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)

The ganglioside GM1 is known to play a pivotal role in neuronal survival and/or regeneration. Recently it has been shown that GM1 binds tightly with membrane-bound amyloid beta protein (A beta) and prevents its conversion from a helical to a beta-sheet structure. To examine the potential physiological consequences of this binding, we studied the effect of GM1 on A beta-stimulated release of proinflammatory cytokines, such as interleukin (IL)-1beta, IL-6 and TNF-alpha, using the human monocytic cell line, THP-1, as a model system. Treatment of THP-1 cells with A beta 1-40 or A beta 25-35 resulted in an increased cytokine release from these cells. However, treatment of A beta-activated THP-1 cells with GM1 and several other complex gangliosides, but not hematosides and neutral glycosphingolipids such as asialo-GM1 (GA1), lactosylceramide, and globoside, significantly decreased the cytokine release. In contrast, this effect was not observed for lipopolysaccharide (LPS)-activated and thrombin-activated THP-1 cells, indicating that the ganglioside effect is specific for A beta-induced cytokine release. A direct interaction between GM1 and A beta was demonstrated using the surface plasmon resonance technique. We found that GM1 ganglioside exhibited higher affinity for A beta 1-40 than GA1, suggesting that the sialic acid moiety of GM1 is necessary for its interaction with A beta. We conclude that the inhibitory effect of GM1 on A beta-induced cytokine release may reflect pre-existing abnormalities in membrane transport at the stage of amyloid formation and that GM1 may induce conformational changes in A beta, resulting in diminished fibrillogenesis and prevention of the inflammatory response of neuronal cells in Alzheimer's disease.
 ...
PMID:GM1 inhibits amyloid beta-protein-induced cytokine release. 997 68

Inflammatory processes may play a critical role in the degeneration of basal forebrain cholinergic cells that underlies some of the cognitive impairments associated with Alzheimer's disease. In the present study, the proinflammagen lipopolysaccharide, from the cell wall of Gram-negative bacteria, was used to produce inflammation within the basal forebrain of rats. The effects of acute, high-dose injections of lipopolysaccharide (2, 20 or 40 microg) upon basal forebrain chemistry and neuronal integrity were compared with the effects of chronic, low-dose lipopolysaccharide infusions (0.18, 0.25, 1.8 or 5.0 microg/h) for either 14, 37, 74 or 112 days. Acute exposure to lipopolysaccharide decreased cortical choline acetyltransferase activity and the number of immunoreactive choline acetyltransferase-positive cells within a small region of the basal forebrain. Regional levels of five different neuropeptides were unchanged by acute, high-dose lipopolysaccharide injections. Chronic lipopolysaccharide infusions produced (i) a time-dependent, but not dose-dependent, decrease in cortical choline acetyltransferase activity that paralleled a decline in the number of choline acetyltransferase- and p75-immunoreactive cells within the basal forebrain, and (ii) a dense distribution of reactive astrocytes and microglia within the basal forebrain. Chronic neuroinflammation might underlie the genesis of some neuropathological changes associated with normal ageing or Alzheimer's disease.
 ...
PMID:Pathological and biochemical consequences of acute and chronic neuroinflammation within the basal forebrain cholinergic system of rats. 1005 Dec

Interest in the basal forebrain cholinergic system has greatly increased since neuropathological studies in humans provided evidence that this system is severely affected in Alzheimer's disease and other dementing disorders. In laboratory animals, disruption of the nucleus basalis cholinergic neurones has been produced by several neurotoxic insults in order to obtain a model reproducing the behavioural impairment related to the cholinergic deficits. The experiments reported in this review demonstrate that excitotoxic amino acids, beta-amyloid and lipopolysaccharide, injected directly in the nucleus basalis are toxic to the cholinergic neurones in the rat. The excitotoxin lesions of the nucleus basalis, although not selective, are a useful tool for producing experimental animals with cholinergic hypofunction and for investigating drugs able to ameliorate the cholinergic functions. Local injections of amyloid peptides in the rat nucleus basalis produced cholinergic hypofunction and some behavioural impairment. Finally, an intense glia reaction with a limited cholinergic hypofunction and no behavioural impairment was induced by a 4-week infusion of lipopolysaccharide in the nucleus basalis. In conclusion, all three models, in spite of their limitations, offer useful tools for the study of the pathogenetic mechanisms of Alzheimer's disease and for investigating potentially useful drugs.
 ...
PMID:Morphological, biochemical and behavioural changes induced by neurotoxic and inflammatory insults to the nucleus basalis. 1019 18

