the other two are not present in the disease. Macrophages can produce the anion of an oxidizing acid known as peroxynitrite (OONO). This material is formed from two free radical gases, namely superoxide anion [.O2]- and nitric oxide (.N = O). Although (OONO)- is very reactive (1000 times more oxidizing than hydrogen peroxide), its half life in solution is only 1 to 2 seconds. Therefore, when it oxidizes a substance (such as protein) peroxynitrite disappears. The brain contains cells called microglia which are produced from monocytes in the same way as other types of macrophages from the lung and liver etc. The macrophages from the lung (alveolar) and liver (Kupfer cells) produce large amounts of peroxynitrite when activated by particles (silica) or infectious agents (lipopolysaccharide or interferon). Microglia produce highly oxidizing substances as well, but no one has ever measured production of peroxynitrite from these cells. Assuming that microglia produce peroxynitrite, or other similar oxidants, anti-oxidant and anti-inflammatory drugs should be helpful in treatment of early forms of the disease. In addition, large doses of anti-oxidant vitamin C and vitamin E might be helpful to people with Alzheimer's disease.
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PMID:The possible role of peroxynitrite in Alzheimer's disease: a simple hypothesis that could be tested more thoroughly. 918 21

The effects of indometacin (CAS 53-86-1) on lipopolysaccharide-induced impairment of active avoidance and on interleukin-6-induced increase of prostaglandin E2 release were investigated in rats. In the experiment on acquisition and retention of one-way active avoidance in a shuttle box model, bilateral infusion of lipopolysaccharides (LPS) into the hippocampus, 1 microgram per side, resulted in a significant impairment both in acquisition and retention by prolonging the latency of avoidance in training and testing. In the meantime, intraperitoneal injection of indometacin 10 mg/kg daily for 7 days, improved the LPS-induced amnesia especially in the testing by shortening the latency from 2.3 to 1.7 s (p < 0.05). In the in vivo microdialysis study in anesthetized rats, intrahippocampal infusion of 80 ng interleukin-6 (IL-6) markedly increased prostaglandin E2 (PGE2) release into hippocampal dialysates which started at 2 h post administration. Perfusion of indometacin (0.3 mol/l) into the hippocampus for 1 h obviously suppressed the IL-6-induced PGE2 response. These findings provide experimental evidence that--assuming that central inflammation may be involved with Alzheimer's disease a non-steroidal anti-inflammatory drug may be used in the treatment of Alzheimer's disease.
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PMID:Suppression of lipopolysaccharide-induced impairment of active avoidance and interleukin-6-induced increase of prostaglandin E2 release in rats by indometacin. 920 71

Cells of the monocyte phagocytic system can generate superoxide and glutamate anions, both of which are neurotoxic at high levels. We used rat peritoneal macrophages as a model system to test the effects of various stimulants on the production of these molecules. Glutamate production by such cells was enhanced, in a concentration-dependent manner, by treatment with serum-opsonized zymosan (OZ), lipopolysaccharide (LPS), phorbol myristate acetate (PMA), and beta-amyloid peptide Abeta (1-40); but not by treatment with the reverse Abeta (40-1) or the Abeta (25-35) subfragment. Superoxide anion production by the cells was stimulated by OZ, PMA, Abeta (1-40), and Abeta (25-35). Moreover, Abeta and its subfragment, when used as priming agents, also enhanced the stimulatory effect of PMA. However, they did not act as priming agents for OZ, suggesting a competition for receptors or intracellular signaling pathways linked to those receptors. Inflammatory mediators, including Abeta, could place glutamate-sensitive neurons at risk by enhancing glutamate and oxygen free radical production by monocyte-derived cells. Such mechanisms could contribute to the pathogenesis of neurodegenerative disorders, including Alzheimer's disease.
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PMID:beta-amyloid protein enhances macrophage production of oxygen free radicals and glutamate. 927 45

