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)

In this study, we investigate the expression of fractalkine (CX3CL1) and the fractalkine receptor (CX3CR1) in the naive rat and mouse central nervous system (CNS). We determine if the expression of this chemokine and its receptor are altered during chronic or acute inflammation in the CNS. In addition, we determine if CX3CL1, which has been reported to be chemoattractant to leukocytes in vitro, is capable of acting as a chemoattractant in the CNS in vivo. Immunohistochemistry was performed using primary antibodies recognizing soluble and membrane-bound CX3CL1 and the N-terminus of the CX3CR1. We found that neurons in the naive rodent brain are immunoreactive for CX3CL1 and CX3CR1, both showing a perinuclear staining pattern. Resident microglia associated with the parenchyma and macrophages in the meninges and choroid plexus constituitively express CX3CR1. In a prion model of chronic neurodegeneration and inflammation, CX3CL1 immunoreactivity is upregulated in astrocytes and CX3CR1 expression is elevated on microglia. In surviving neurons, expression of CX3CL1 appears unaltered relative to normal neurons. There is a decrease in neuronal CX3CR1 expression. Acute inflammatory responses in the CNS, induced by stereotaxic injections of lipopolysaccharide or kainic acid, results in activation of microglia and astrocytes but no detectable changes in the glial expression of CX3CL1 or CX3CR1. The expression of CX3CL1 and CX3CR1 by glial cells during inflammation in the CNS may be influenced by the surrounding cytokine milieu, which has been shown to differ in acute and chronic neuroinflammation.
 ...
PMID:Expression of fractalkine (CX3CL1) and its receptor, CX3CR1, during acute and chronic inflammation in the rodent CNS. 1187 Aug 71

Peripheral infections in mammals are characterised by local, systemic and CNS effects. The latter give rise to sickness behaviour. Pro-inflammatory cytokines such as interleukin-1beta (IL-1beta) are thought to be important mediators of this neuro-immune signalling (Cartmell et al., 1999). There is anecdotal evidence suggesting that peripheral infections in patients with Alzheimer's disease have more severe behavioural consequences than those in otherwise healthy elderly subjects, and it is well known that brain microglia are activated in the elderly and in Alzheimer's disease (McGeer et al., 1987). Using ME7-induced murine prion disease as a model of chronic neurodegeneration that displays chronic microglial activation, and the intra-peritoneal injection of bacterial lipopolysaccharide to mimic a peripheral infection, we have shown that the temperature and activity responses of animals with pre-clinical prion disease were exaggerated compared with controls, and that this was associated with a significant increase in brain levels of IL-1beta. We hypothesise that prior priming of microglia by the degenerative process, followed by further activation through signalling from the periphery, resulted in increased brain IL-1beta synthesis and the consequent acute sickness behavioural responses. These findings demonstrate an interaction between peripheral infection and pre-existing CNS inflammation and suggest that further stimulation of an already primed microglial population by a peripheral infection may drive disease progression in chronic inflammatory conditions such as Alzheimer's disease and prion disease.
 ...
PMID:Peripheral infection evokes exaggerated sickness behaviour in pre-clinical murine prion disease. 1204 67

In scrapie-infected cells, the conversion of the cellular prion protein to the pathogenic prion has been shown to occur in lipid rafts, which are suggested to function as signal transduction platforms. Neuronal cells may respond to bacterial lipopolysaccharide (LPS) treatment with a sustained and elevated nitric oxide (NO) release. Because prions and the major LPS receptor CD14 are colocalized in lipid rafts, the LPS-induced NO production in scrapie-infected neuroblastoma cells was studied. This study shows that LPS induces a dose- and time-dependent increase in NO release in the murine neuroblastoma cell line N2a, with a 50-fold increase in NO production at 1 microg/ml LPS after 96 hr, as measured by nitrite in the medium. This massive NO release was not caused by activation of the neuronal NO synthase (nNOS), but by increased expression of the inducible NOS (iNOS) mRNA and protein. However, in scrapie-infected N2a cells (ScN2a), the LPS-induced NO production was completely abolished. The absence of LPS-induced NO production in ScN2a was due not to abolished enzymatic activity of iNOS but to a complete inhibition of the LPS-induced iNOS gene expression as measured by Western blot and RT-PCR. These results indicate that scrapie infection inhibits the LPS-mediated signal transduction upstream of the transcriptional step in the signaling cascade and may reflect the important molecular and cellular changes induced by scrapie infection.
 ...
PMID:Loss of lipopolysaccharide-induced nitric oxide production and inducible nitric oxide synthase expression in scrapie-infected N2a cells. 1250 93

