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)

Inflammation processes may play a critical role in the pathogenesis of the degenerative changes and cognitive impairments associated with Alzheimer's disease (AD). Non-steroidal anti-inflammatory drugs are reported to be effective in reducing the risk of developing AD or cognitive impairments. Present experiments were performed to study the possible effect of various NSAIDs on cognitive performance of young, aged and scopolamine or lipopolysaccharide (LPS) treated mice (an animal model of AD) using one trial step through type of passive avoidance and in elevated plus maze task. Chronic administration of NSAIDs at the ED(50) doses (nimesulide, rofecoxib and naproxen for 15 days) significantly reversed the age or scopolamine-induced retention deficits in both test paradigms. However, in both the memory paradigms chronic administration of NSAIDs failed to modulate the retention performance of young mice. Acute administration of LPS (50 mcg/mouse, i.p.) significantly exhibited retention deficits after 24 h and seventh day of its administration in both test paradigms. Chronic administration (7 days) of rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor (1.92 mg/kg, p.o.) significantly reversed the LPS-induced retention deficits in both tests. The results of this study showed chronic treatment of NSAIDs reverses the cognitive deficits in age and scopolamine or LPS treated mice. These findings establish a link between the central nervous system expression of various pro-inflammatory cytokines and learning impairment in mice.
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PMID:Modulatory role of cyclooxygenase inhibitors in aging- and scopolamine or lipopolysaccharide-induced cognitive dysfunction in mice. 1211 Apr 71

Enriched populations of human microglial cells were isolated from mixed cell cultures prepared from embryonic human telencephalon tissues. Human microglial cells exhibited cell type-specific antigens for macrophage-microglia lineage cells including CD11b (Mac-1), CD68, B7-2 (CD86), HLA-ABC, HLA-DR and ricinus communis aggulutinin lectin-1 (RCA-1), and actively phagocytosed latex beads. Gene expression and protein production of cytokines, chemokines and cytokine/chemokine receptors were investigated in the purified populations of human microglia. Normal unstimulated human microglia expressed constitutively mRNA transcripts for interleukin- 1beta (IL-1beta) -6, -8, -10, -12, -15, tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, and monocyte chemoattractant protein-1 (MCP-1), while treatment with lipopolysaccharide (LPS) or amyloid beta peptides (Abeta) led to increased expression of mRNA levels of IL-8, IL-10, IL-12, TNF-alpha, MIP-1alpha, MIP-1beta, and MCP-1. Human microglia, in addition, expressed mRNA transcripts for IL-1RI, IL-1RII, IL-5R, IL-6R, IL-8R, IL-9R, IL-10R, IL-12R, IL-13R, and IL-15R. Enzyme-linked immunosorbent assays (ELISA) showed increased protein levels in culture media of IL-1beta, IL-8, TNF-alpha, and MIP-1alpha in human microglia following treatment with LPS or Abeta. Increased TNF-alpha release from human microglia following LPS treatment was completely inhibited with IL-10 pretreatment, but not with IL-6, IL-9, IL-12, IL-13, or transforming growth factor-beta (TGF-beta). Present results should help in understanding the basic microglial biology, but also the pathophysiology of activated microglia in neurological diseases such as Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, stroke, and neurotrauma.
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PMID:Cytokines, chemokines, and cytokine receptors in human microglia. 1211 20

Metallothionein (MT)-III is a metal binding protein, called growth inhibitory factor, and is mainly expressed in the central nervous system. Since MT-III decreases in the brain of Alzheimer's disease (AD), a growing interest has been focused on its relationship to neurodegenerative diseases. To clarify age-related changes in the MT-III expression and its inducibility against oxidative stress, we analyzed the expression of MT-III and its mRNA in the brain of lipopolysaccharide (LPS)-treated aged rats. In the frontal cortex, basal expression of MT-III mRNA was significantly increased with aging, while it was observed no induction of MT-III mRNA against LPS administration in the aged rat brain. MT-III immunopositive cells were increased in the frontal, parietal and piriform cortices, hypothalamus and amygdaloid nucleus with aging. The LPS treatment induced MT-III expression in the brain of young-adult rats, but not in the aged rat brain. Furthermore, the MT-III induction with LPS treatment was mainly observed in oligodendrocyte and microglia. In the present study, we showed that inducibility of brain MT-III against oxidative stress may be reduced with aging. Since it has been reported that MT-III has neuroprotective roles as an antioxidant, present results suggest that MT-III is closely related to the neurodegeneration in the aged animals.
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PMID:Age-related changes in expression of metallothionein-III in rat brain. 1213 76

