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 release of proinflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha) and nitric oxide by microglia has been implicated in neurotoxicity in chronic neurodegenerative diseases such as Alzheimer's disease. As all-trans-retinoic acid (RA) has been reported to exert anti-inflammatory actions in various cell types, we have examined its effects on the expression of TNF-alpha and inducible nitric oxide synthase (iNOS) in microglia activated by beta-amyloid peptide (Abeta) and lipopolysaccharide (LPS). Exposure of primary cultures of rat microglial cells to Abeta or LPS stimulated the mRNA expression level of TNF-alpha (6-116-fold) and iNOS (8-500-fold) significantly. RA acted in a dose-dependent manner (0.1-10 microM) by attenuating both TNF-alpha (29-97%) and iNOS (61-96%) mRNA expression in microglia exposed to Abeta or LPS. RA-induced inhibition of TNF-alpha and iNOS mRNA expression in activated microglia was accompanied by the concomitant reduction in release of iNOS and TNF-alpha proteins as revealed by nitrite assay and ELISA, respectively. The anti-inflammatory effects of RA were correlated with the enhanced expression of retinoic acid receptor-beta, and transforming growth factor-beta1 as well as the inhibition of NF-kappaB translocation. These results suggest that RA may inhibit the neurotoxic effect of activated microglia by suppressing the production of inflammatory cytokines and cytotoxic molecules.
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PMID:Retinoic acid inhibits expression of TNF-alpha and iNOS in activated rat microglia. 1560 48

In most neurodegenerative disorders, including multiple sclerosis, Parkinson disease, and Alzheimer disease, a massive neuronal cell death occurs as a consequence of an uncontrolled inflammatory response, where activated astrocytes and microglia and their cytotoxic agents play a crucial pathological role. Current treatments for these diseases are not effective. In the present study we investigate the effect of thiadiazolidinone derivatives, which have been recently suggested to play a role in neurodegenerative disorders. We have found that thiadiazolidinones are potent neuroprotector compounds. Thiadiazolidinones inhibited inflammatory activation of cultured brain astrocytes and microglia by diminishing lipopolysaccharide-induced interleukin 6, tumor necrosis factor alpha, inducible nitric-oxide synthase, and inducible cyclooxygenase type 2 expression. In addition, thiadiazolidinones inhibited tumor necrosis factor-alpha and nitric oxide production and, concomitantly, protected cortical neurons from cell death induced by the cell-free supernatant from activated microglia. The neuroprotective effects of thiadiazolidinones are completely inhibited by the peroxisome proliferator-activated receptor gamma antagonist GW9662. In contrast the glycogen synthase kinase 3beta inhibitor LiCl did not show any effect. These findings suggest that thiadiazolidinones potently attenuate lipopolysaccharide-induced neuroinflammation and reduces neuronal death by a mechanism dependent of peroxisome proliferator-activated receptor gamma activation.
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PMID:Regulation of inflammatory response in neural cells in vitro by thiadiazolidinones derivatives through peroxisome proliferator-activated receptor gamma activation. 1581 69

The pathological hallmarks of Alzheimer's disease (AD) consist of beta-amyloid plaques and neurofibrillary tangles in affected brain areas. The processes, which drive this host reaction are unknown. To determine whether an analogous host reaction to that occurring in AD could be induced by infectious agents, we exposed mammalian glial and neuronal cells in vitro to Borrelia burgdorferi spirochetes and to the inflammatory bacterial lipopolysaccharide (LPS). Morphological changes analogous to the amyloid deposits of AD brain were observed following 2-8 weeks of exposure to the spirochetes. Increased levels of beta-amyloid precursor protein (AbetaPP) and hyperphosphorylated tau were also detected by Western blots of extracts of cultured cells that had been treated with spirochetes or LPS. These observations indicate that, by exposure to bacteria or to their toxic products, host responses similar in nature to those observed in AD may be induced.
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PMID:Beta-amyloid deposition and Alzheimer's type changes induced by Borrelia spirochetes. 1589 9