Interleukins (IL)-1 alpha, beta and IL-6 may play essential roles in early inflammatory processes in response to degenerating cholinergic cells observed in the basal forebrain of Alzheimer patients. To address this question in vivo, two distinct lesion paradigms were used. A specific and selective basal forebrain cholinergic cell loss was achieved by a single intracerebroventricular application of the cholinergic immunotoxin, 192IgG-saporin. Intrahippocampal injection of lipopolysaccharide and interferon-gamma was used to produce an exogenously-induced acute inflammation in the brain. In order to disclose the lesion-induced temporal cascade of the expression pattern of IL-1 alpha, IL-1 beta, and IL-6, and the cell types expressing IL-1 alpha, beta/IL-6 mRNA, Western analysis, RT-PCR, and double labeling immunocytochemistry were applied. In the intact brain, IL-6, IL-1 alpha and IL-1 beta demonstrated a constitutive expression in neurons. Following cholinergic lesion neither IL-1 beta nor IL-6 expression could be detected in any of the activated glial cell types, whereas IL-1 alpha was found to be expressed in astroglial cells only. In contrast, hippocampal administration of lipopolysaccharides/interferon-gamma resulted in expression of IL-1 alpha in microglial but not astroglial cells. These in vivo studies clearly demonstrate that the cellular expression of IL-1 alpha, IL-1 beta, and IL-6 in the brain is differentially regulated depending on the kind of injury producing the inflammatory response in the brain. The data suggest that each glial cell seems to be equally capable of expressing a number of various cytokines, but it depends on the kind of stimulus which temporal and cellular cascade of cytokine expression pattern is initiated under a particular pathological condition in the brain.
 ...
PMID:Differential injury-dependent glial expression of interleukins-1 alpha, beta, and interleukin-6 in rat brain. 1040 34

There is mounting evidence that inflammatory processes, including activation of microglia, are upregulated in Alzheimer's disease. The importance of this phenomenon is indicated by multiple epidemiological studies showing that patients taking non-steroidal anti-inflammatory drugs (NSAIDs) have a substantially reduced prevalence of Alzheimer's disease. The pharmacological actions of anti-inflammatory drugs in brain are still uncertain. As a step towards identifying key pharmacological targets, we developed a neurotoxicity assay based on the property of supernatant media from stimulated human monocytic THP-1 cells to cause human neuroblastoma cell death. Similar neurotoxicity was observed when postmortem human microglia were substituted for THP-1 cells, establishing the validity of the assay for simulating neurotoxicity in human brain. A combination of lipopolysaccharide and interferon-gamma was used to activate the THP-1 cells. NSAIDs were effective in inhibiting neurotoxicity by this assay, while steroidal anti-inflammatories and propentofylline had no effect. The neuroprotective potency of NSAIDs appeared to be unrelated to their selective ability to inhibit cyclooxygenase-1 (COX-1) or cyclooxygenase-2 (COX-2). It is suggested that inhibition of monocyte cytotoxicity might be responsible for the apparent beneficial effects of NSAIDs in Alzheimer's disease.
 ...
PMID:Toxicity of human THP-1 monocytic cells towards neuron-like cells is reduced by non-steroidal anti-inflammatory drugs (NSAIDs). 1042 20

Tepoxalin is a structurally and functionally novel non-steroidal anti-inflammatory drug (NSAID) with potent anti-inflammatory and analgesic properties. Apart from its inhibitory effect on cyclooxygenase activity, tepoxalin is able to inhibit production of cytokines in peripheral cells outside the CNS. No data, however, are available concerning the effects of this drug in the CNS. Since cytokines such as interleukin-1 (IL-1) or interleukin-6 (IL-6) as well as acute-phase proteins such as alpha1-anti-chymotrypsin (ACT) participate in the etiopathology of Alzheimer's disease (AD), we were interested whether tepoxalin is able to inhibit the synthesis of these immunomodulators in primary rat microglia and astrocytes as well as in the human astrocytoma cell line U373 MG. We found that tepoxalin markedly inhibits IL-1beta-induced IL-6 and ACT synthesis in astrocytes and the synthesis of IL-1beta and IL-6 in lipopolysaccharide (LPS)-stimulated microglial cells. Electrophoretic mobility shift and reporter gene assays revealed that tepoxalin exerts its inhibitory effect through the inhibition of nuclear factor kappaB (NF-kappaB), a transcription factor involved in the induction of IL-1, IL-6 and ACT gene expression. We show that inhibition of NF-kappaB activation by tepoxalin is mediated by preventing IkappaB-alpha degradation. Based on this inhibitory effect of tepoxalin on cytokine and ACT synthesis and the documented therapeutic efficacy of NSAIDs in AD, we conclude that tepoxalin may be of therapeutic benefit for the treatment of AD patients and should therefore be tested in clinical trials.
 ...
PMID:The non-steroidal anti-inflammatory drug tepoxalin inhibits interleukin-6 and alpha1-anti-chymotrypsin synthesis in astrocytes by preventing degradation of IkappaB-alpha. 1047 Oct 86