In vitro studies show that microglial cells kill neurons treated with the synthetic miniprion (sPrP106) or with amyloid-beta1-42 (a neurotoxic peptide found in Alzheimer's disease) by a process requiring the CD14 protein. The killing of treated primary cortical neurons by microglial cells was reduced by the addition of detoxified lipopolysaccharide (LPS), a deacylated form of LPS. Detoxified LPS also increased the survival of prion-infected neuroblastoma cells incubated with microglial cells. The presence of detoxified LPS reduced cytokine production in these co-cultures, and from isolated microglial cells incubated with native LPS, or fibrils of sPrP106 or amyloid-beta1-42. These results suggest that some compounds that bind to CD14 might reduce microglial cell activation and increase neuronal survival in prion and Alzheimer's diseases.
 ...
PMID:Detoxified lipopolysaccharide reduces microglial cell killing of prion-infected neurons. 1559 50

The prion diseases or transmissible spongiform encephalopathy, such as human Creutzfeldt-Jakob disease (CJD) and so-called mad cow disease, are attributed to the causative agent, the scrapie variant of prion protein (PrP(Sc)) which causes fatal neurodegeneration. To investigate if stresses such as nitric oxide (NO) induced the cellular isoform of prion protein (PrP(C)), lipopolysaccharide, and sodium nitroprusside were used to treat N2a and NT2 cells, which resulted in elevated levels of the PRNP mRNA and prion protein. The signaling pathway for the NO-induced PrP(C) production involved guanylyl cyclase, MEK, and p38 MAPK as shown by the effect of specific pharmacological inhibitors ODQ, PD98059, and SB203580, respectively. Knowing the PrP induction by the biologically existing stimulus, this study provides useful information about the possible cellular mechanism and strategies for the treatment of CJD.
 ...
PMID:Nitric oxide induces prion protein via MEK and p38 MAPK signaling. 1593 14

The contribution of inflammation to the progression of neurodegenerative diseases such as Alzheimer's, Parkinson's, and prion diseases is poorly understood. Brain inflammation in animal models of these diseases is dominated by chronic microglial activation with minimal proinflammatory cytokine expression. However, these inflammatory cells are "primed" to produce exaggerated inflammatory responses to subsequent lipopolysaccharide (LPS) challenges. We show that, using the ME7 model of prion disease, intracerebral challenge with LPS results in dramatic interleukin-1beta (IL-1beta) expression, neutrophil infiltration, and inducible nitric oxide synthase expression in the brain parenchyma of prion-diseased mice compared with the same challenge in normal mice. Systemic inflammation evoked by LPS also produced greater increases in proinflammatory cytokines, pentraxin 3, and inducible nitric oxide synthase transcription in prion-diseased mice than in control mice and induced microglial expression of IL-1beta. These systemic challenges also increased neuronal apoptosis in the brains of ME7 animals. Thus, both central and peripheral inflammation can exacerbate local brain inflammation and neuronal death. The finding that a single acute systemic inflammatory event can induce neuronal death in the CNS has implications for therapy in neurodegenerative diseases.
 ...
PMID:Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. 1620 87

The inflammatory responses in Alzheimer's disease (AD) and prion-related encephalopathies (PRE) are dominated by microglia activation. Several studies have reported that the amyloid-beta (Abeta) peptides, which are associated with AD, and the pathogenic isoform of prion protein (PrPSc) have a crucial role in neuronal death and gliosis that occur in both of these disorders. In this study, we investigate whether Abeta and PrPSc cause microglia activation per se and whether these amyloidogenic peptides differentially affect these immunoeffector cells. In addition, we also determined whether substances released by Abeta- and PrP-activated microglia induce neuronal death. Cultures of rat brain microglia cells were treated with the synthetic peptides Abeta1-40, Abeta1-42 and PrP106-126 for different time periods. The lipopolysaccharide was used as a positive control of microglia activation. Our results show that Abeta1-40 and PrP106-126 caused similar morphological changes in microglia and increased the production of nitric oxide and hydroperoxides. An increase on inducible nitric oxide synthase expression was also observed in microglia treated with Abeta1-40 or PrP106. However, these peptides affected in a different manner the secretion of interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) secretion. In cocultures of microglia-neurons, it was observed that microglia treated with Abeta1-40 or PrP106-126 induced a comparable extent of neuronal death. The neutralizing antibody for IL-6 significantly reduced the neuronal death induced by Abeta- or PrP-activated microglia. Taken together, the data indicate that Abeta and PrP peptides caused microglia activation and differentially affected cytokine secretion. The IL-6 released by reactive microglia caused neuronal injury.
 ...
PMID:Comparative study of microglia activation induced by amyloid-beta and prion peptides: role in neurodegeneration. 1663 56