Ceramide is a pro-apoptotic lipid messenger that induces oxidative stress and may mediate apoptosis in cerebral endothelial cells (CECs) induced by TNF-alpha/cycloheximide, lipopolysaccharide, oxidized LDL, IL-1, and amyloid peptide. Exposure of CECs to C2 ceramide for 12 h caused cell death in a concentration-dependent manner, with a LC50 of 30 microM. Statins are inhibitors of 3-hydroxyl-3-methyl coenzyme A reductase which is the rate-limiting enzyme for cholesterol biosynthesis. Pretreatment with pravastatin at 20 microM for 16 h substantially attenuated ceramide cytotoxicity in mouse CECs. Increases in vascular endothelial growth factor (VEGF) expression were detected within 1-3 h after pravastatin treatment. This pravastatin action was accompanied by the activation of hypoxia-inducible factor-1 (HIF-1), a transcription factor known to activate VEGF expression. These results raise the possibility that pravastatin may protect CECs against ceramide-induced death via the HIF-VEGF cascade.
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PMID:Pravastatin attenuates ceramide-induced cytotoxicity in mouse cerebral endothelial cells with HIF-1 activation and VEGF upregulation. 1596 81

The processing of the amyloid precursor protein (APP) by the secretase family of protease enzymes can be influenced by a variety of diverse factors, including elements of the immune response. In this study, we have investigated the effect of the pro-inflammatory lipopolysaccharide (LPS) on APP processing in rat glial cell cultures derived from both cortex and cerebellum. LPS activation of the cells, as monitored by the induction of the pro-inflammatory nitric oxide synthase (iNOS) enzyme, elicited no change in the overall cellular expression levels of APP, although there was a marked concentration-related increase in the secretion of the soluble APPs following both short- (4 h) and long-term (18 h) drug treatment times. The stimulation of APPs secretion was blocked by the protein kinase C (PKC) inhibitor GF109203x, suggesting that LPS may act via a PKC-mediated pathway to increase APPs secretion.
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PMID:Lipopolysaccharide stimulates the secretion of the amyloid precursor protein via a protein kinase C-mediated pathway. 1602 82

Inflammation is a critical component of the pathogenesis of Alzheimer's disease (AD). Although not an initiator of this disorder, inflammation nonetheless plays a pivotal role as a driving force that can modulate the neuropathology. Here, we characterized the time course of microglia activation in the brains of a transgenic model of AD (3xTg-AD) and discerned its relationship to the plaque and tangle pathology. We find that microglia became activated in a progressive and age-dependent manner, and this activation correlated with the onset of fibrillar amyloidbeta-peptide plaque accumulation and tau hyperphosphorylation. To determine whether microglial activation can exacerbate the pathology, we exposed young 3xTg-AD mice to lipopolysaccharide (LPS), a known inducer of CNS inflammation. Although amyloid precursor protein processing appeared unaffected, we find that LPS significantly induced tau hyperphosphorylation at specific sites that were mediated by the activation of cyclin-dependent kinase 5 (cdk5) through increased formation of the p25 fragment. We further show that administration of roscovitine, a selective and potent inhibitor of cdk5, markedly blocked the LPS-induced tau phosphorylation in the hippocampus. Therefore, this study clearly demonstrates that microglial activation exacerbates key neuropathological features such as tangle formation.
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PMID:Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer's disease. 1619 74

The human G-protein-coupled formyl peptide receptor-like 1 (FPRL1) and its mouse homologue mFPR2 mediate the chemotactic activity of a variety of polypeptides associated with inflammation and bacterial infection, including the 42-amino acid form of amyloid beta peptide (Abeta42), a pathogenic factor in Alzheimer disease. Because mFPR2 was inducible in mouse microglial cells by proinflammatory stimulants, such as bacterial lipopolysaccharide, a ligand for the Toll-like receptor 4 (TLR4), we investigated the role of TLR2 in the regulation of mFPR2. We found that a TLR2 agonist, peptidoglycan (PGN) derived from Gram-positive bacterium Staphylococcus aureus, induced considerable mFpr2 mRNA expression in a mouse microglial cell line and primary microglial cells. This was associated with a markedly increased chemotaxis of the cells in response to mFPR2 agonist peptides. In addition, activation of TLR2 markedly enhanced mFPR2-mediated uptake of Abeta42 by microglia. Studies of the mechanistic basis showed that PGN activates MAPK and IkappaBalpha, and the effect of PGN on induction of mFPR2 was dependent on signaling pathways via ERK1/2 and p38 MAPKs. The use of TLR2 on microglial cells by PGN was supported by the fact that N9 cells transfected with short interfering RNA targeting mouse TLR2 failed to show increased expression of functional mFPR2 after stimulation with PGN. Our results demonstrated a potentially important role for TLR2 in microglial cells of promoting cell responses to chemoattractants produced in lesions of inflammatory and neurodegenerative diseases in the brain.
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PMID:Activation of Toll-like receptor 2 on microglia promotes cell uptake of Alzheimer disease-associated amyloid beta peptide. 1633 65