We report that mRNA levels for alpha(1)-antichymotrypsin (ACT), a component of beta-amyloid plaques in Alzheimer's disease, are significantly increased in the brains of two different mouse models that develop inflammation: (1) acute inflammation caused by intraperitoneal injection with lipopolysaccharide (LPS) and (2) chronic inflammation in knockout mice lacking the anti-inflammatory cytokine transforming growth factor beta1 (TGF-beta1). While brain mRNA levels for the inflammatory cytokines TNFalpha, IL-1beta, and IL-6 were all elevated in the LPS-injected mice, only the mRNA for IL-1beta increased significantly in TGF-beta1-deficient mice. The transcription factor C/EBPbeta was strongly activated in the brains of both models. These results support the hypothesis that, through induction of the ACT gene in the brain, inflammation plays an important role during the development of Alzheimer's disease and that IL-1beta and C/EBPbeta may be involved in this process.
 ...
PMID:Induction of the alpha(1)-antichymotrypsin gene in the brain associated with TGF-beta1 deficiency or systemic administration of endotoxin. 1049 Dec 83

We studied the expression of the mannose receptor (ManR) in rat microglial cells. Microglial cells are the central nervous system resident macrophages, key participants of the innate immune response. ManR is a differentiation marker and a relevant glycoprotein for the phagocytic and endocytic function of macrophages. Because there is evidence suggesting that ManR could mediate some of the nonenzymatic effects of acetilcholinesterase (AchE) and the enzyme seems to be involved in Alzheimer's disease (AD), we looked for ManR in microglia, evaluating the functionality of the receptor. We isolated microglial cells from the brain of 2-day-old neonatal rats. Microglial cells, identified by their specific staining with the lectin Griffonia simplicifolia, expressed ManR, being detected by immunocytochemistry, Western blot, and immunoprecipitation. Microglial ManR was downregulated by lipopolysaccharide (LPS) and upregulated by dexamethasone, as described for peripheral macrophages. Microglial ManR was functional and able to internalize horseradish peroxidase (HRP), a known ManR ligand, in a mannan-inhibitable manner. The presence of a functional ManR in microglia opens the possibility that ManR could participate in multiple physiologic and pathologic conditions in the central nervous system (CNS), including inflammation, ischaemia, and neurodegenerative diseases such as AD.
 ...
PMID:Mannose receptor is present in a functional state in rat microglial cells. 1051 12

A non-nuclear isoform of histone H1 is constitutively expressed in neurones. This protein is the major lipopolysaccharide (LPS)-binding protein in the brain. Since the major systemic LPS-binding protein is released in the liver and is an acute phase reactant, we were interested to learn whether this novel CNS histone showed altered expression following neuronal injury. We have therefore examined the changes in the expression of this molecule in acute neuronal injury and in two neurodegenerative pathologies, murine scrapie and Alzheimer's disease. No upregulation or change in H1 staining was observed in acute neurodegeneration induced by the intrastriatal injection of the glutamate antagonist N-methyl d-aspartic acid. In contrast, Western blotting indicated that histone H1 is upregulated in the brains of mice with clinical signs of scrapie. Immunohistochemistry revealed that in the regions of pathology there was increased staining for histone H1 in the neurones and the surrounding neuropil. Cells with an astrocytic appearance were also seen to stain positively for H1 but only in the regions of pathology. Immunofluorescent double staining for glial fibrillary acid protein (GFAP) and histone H1 confirmed that these cells were indeed astrocytes. Alzheimer's disease brain also showed an increase in the neuronal and astrocytic staining but only in regions of pathology. The function of histone in the CNS is unknown but the data presented here demonstrate an upregulation in areas of neuronal degeneration, which indicates that it may be involved in disease pathogenesis.
 ...
PMID:Non-nuclear histone H1 is upregulated in neurones and astrocytes in prion and Alzheimer's diseases but not in acute neurodegeneration. 1056 33

Chronic inflammation may play an important role in the pathogenesis of Alzheimer's disease (AD). The present study compared the effects of chronic neuroinflammation, produced by infusion of lipopolysaccharide (LPS) into the fourth ventricle, upon memory in young, adult, and old rats. Nonsteroidal anti-inflammatory drug (NSAID) therapy may delay the onset of AD. We show that NO-Flurbiprofen (NFP), a novel NSAID that lacks gastrointestinal side effects, attenuated the neuroinflammatory reaction and reduced the inflammation-induced memory deficit. Chronic LPS infusions impaired performance of young rats but not adult or old rats. Treatment with NFP improved the performance of LPS-infused young rats, but not LPS-infused adult or old rats. LPS infusions increased the number of activated microglia in young and adult rats but not old rats. NFP treatment attenuated the effects of LPS upon microglia activation in young and adult rats, but not old rats. The results suggest that NSAID therapies designed to influence the onset of AD should be initiated in adults before age-associated inflammatory processes within the brain have a chance to develop.
 ...
PMID:The effects of a novel NSAID on chronic neuroinflammation are age dependent. 1058 78


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>