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)

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

Phagocytic cells contain NADPH oxidase that they use for host defense by catalyzing the production of superoxide. Bacterial lipopolysaccharide (LPS) has been found to stimulate NADPH oxidase in mobile and sessile macrophages and microglia. It also evokes fever in homeothermic animals and men, a reaction mediated by central nervous system (CNS) activities. The purpose of the present study was to determine whether reactive oxygen species are involved in LPS-induced fever. In rabbits we found that plasma hydroperoxide levels increased and catalase activity decreased 15 min after LPS injection and that fever started with a similar latency, while plasma levels of tumor necrosis factor-alpha (TNFalpha) increased 30 min after the injection. Treating rabbits with methylene blue or aspirin did not affect TNFalpha secretion but prevented the LPS-induced rise of hydroperoxides and the inactivation of catalase, abolishing fever. Incubation of human blood with nitroblue tetrazolium and LPS increased the number of formazan-positive neutrophils from 10 +/- 5 to 52 +/- 9%. Adding LPS to blood preincubated with either methylene blue, alpha-lipoic acid, or aspirin respectively decreased the number of formazan-positive neutrophils to 0.9 +/- 0.8, 0.8 +/- 0.9, or 2.0 +/- 0.9%, disclosing the antioxidant capacity of these drugs. Systemic application of 80 mg/kg alpha-lipoic acid elicited heat-loss reactions within 15 min and decreased core temperature by 2.2 +/- 0.3 degrees C within 2 h. Alpha-lipoic acid applied 45 min after LPS induced antipyresis within 15 min, and this antipyresis was associated with a decrease of elevated hydroperoxide levels and restoration of catalase activity. Our results show that fever is prevented when the production of reactive oxygen species is blocked and that an elevated body temperature returns to normal when oxygen radical production decreases. Estimation of plasma dihydrolipoic acid (DHLA) levels following injection of 80 mg/kg alpha-lipoic acid in afebrile and febrile rabbits revealed that this acid is converted into DHLA, which in afebrile rabbits increased the plasma DHLA concentration from 2.22 +/- 0.26 microg/ml to peak values of 8.60 +/- 2.28 microg/ml DHLA within 30 min and which in febrile rabbits increased it from 0.84 +/- 0.22 microg/ml to peak values of 3.90 +/- 0.94 microg/ml within 15 min. Methylene blue, aspirin, and alpha-lipoic acid, which all cross the blood-brain barrier, seem to act not only on peripheral tissues but also on the CNS. Brain structures that have been shown to sense oxidative stress are vicinal thiol groups attached to the NMDA subtype of glutamate receptor. Their reduction by thiol-reducing drugs like dithiothreitol or DHLA has been found to increase glutamate-mediated neuronal excitability, while the opposite effect has been observed after their oxidation. Because we found that systemic application of alpha-lipoic acid in the afebrile state elicits hypothermia and in the febrile state is antipyretic, we think this type of NMDA receptor is involved in thermoregulation and that oxidation of its thiol groups induces fever. It appears that temperature homeostasis can be maintained only if the redox homeostasis of the brain is guaranteed.
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PMID:Inhibition of oxygen radical formation by methylene blue, aspirin, or alpha-lipoic acid, prevents bacterial-lipopolysaccharide-induced fever. 1284 35

Interleukin-1 receptor antagonist (IL-1ra) is an important anti-inflammatory cytokine that blocks all known actions of IL-1 and markedly protects against experimentally induced ischemic, excitotoxic, and traumatic brain insults. Cannabinoids (CBs) also exert potent anti-inflammatory and neuroprotective effects, but the mechanisms of their actions are unknown. Here we tested the hypothesis that the actions of CBs are mediated by endogenous IL-1ra. We report for the first time that both CB1 and CB2 receptors modulate release of endogenous IL-1ra from primary cultured glial cells. Activation of CB1 or CB2 receptors increased lipopolysaccharide-induced IL-1ra release, and specific CB1 or CB2 antagonists blocked lipopolysaccharide-induced production of IL-1ra from glial cells. Comparison of neuronal cultures from wild-type mice and mice lacking IL-1ra (knock-out) indicates that endogenous IL-1ra is essential for the neuro-protective effects of CBs against excessive activation of glutamate receptors (excitotoxicity) in response to S-AMPA or NMDA. Similarly, analysis of mixed glial cultures from IL-1ra knock-out mice indicates that endogenous IL-1ra is required for the CB-induced inhibition of nitric oxide production in response to bacterial lipopolysaccharide. These data suggest a novel neuroprotective mechanism of action for CBs in response to inflammatory or excitotoxic insults that is mediated by both CB1 and CB2 receptor-dependent pathways.
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PMID:Endogenous interleukin-1 receptor antagonist mediates anti-inflammatory and neuroprotective actions of cannabinoids in neurons and glia. 1287 87