Melatonin's actions in organisms are more widespread than originally envisaged. Over three decades ago, the changing pattern of nocturnal melatonin production was found to be the signal for the annual cycle of reproduction in photoperiodic species. Since then, melatonin's actions also have been linked to circadian rhythms, immune function, sleep, retinal physiology and endocrine functions in general. In recent years, however, the sphere of influence of melatonin was further expanded when the indole was found to be an effective free radical scavenger and antioxidant. Free radicals are toxic molecules, many being derived from oxygen, which are persistently produced and incessantly attack and damage molecules within cells; most frequently this damage is measured as peroxidized lipid products, carbonyl proteins, and DNA breakage or fragmentation. Collectively, the process of free radical damage to molecules is referred to as oxidative stress. Melatonin reduces oxidative stress by several means. Thus, the indole is an effective scavenger of both the highly toxic hydroxyl radical, produced by the 3 electron reduction of oxygen, and the peroxyl radical, which is generated during the oxidation of unsaturated lipids and which is sufficiently toxic to propagate lipid peroxidation. Additionally, melatonin may stimulate some important antioxidative enzymes, i.e., superoxide dismutase, glutathione peroxidase and glutathione reductase. In in vivo tests, melatonin in pharmacological doses has been found effective in reducing macromolecular damage that is a consequence of a variety of toxic agents, xenobiotics and experimental paradigms which induce free radical generation. In these studies, melatonin was found to significantly inhibit oxidative damage that is a consequence of paraquat toxicity, potassium cyanide administration, lipopolysaccharide treatment, kainic acid injection, carcinogen administration, carbon tetrachloride poisoning, etc., as well as reducing the oxidation of macromolecules that occurs during strenuous exercise or ischemia-reperfusion. In experimental models which are used to study neurodegenerative changes associated with Alzheimer's and Parkinson disease, melatonin was found to be effective in reducing neuronal damage. Its lack of toxicity and the ease with which melatonin crosses morphophysiological barriers and enters subcellular compartments are essential features of this antioxidant. Thus far, most frequently pharmacological levels of melatonin have been used to combat oxygen toxicity. The role of physiological levels of melatonin, which are known to decrease with age, is being investigated as to their importance in the total antioxidative defense capacity of the organism.
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PMID:Melatonin in relation to cellular antioxidative defense mechanisms. 928 72

Glutamate, an excitatory neurotransmitter, is neurotoxic at high concentrations. Neuroglial cells, including astrocytes and microglia, play an important role in regulating its extracellular levels. Cultured human monocytic THP-1 cells increased their glutamate secretion following 18 and 68 h exposure to the inflammatory mediators zymosan, phorbol myristate acetate (PMA), lipopolysaccharide, interferon-gamma, tumor-necrosis factor-alpha and interleukin-1beta. Cultured astrocytoma U-373 MG cells increased their glutamate secretion following similar exposure to zymosan and PMA. DL-Alpha-aminopimelic acid, an inhibitor of the glutamate secretion system, reduced extracellular glutamate in both cell culture systems, while the high-affinity glutamate uptake inhibitors D-Aspartic acid, DL-threo-beta-hydroxyaspartic acid and L-trans-pyrrolidine-2,4-dicarboxylic acid increased extracellular glutamate in U-373 MG, but not THP-1 cell cultures. In co-cultures of THP-1 and U-373 MG cells, extracellular glutamate levels were increased significantly by the Alzheimer beta-amyloid peptide (1-40) and were decreased significantly by the anti-inflammatory drug dexamethasone. These data indicate that inflammatory stimuli may increase extracellular glutamate while antiinflammatory drugs decrease it.
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PMID:Regulation of glutamate in cultures of human monocytic THP-1 and astrocytoma U-373 MG cells. 930 40

The effect of a peptide homologous to the biologically active fragment of beta amyloid 25-35 (beta 25-35) was studied on interleukin 6 (IL-6) and tumour necrosis factor (TNF-alpha) secretion induced by lipopolysaccharide (LPS) in primary rat astrocytes and microglia. Twenty-four hour exposure to LPS (50 ng/ml) induced IL-6 and TNF-alpha both in astrocytes and in microglial cells, while the effect of beta 25-35 (50 microM) per se was negligible in both cell types. In microglial cells, the application of beta peptide did not alter the production of either cytokine induced by LPS. However, beta 25-35 strongly amplified the production of both IL-6 and TNF-alpha in astrocytes. These findings confirm the complex interaction between cytokines and amyloidogenesis in Alzheimer's disease and indicate that astrocytes rather than microglia respond to the beta amyloid fragment, suggesting that these cells may be actively involved in cytokine-mediated events in AD.
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PMID:Beta-amyloid fragment potentiates IL-6 and TNF-alpha secretion by LPS in astrocytes but not in microglia. 934 8


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