Virtually all rodents display burrowing behavior, yet measurement of this behavior has not yet been standardized or formalized. Previously, parameters such as the latency to burrow and the complexity of the burrow systems in substrate-filled boxes in the laboratory or naturalistic outdoor environments have been assessed. We describe here a simple protocol that can quantitatively measure burrowing in laboratory rodents, using a simple apparatus that can be placed in the home cage. The test is very cheap to run and requires minimal experimenter training, yet seems sensitive to a variety of treatments, such as the early stages of prion disease in mice, mouse strain differences, lesions of the hippocampus and prefrontal cortex in mice, also effects of lipopolysaccharide and IL-1beta in rats. Other species such as hamsters, gerbils and Egyptian spiny mice also burrow in this apparatus, and with suitable size modification probably almost any burrowing animal could be tested in it. The simplicity, sensitivity and robustness of burrowing make it ideal for assessing genetically modified animals, which in most cases would be mice. The test is run from late afternoon until the next morning, but only two measurements need to be taken.
 ...
PMID:Burrowing in rodents: a sensitive method for detecting behavioral dysfunction. 1740 22

Cells of the innate immune system play important roles in the progression of prion disease after peripheral infection. It has been found in vivo and in vitro that the expression of the cellular prion protein (PrP(c)) is up-regulated on stimulation of immune cells, also indicating the functional importance of PrP(c) in the immune system. The aim of our study was to investigate the impact of cytosine-phosphate-guanosine- and lipopolysaccharide-induced PrP(c) up-regulation on the uptake and processing of the pathological prion protein (PrP(Sc)) in phagocytic innate immune cells. For this purpose, we challenged the macrophage cell line J774, the microglial cell line BV-2 and primary bone marrow-derived macrophages in a resting or stimulated state with various prion strains, and monitored the uptake and clearance of PrP(Sc). Interestingly, stimulation led either to a transient increase in the level of PrP(Sc) relative to unstimulated cells or to a decelerated degradation of PrP(Sc). These features were dependent on cell type and prion strain. Our data indicate that the stimulation of innate immune cells may be able to support transient prion propagation, possibly explained by an increased PrP(c) cell surface expression in stimulated cells. We suggest that stimulation of innate immune cells can lead to an imbalance between the propagation and degradation of PrP(Sc).
 ...
PMID:CpG and LPS can interfere negatively with prion clearance in macrophage and microglial cells. 1794 38

Amphotericin B (AmB) is a polyene antibiotic and reported to have therapeutic effects on prion diseases, in which the microglial activation has been suggested to play important roles by proliferating and producing various factors such as nitric oxide, proinflammatory cytokines, and so on. However, the therapeutic mechanism of AmB on prion diseases remains elusive. In the present study, we investigated the effects of AmB on cellular functions of rat primary cultured microglia. We found that AmB, similarly as lipopolysaccharide (LPS), could activate microglia to produce nitric oxide via inducible nitric oxide synthase. Both AmB and LPS also induced mRNA expressions of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in microglia. AmB also changed the expression levels of neurotrophic factors mRNAs. AmB and LPS significantly down-regulated the level of ciliary neurotrophic factor mRNA. However, AmB, but not LPS, significantly up-regulated the level of glial cell-line derived neurotrophic factor mRNA in microglia. In addition, brain-derived neurotrophic factor mRNA expression level was tending upward by treatment with AmB, but not with LPS. Taken together, these results suggest that AmB regulates the microglial activation in different manner from LPS and that microglia may participate in the therapeutic effects of AmB on prion diseases by controlling the expression and production of such mediators.
 ...
PMID:Effects of Amphotericin B on the expression of neurotoxic and neurotrophic factors in cultured microglia. 1832 1


1 2 3 Next >>