The aim of this study was to determine whether glutamate receptors modulate the innate immune response in the brain of C3H/HeN and C3H/HeJ mice; the latter bear a loss of function in the toll-like receptor (TLR) 4 gene. Mice received an intrastriatal (IS) infusion of lipopolysaccharide (LPS), the exogenous ligand for TLR4, and were killed at several times thereafter. This treatment activated the transcription of a wide variety of genes involved in the control of the innate immune response. MK-801, an antagonist of NMDA glutamate receptor subtype, exacerbated the effects of the endotoxin in the brain of C3H/HeN mice but not in TLR4-deficient animals. The ipsilateral side of C3H/HeN mice exhibited stronger hybridization signals for the mRNA encoding TLR2, CD14, tumor necrosis factor-alpha, and inhibitory factor-kappaBalpha at various times after the treatment combining MK-801 and LPS. This robust inflammatory response in the brain of C3H/HeN mice was not associated with any convincing signs of neurodegeneration or demyelination that was verified via numerous approaches and at time up to 2 weeks after injection. However, animals that received long-term IS infusion of LPS, together with MK-801, exhibited a significant increase in demyelination levels within the ipsilateral side. Our results demonstrate that binding of glutamate to its cognate NMDA receptor modulates LPS-induced innate immune reaction in a TLR4-dependent manner. This acute response may be crucial to eliminate bacterial cell wall components and minimizing tissue injury. However, sustained deregulation of proinflammatory signaling involving NMDA receptors leads to demyelination and is likely to be a mechanism participating in such pathological conditions.
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PMID:Modulation of the innate immune response by NMDA receptors has neuropathological consequences. 1465 67

Patients with lupus (SLE) experience progressive cognitive loss without evidence of CNS vascular disease or inflammation. SLE patients produce anti-DNA antibodies that crossreact with NMDA receptors and are capable of mediating excitotoxic death. We now show that mice induced by antigen to express these antibodies have no neuronal damage until breakdown of the blood-brain barrier occurs. Following administration of lipopolysaccharide (LPS) to immunized mice, antibodies gain access to the brain. They bind preferentially to hippocampal neurons and cause neuronal death with resulting cognitive dysfunction and altered hippocampal metabolism on magnetic resonance spectroscopy. Memantine, an NMDA receptor antagonist, given prior to LPS administration, prevents neuronal damage. Thus, systemic immune responses can cause cognitive impairment in the absence of an inflammatory cascade, implicating the immune system in yet another arena of human pathobiology. Furthermore, NMDA receptor antagonists prevent antibody-mediated damage and may constitute a new approach to therapy in SLE.
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PMID:Cognition and immunity; antibody impairs memory. 1530 99

Intraperitoneal (i.p.) injection of toxins, such as the bacterial endotoxin lipopolysaccharide (LPS), is associated with a well-characterized increase in sensitivity to painful stimuli (hyperalgesia) [Watkins LR, Maier SF, Goehler LE. Immune activation: the role of pro-inflammatory cytokines in inflammation, illness responses and pathological pain states. Pain 1995;63:289-302. [53]] and a longer-lasting reduction in opioid analgesia (anti-analgesia) when pain sensitivity returns to basal levels [Johnston IN, Westbrook RF. Acute and conditioned sickness reduces morphine analgesia. Behav Brain Res 2003;142:89-97]. Here we show that this inhibition of morphine analgesia 24 h after a single i.p. injection of LPS involves mechanisms that contribute to illness-induced hyperalgesia and the development of analgesic tolerance to morphine. Specifically, morphine analgesia was restored if LPS was preceded by systemic administration of a non-competitive NMDA receptor antagonist (MK-801), spinal infusion of a glial metabolic inhibitor (fluorocitrate), or intracerebroventricular microinjection of an opioid receptor antagonist (naloxone). Morphine analgesia was also restored if MK-801 was administered after LPS. These results demonstrate that LPS recruits similar, if not the same mechanisms that reduce morphine tolerance following opiate administration: namely, stimulation of opioid and NMDA receptors and recruitment of spinal glia.
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PMID:Inhibition of morphine analgesia by LPS: role of opioid and NMDA receptors and spinal glia. 1547 52

