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)

Microglia become activated in a wide range of neurodegenerative disorders, including Alzheimer's disease. Such activation may lead to autodestruction of neurons. It is demonstrated here that activation of both human microglia and monocytic THP-1 cells by a combination of lipopolysaccharide and interferon-gamma results in secretion of neurotoxins that kill human neuronal SH-SY5Y cells. This neurotoxicity can be partially blocked by inhibitors of cytosolic phospholipase A2, cGMP-selective phosphodiesterases, or protein kinase C. When combinations of these inhibitors, or combinations of an inhibitor plus nordihydroguaiaretic acid, or the nonsteroidal anti-inflammatory drug diclofenac were tried, additive reductions in neurotoxicity were observed. It is concluded that the stimulants activated multiple intracellular pathways, and that combination therapies inhibiting these pathways might be beneficial for treating neurodegenerative disorders.
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PMID:Interaction of various intracellular signaling mechanisms involved in mononuclear phagocyte toxicity toward neuronal cells. 1064 7

Activated microglia surrounding amyloid beta-containing senile plaques synthesize interleukin-1, an inflammatory cytokine that has been postulated to contribute to Alzheimer's disease pathology. Studies have demonstrated that amyloid beta treatment causes increased cytokine release in microglia and related cell cultures. The present work evaluates the specificity of this cellular response by comparing the effects of amyloid beta to that of amylin, another amyloidotic peptide. Both lipopolysaccharide-treated THP-1 monocytes and mouse microglia showed significant increases in mature interleukin-1beta release 48 h following amyloid beta or human amylin treatment, whereas nonfibrillar rat amylin had no effect on interleukin-1beta production by THP-1 cells. Lipopolysaccharide-stimulated THP-1 cells treated with amyloid beta or amylin also showed increased release of the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6, as well as the chemokines interleukin-8 and macrophage inflammatory protein-1alpha and -1beta. THP-1 cells incubated with fibrillar amyloid beta or amylin in the absence of lipopolysaccharide also showed significant increases of both interleukin-1beta and tumor necrosis factor-alpha mRNA. Furthermore, treatment of THP-1 cells with amyloid fibrils resulted in an elevated expression of the immediate-early genes c-fos and junB. These studies provide further evidence that fibrillar amyloid peptides can induce signal transduction pathways that initiate an inflammatory response that is likely to contribute to Alzheimer's disease pathology.
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PMID:Amyloid beta and amylin fibrils induce increases in proinflammatory cytokine and chemokine production by THP-1 cells and murine microglia. 1069 32

Cerebellar granule cells (CGCs) can express the inducible isoform of nitric oxide synthase (iNOS) in response to inflammatory stimuli. We demonstrate that induction of iNOS in CGCs by bacterial lipopolysaccharide and pro-inflammatory cytokines results in cell death that was potentiated by excess L-arginine and inhibited by the selective iNOS inhibitor, 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine. The NO-mediated cell death was accompanied by increased caspase-3-like activity, DNA fragmentation and positive terminal transferase dUTP nick end labeling (TUNEL), suggesting that apoptosis mediates CGC cell death. Incubation of CGCs with the non-steroidal anti-inflammatory drugs (NSAIDs), ibuprofen or indomethacin, or with 15-deoxy-delta12,14 prostaglandin J2 (PGJ2) downregulates iNOS expression and reduces subsequent cell death. Since in other cell types, both NSAIDs and PGJ2 can activate the peroxisome proliferator-activated receptor-gamma (PPARgamma) and downregulate cytokine levels and iNOS expression, and since CGCs express PPARgamma in vivo and in vitro, our data suggest that activation of CGC PPARgamma mediates iNOS suppression and reduced cell death. Because PPARgamma is expressed in brains of Alzheimer's Disease (AD) patients, in which neuronal iNOS expression and apoptotic cell death have been described, these results may help explain the basis for the beneficial effects of NSAIDs in AD.
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PMID:Peroxisome proliferator-activated receptor gamma agonists protect cerebellar granule cells from cytokine-induced apoptotic cell death by inhibition of inducible nitric oxide synthase. 1069 26