beta-Amyloid peptide (Abeta), a major component of senile plaques, the formation of which is characteristic of Alzheimer's disease (AD), is believed to induce inflammation in the brain leading to cell loss and cognitive decline. Accumulating evidence shows Abeta activates microglia, which play the role of the brain's immune system, and mediates inflammatory responses in the brain. Thus, a compound inhibiting Abeta-induced activation of microglia may lead to a novel therapy for AD. However, the compound should not inhibit natural immune responses during events such as bacterial infections. We investigated the effect of a synthesized compound, 7,8-dihydro-5-methyl-8-(1-phenylethyl)-6H-pyrrolo [3,2-e] [1,2,4] triazolo [1,5-a] pyrimidine (RS-1178) on macrophage activation induced by various stimulants. The activation of macrophages was determined by nitric oxide or tumor necrosis factor alpha production. RS-1178 inhibited Abeta-induced macrophage activation but did not inhibit zymosan A- nor lipopolysaccharide (LPS)-induced macrophage activation. Moreover, RS-1178 attenuated neurotoxicity due to Abeta-induced macrophage activation in neuron-macrophage co-cultures but not neurotoxicity due to zymosan A- or LPS-induced macrophage activation. In conclusion, RS-1178 showed a specific inhibitory effect on Abeta-induced macrophage activation. Although the exact mechanisms of this effect remain unknown, RS-1178 may provide a novel therapy for AD.
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PMID:A novel compound, RS-1178, specifically inhibits neuronal cell death mediated by beta-amyloid-induced macrophage activation in vitro. 1213 34

Inflammatory processes involving glial cell activation are associated with amyloid plaques and neurofibrillary tangles, the cardinal neuropathological lesions in the brains of Alzheimer's disease (AD) patients, However, it is unclear whether these inflammatory processes occur as a response to neuronal degeneration or might represent more seminal events in the disease process. Some cases of AD are caused by mutations in presenilin-1 (PS1), and it has been shown that PS1 mutations perturb neuronal calcium homeostasis, promote increased production of amyloid beta-peptide (Abeta), and render neurons vulnerable to synaptic dysfunction, excitotoxicity, and apoptosis. Although glial cells express PS1, it is not known if PS1 mutations alter glial cell functions. We now report on studies of glial cells in PS1 mutant knockin mice that demonstrate an adverse effect PS1 mutations in microglial cells. Specifically, PS1 mutant mice exhibit an enhanced inflammatory cytokine response to immune challenge with bacterial lipopolysaccharide (LPS). LPS-induced levels of mRNAs encoding tumor necrosis fctor-alpha (TNFalpha), interleukin (IL)-1alpha, IL-1beta, IL-1 receptor antagonist, and IL-6 are significantly greater in the hippocampus and cerebral cortex of PS1 mutant mice as compared to wild-type mice. In contrast, the cytokine responses to LPS in the spleen is unaffected by the PS1 mutation. Studies of cultured microglia from PS1 mutant and wild-type mice reveal that PS1 is expressed in microglia and that the PS1 mutation confers a heightened sensitivity to LPS, as indicated by superinduction of inducible nitric oxide synthase (NOS) and activation of mitogen-activated protein kinase (MAPK). These findings demonstrate an adverse effect of PS1 mutations on microglial cells that results in their hyperactivation under pro-inflammatory conditions, which may, together with direct effects of mutant PS1 in neurons, contribute to the neurodegenerative process in AD. These findings also have important implications for development of a "vaccine" for the prevention or treatment of AD.
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PMID:Adverse effect of a presenilin-1 mutation in microglia results in enhanced nitric oxide and inflammatory cytokine responses to immune challenge in the brain. 1223 Mar 3

Microglial cyclo-oxygenase (COX) expression is considered to be important in the pathogenesis of Alzheimer's disease (AD) and, therefore, constitutes a key target for therapeutic intervention. We investigated the influence of AD plaque associated factors on COX-1 and COX-2 expression and activity in adult human microglial cells in vitro. COX-2 immunoreactivity and mRNA were induced by lipopolysaccharide (LPS), not by AD plaque associated cytokines interleukin (IL)-1alpha, IL-1beta, IL-6, tumor necrosis factor (TNF)-alpha, or amyloid (A)beta(1-42). To assess functional COX activity, the release of PGE(2) into the culture medium was determined. LPS and also arachidonic acid (AA) dose-dependently stimulated PGE(2) release. The effects of AA are independent from induction of COX mRNA expression, or of de novo protein synthesis. No effects of either plaque-associated cytokines or Abeta(1-42) on PGE(2) secretion were seen, even when cells were co-stimulated with AA, to provide enough substrate. COX isotype selective inhibitors were used to discern relative contributions of COX-1 and COX-2 activities to microglial PGE(2) secretion. COX-2 and in part COX-1-selective inhibitors inhibited LPS-induced PGE(2) secretion, whereas the AA-induced PGE(2) secretion was reduced by COX-1-selective inhibitors only. Apparently, adult human microglia in vitro (1) constitutively express COX-1, and (2) do not express COX-2 upon exposure to either Abeta or plaque associated cytokines. In the light of microglial COX activity as a potential therapeutical target in AD, the data presented in this study suggest that classical NSAIDs, rather than selective COX-2 inhibitors, are more potent in reducing microglial prostaglandin secretion.
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PMID:The role of cyclo-oxygenase 1 and 2 activity in prostaglandin E(2) secretion by cultured human adult microglia: implications for Alzheimer's disease. 1227 May