MAPK-activated protein kinase 2 (MAPKAP K2 or MK2) is one of several kinases directly regulated by p38 MAPK. A role for p38 MAPK in the pathology of Alzheimer disease (AD) has previously been suggested. Here, we provide evidence to suggest that MK2 also plays a role in neuroinflammatory and neurodegenerative pathology of relevance to AD. MK2 activation and expression were increased in lipopolysaccharide (LPS) + interferon gamma-stimulated microglial cells, implicating a role for MK2 in eliciting a pro-inflammatory response. Microglia cultured ex vivo from MK2-deficient (MK2-/-) mice demonstrated significant inhibition in release of tumor necrosis factor alpha, KC (mouse chemokine with highest sequence identity to human GROs and interleukin-8), and macrophage inflammatory protein 1alpha on stimulation with LPS + interferon gamma or amyloid-beta peptide (1-42) compared with MK2+/+ wild-type microglia. Consistent with an inhibition in pro-inflammatory mediator release, cortical neurons co-cultured with LPS + interferon gamma-stimulated or amyloid-beta peptide (1-42)-stimulated MK2-/- microglia were protected from microglial-mediated neuronal cell toxicity. In a transgenic mouse model of AD in which amyloid precursor protein and presenilin-1 harboring familial AD mutations are overexpressed in specific regions of the brain, elevated activation and expression of MK2 correlated with beta-amyloid deposition, microglial activation, and up-regulation of tumor necrosis factor alpha, macrophage inflammatory protein 1alpha, and KC gene expression in the same brain regions. Our data propose a role for MK2 in AD brain pathology, for which neuroinflammation involving cytokines and chemokines and overt neuronal loss have been documented.
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PMID:MAPK-activated protein kinase 2 deficiency in microglia inhibits pro-inflammatory mediator release and resultant neurotoxicity. Relevance to neuroinflammation in a transgenic mouse model of Alzheimer disease. 1677 24

Cannabinoid receptors (CBr) stimulation induces numerous central and peripheral effects. A growing interest in the beneficial properties of manipulating the endocannabinoid system has led to the possible involvement of CBr in the control of brain inflammation. In the present study we examined the effect of the CBr agonist, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)-pyrrolo[1,2,3-de]-1,4benzoxazin-6-yl]-1-naphthalenyl-methanone mesylate (WIN-55212-2), on microglial activation and spatial memory performance, using a well-characterized animal model of chronic brain inflammation produced by the infusion of lipopolysaccharide (LPS, 250 ng/h for 3 weeks) into the fourth ventricle of young rats. WIN-55212-2 (0.5 or 1.0 mg/kg/day, i.p.) was administered for 3 weeks. During the third week of treatment, spatial memory ability was examined using the Morris water-maze task. We found that 0.5 and 1 mg/kg WIN-55212-2 reduced the number of LPS-activated microglia, while 1 mg/kg WIN-55212-2 potentiated the LPS-induced impairment of performance in the water maze task. Cannabinoid receptors 1 were not expressed by microglia and astrocytes, suggesting an indirect effect of WIN-55212-2 on microglia activation and memory impairment. Our results emphasize the potential use of CBr agonists in the regulation of inflammatory processes within the brain; this knowledge may lead to the use of CBr agonists in the treatment of neurodegenerative diseases associated with chronic neuroinflammation, such as Alzheimer disease.
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PMID:Anti-inflammatory property of the cannabinoid agonist WIN-55212-2 in a rodent model of chronic brain inflammation. 1717 96

Accumulating evidence indicates that mutations in the presenilin 1 (PS1) gene are responsible for most cases of familial Alzheimer's disease (AD). Although its biological functions are not yet fully understood, it appears that PS1 plays a role in the processing and trafficking of the amyloid precursor protein (APP). However, little is known about factors that are involved in regulating the metabolism of PS1 especially in relation to AD pathology. In this study, we have examined the effect of optic nerve crush, intravitreal injection of the inflammatory agent lipopolysaccharide (LPS) or injection of amyloid beta(1-42) (A beta(1-42)) on the expression and processing of PS1 in the rat retina. We found that 48 h after injection of A beta(1-42) there was a dramatic alteration in the banding pattern of PS1 on Western blots, as indicated by marked changes in the levels of expression of some of its C- and N-terminal fragments in retinal homogenates. These results suggest an A beta(1-42)-induced potentiation of a non-specific stress-related but inflammation-independent alteration of processing of PS1 in this in vivo model.
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PMID:Alterations in presenilin 1 processing by amyloid-beta peptide in the rat retina. 1733 7


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