We investigated the ultrastructural, immunohistochemical, biochemical and behavioral effects of chronic neuroinflammation in young rats produced by injection of lipopolysaccharide (LPS) into the 4th ventricle. The 37-day infusion of LPS impaired spatial memory but not object recognition ability. Electron microscopic studies of neurons within the hippocampus identified numerous paired cisternae of the rough endoplasmic reticulum (RER) and other ultrastructural changes that suggested impaired or reduced synthesis of cellular proteins within the cytoplasm. Immunohistochemical staining found numerous highly activated microglia distributed throughout the cingulate gyrus, entorhinal cortex, hippocampus and dentate gyrus. This animal model may be useful to test potential pharmacotherapies that are directed at the prevention of the cytotoxic consequences of chronic neuroinflammation associated with normal aging or Alzheimer's disease.
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PMID:Behavioral and ultrastructural changes induced by chronic neuroinflammation in young rats. 1072 Jun 25

Cortisol is a steroid hormone produced in response to stress. This glucocorticoid can be toxic to neurons, and thus may be important in neurodegenerative diseases including Alzheimer's disease. Activated microglia produce molecules including nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) which can also be toxic to neurons. The current study was designed to determine the effect of cortisol upon the activation of primary cultured microglia and transformed N9 microglial cells. The studies indicate that cortisol represses lipopolysaccharide (LPS) induction of nitric oxide production in these microglial cells. The hormone acts by inhibiting the production of inducible nitric oxide synthase (iNOS) which catalyses the synthesis of NO. Cortisol likely acts by blocking transcription of iNOS gene expression since the hormone represses LPS induction of iNOS RNA levels in these cells. Activated microglia produce increased TNF-alpha, in addition to increased NO. The current studies demonstrate that cortisol inhibits release of TNF-alpha from LPS-treated microglial cells. Collectively, these data suggest that although cortisol may be directly toxic to neurons, the hormone may indirectly protect neurons by blocking the production of cytotoxic molecules by microglia.
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PMID:Inhibition of microglial cell activation by cortisol. 1092 18

Inflammatory processes may play an important role in the degeneration of basal forebrain cholinergic cells Alzheimer's disease. We infused the proinflammagen lipopolysaccharide into the basal forebrain of young rats and determined whether the chronic administration of two novel non-steroidal anti-inflammatory drugs or a pan-caspase synthesis inhibitor, z-Val-Ala-Asp(OMe)-fluoromethyl ketone (zVAD), could provide neuroprotection from the cytotoxic effects of the neuroinflammation. Chronic lipopolysaccharide infusions decreased choline acetyltransferase activity and increased the number of activated microglia within the basal forebrain region. The level of caspases 3, 8 and 9 was increased in ventral caudate/putamen. Non-steroidal anti-inflammatory drug therapy attenuated the toxicity of the inflammation upon cholinergic cells and reduced caspases 3, 8 and 9 activity in the caudate/putamen. zVAD treatment significantly decreased the levels of caspases 3, 8 and 9 but did not provide neuroprotection for the cholinergic neurons. These results suggest that prostaglandins contribute to the degeneration of forebrain cholinergic neurons in Alzheimer's disease.
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PMID:Mechanisms to prevent the toxicity of chronic neuroinflammation on forebrain cholinergic neurons. 1094 Mar 60

Brain inflammation may have a pathogenic role in many neurodegenerative diseases, including Alzheimer's disease. In the present study, we investigated the effects of chronic neuroinflammation upon anatomical changes in two regions of interest in the temporal lobe using high-resolution magnetic resonance imaging techniques. We show that chronic infusion of lipopolysaccharide into the fourth ventricle for 4 consecutive weeks enlarged the lateral ventricles and significantly decreased the size of the hippocampal formation and the temporal lobe region. These changes are comparable to those observed in humans during the early stages of Alzheimer's disease.
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PMID:Quantitative volumetric analyses of brain magnetic resonance imaging from rat with chronic neuroinflammation. 1099 94