Following induction of acute neuroinflammation by intracisternal injection of endotoxin (lipopolysaccharide) in rats, quantitative autoradiography was used to assess the regional level of microglial activation and glutamate (NMDA) receptor binding. The possible protective action of the antioxidant phenyl-tert-butyl nitrone in this model was tested by administering the drug in the drinking water for 6 days starting 24 hafter endotoxin injection. Animals were killed 7 days post-injection and consecutive cryostat brain sections labeled with [3H]PK11195 as a marker of activated microglia and [125I]iodoMK801 as a marker of the open-channel, activated state of NMDA receptors. Lipopolysaccharide increased [3H]PK11195 binding in the brain, with the largest increases (two- to threefold) in temporal and entorhinal cortex, hippocampus, and substantia innominata. A significant (> 50%) decrease in [125I]iodoMK801 binding was found in the same brain regions. Phenyl-tert-butyl nitrone treatment resulted in a partial inhibition (approx. 25% decrease) of the lipopolysaccharide-induced increase in [3H]PK11195 binding but completely reversed the lipopolysaccharide-induced decrease in [125I]iodoMK80 binding in the entorhinal cortex, hippocampus, and substantia innominata. Loss of NMDA receptor function in cortical and hippocampal regions may contribute to the cognitive deficits observed in diseases with a neuroinflammatory component, such as meningitis or Alzheimer's disease.
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PMID:Region-selective effects of neuroinflammation and antioxidant treatment on peripheral benzodiazepine receptors and NMDA receptors in the rat brain. 1235 98

Alzheimer's disease (AD) is characterized by chronic neuroinflammation, significant temporal lobe cell loss, and dementia. We investigated the influence of chronic neuroinflammation produced by chronic infusion of lipopolysaccharide (LPS) into the fourth ventricle for 4 weeks upon the induction and maintenance of long-term potentiation (LTP) in the dentate gyrus of the hippocampus, a well-characterized model of cellular synaptic plasticity. We also examined for pyramidal cell loss within the entorhinal cortex an area of the brain that contains the cell bodies of the perforant path. The results demonstrate that chronic neuroinflammation results in the loss of pyramidal cells within layers II and III of the entorhinal cortex and a significant attenuation of LTP within the dentate gyrus. Similar changes may underlie the temporal lobe pathology and dementia associated with AD.
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PMID:Chronic brain inflammation results in cell loss in the entorhinal cortex and impaired LTP in perforant path-granule cell synapses. 1235 75

Alzheimer's disease (AD) is accompanied by chronic neuroinflammation and occurs with greater incidence in postmenopausal women. The increased incidence may be delayed by estrogen replacement therapy (ERT). The authors investigated the interaction of chronic ERT and lipopolysaccharide (LPS)-induced neuroinflammation in the female rat. Ovariectomy did not impair water maze performance; however, addition of chronic ERT or neuroinflammation resulted in an impairment that became exacerbated by the simultaneous occurrence of both conditions. Chronic LPS activated microglia, which was not reduced by ERT. Intact females receiving LPS infusion were not impaired in the water maze and had significantly fewer activated microglia. Results suggest that chronic ERT in postmenopausal women may exacerbate the memory impairment induced by the chronic neuroinflammation associated with AD.
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PMID:Long-term estrogen therapy worsens the behavioral and neuropathological consequences of chronic brain inflammation. 1236 9

Alzheimer's disease is associated with glial activation and increased levels of the cytokines as well as impaired forebrain cholinergic function. Current therapies focus on enhancing cholinergic function by administrating acetylcholinesterase inhibitors, such as galantamine. Epidemiological results also suggest that anti-inflammatory therapies might be effective in slowing the onset of the symptoms of Alzheimer's disease. The current study investigated the ability of a nitric oxide (NO)-donating derivative of the nonsteroidal anti-inflammatory drug (NSAID) flurbiprofen, HCT1026, to reduce brain inflammation in young rats. Inflammation was produced by chronic infusion of lipopolysaccharide (LPS) into the 4th ventricle. The release of NO from HCT1026 requires the action of esterase enzymes. The current study determined whether the effectiveness of HCT1026 was attenuated by simultaneous treatment with the acetylcholinesterase inhibitor galantamine. Daily administration of the HCT1026 significantly reduced microglial activation and these effects were not attenuated by galantamine therapy.
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PMID:A nitric oxide-donating flurbiprofen derivative reduces neuroinflammation without interacting with galantamine in the rat. 1239 20


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