Expression of the inducible form of nitric oxide synthase (iNOS) in brain may contribute to neurotoxicity in Alzheimer's disease (AD). Expression of iNOS can be induced in cerebellar granule cells (CGCs) in vivo as well as in vitro, allowing these cells to be used to study regulation of neuronal iNOS expression. We report here that microinjection of bacterial lipopolysaccharide and interferon gamma into rat cerebellum induced iNOS expression in CGCs and subsequent cell death assessed by staining for DNA fragmentation. Co-injection of three structurally distinct agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma), including the antidiabetic thiazolidinedione troglitazone, the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen, and the prostanoid 15-deoxy-Delta(12,14) prostaglandin J(2), reduced both iNOS expression and cell death, whereas co-injection of the selective cyclo-oxygenase inhibitor NS-398 had no effect. These data demonstrate that PPARgamma agonists can modulate inflammatory responses in brain. Because sustained medication with NSAIDs reduces the risk and delays the onset of AD, these results further suggest that NSAIDs provide therapeutic value by binding to PPARgamma present in AD brain, thereby preventing iNOS expression and neuronal cell death.
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PMID:Peroxisome proliferator-activated receptor-gamma ligands reduce neuronal inducible nitric oxide synthase expression and cell death in vivo. 1099 30

In the present study the effects of 17beta-estradiol on microglial activation are described. Estrogen replacement therapy has been associated with decreased severity of age-related neurodegenerative diseases such as Alzheimer's disease, and estrogens have potent immunosuppressive properties outside of the brain. To determine the role that microglial cells might play in estrogen-mediated neuroprotection, primary rat microglia and N9 microglial cell lines were treated with increasing doses of 17beta-estradiol before or during immunostimulation by lipopolysaccharide, phorbol ester, or interferon-gamma. Pretreatment with 17beta-estradiol, but not 17alpha-estradiol or progesterone, dose dependently attenuated microglial superoxide release and phagocytic activity. Additionally, 17beta-estradiol attenuated increases in inducible nitric oxide synthase protein expression, but did not alter nuclear factor-KB activation. The antiinflammatory effects of 17beta-estradiol were blocked by the antiestrogen ICI 182,780. Additionally, 17beta-estradiol induced rapid phosphorylation of the p42/p44 mitogen-activated protein kinase (MAP kinase), and the MAP kinase inhibitor PD 98059 blocked the antiinflammatory effects of 17beta-estradiol. Overall, these results suggest that estrogen receptor-dependent activation of MAP kinase is involved in estrogen-mediated antiinflammatory pathways in microglial cells. These results describe a novel mechanism by which estrogen may attenuate the progression of neurodegenerative disease and suggest new pathways for therapeutic intervention in clinical settings.
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PMID:Antiinflammatory effects of estrogen on microglial activation. 1101 19

Dehydroepiandrosterone (DHEA) is a steroid that circulates in abundance in the form of a sulfated reserve (DHEA-S). The levels of DHEA decline with age and further in age-related neuropathologies, including Alzheimer disease. Because of their reported anti-inflammatory effects, we tested the actions of these compounds on microglia. At concentrations of 3(-9) to 1(-6) M, DHEA and DHEA-S inhibited the production of nitrite and morphological changes stimulated by lipopolysaccharide. DHEA and DHEA-S also inhibited LPS induction of iNOS protein, but neither inhibited LPS-induced iNOS mRNA or the activation of NF-kappaB. These data suggest that the hormone regulates nitrite production through a post-transcriptional mechanism. Interestingly, microglial nitrite production in response to a secreted form of the beta-amyloid precursor protein (sAPP) was unaffected by DHEA. Another Alzheimer-related factor, amyloid beta-peptide, also stimulated microglial nitrite production but in a manner dependent on the co-stimulus interferon-gamma. DHEA was found to inhibit only the interferon-gamma component of the microglial response. These data add to a growing body of evidence for differences in the profiles of mononuclear phagocytes activated by distinct stimuli.
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PMID:Dehydroepiandrosterone inhibits microglial nitric oxide production in a stimulus-specific manner. 1107 Apr 93


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