Serine racemase (SRace) is an enzyme that catalyzes the conversion of L-serine to pyruvate or D-serine, an endogenous agonist for NMDA receptors. Our previous studies showed that inflammatory stimuli such as Abeta could elevate steady-state mRNA levels for SRace, perhaps leading to inappropriate glutamatergic stimulation under conditions of inflammation. We report here that a proinflammatory stimulus (lipopolysaccharide) elevated the activity of the human SRace promoter, as indicated by expression of a luciferase reporter system transfected into a microglial cell line. This effect corresponded to an elevation of SRace protein levels in microglia, as well. By contrast, dexamethasone inhibited the SRace promoter activity and led to an apparent suppression of SRace steady-state mRNA levels. A potential binding site for NFkappaB was explored, but this sequence played no significant role in SRace promoter activation. Instead, large deletions and site-directed mutagenesis indicated that a DNA element between -1382 and -1373 (relative to the start of translation) was responsible for the activation of the promoter by lipopolysaccharide. This region fits the consensus for an activator protein-1 binding site. Lipopolysaccharide induced an activity capable of binding this DNA element in electrophoretic mobility shift assays. Supershifts with antibodies against c-Fos and JunB identified these as the responsible proteins. An inhibitor of Jun N-terminal kinase blocked SRace promoter activation, further implicating activator protein-1. These data indicate that proinflammatory stimuli utilize a signal transduction pathway culminating in activator protein-1 activation to induce expression of serine racemase.
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PMID:Induction of serine racemase by inflammatory stimuli is dependent on AP-1. 1568 5

Neuroinflammation has been suggested to play an integral role in the pathophysiology of various neurodegenerative diseases. Bacterial lipopolysaccharide (LPS) endotoxins are general activators of immune-cells, including microglial cells, which induce expression of pro-inflammatory factors. The aim of this study was to characterize neurodegenerative effects of exposure to LPS, derived from Salmonella abortus equi bacteria, in an in vitro brain slice culture system. Quasi-monolayer cultures were obtained using roller-drum incubations of hippocampal slices from neonatal Sprague Dawley rats for three weeks. Microglia/macrophages were identified in the monolayer cultures by CD11b immunostaining, while neuronal populations identified included N-methyl-D-aspartate (NMDA-R1) receptor immunoreactive pyramidal neurons and smaller GABA-immunoreactive cells. Following exposure to LPS (100 ng/ml) an increased density of CD11b positive cells was found in the cultures. In addition, the LPS exposure produced a concentration-dependent loss of the NMDA-R1 immunoreactive neurons in the cultures which was substantial at 100 ng/ml LPS. The loss of NMDA-R1 cells was apparent already after 24 h exposure to LPS and seemed to be primarily due to necrotic-like cell death. However, a continued loss of cells was found when cultures were analyzed at 72 h, concomitant with an increase in the expression of p53 in the NMDA-R1 cells and TUNEL labeling of a few cells. Also the number of GABA-immunoreactive cells decreased rapidly and to a substantial extent after 24 h exposure to LPS, with a continued decrease up to 72 h. The findings show that Salmonella LPS increases the density of CD11b positive cells and acts as a potent neurotoxin in hippocampal roller-drum slice cultures. The LPS-induced neurodegeneration has both necrotic- and apoptotic-like properties and appears to be non-selective, affecting both pyramidal and GABA neurons. LPS-induced neurotoxicity in slice cultures may be a useful system to study processes involved in inflammatory-mediated neurodegeneration.
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PMID:Salmonella lipopolysaccharide (LPS) mediated neurodegeneration in hippocampal slice cultures. 1637 15

Microglia are the resident immune cells of the brain, and they are under permanent activity to patrol the cerebral microenvironment. A proper inhibitory feedback onto these cells is critical during both intact and injury conditions. In this issue of Neuron, Eljaschewitsch and colleagues report that such feedback is provided by the endogenous cannabinoid anandamine and CB(1/2) receptor signaling, which ultimately leads to mitogen-activated protein kinase phosphatase-1 (MKP-1) induction. MKP-1 interferes with lipopolysaccharide-induced toll-like receptor 4 signaling and limits brain damage due to exaggerated microglial reactivity following acute NMDA injury.
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PMID:Cannabinoids in microglia: a new trick for immune surveillance and neuroprotection. 1638 40

Protein tyrosine nitration may be relevant for the pathogenesis of hepatic encephalopathy (HE). Infections, sepsis, and trauma precipitate HE episodes. Recently, serum levels of tumor necrosis factor (TNF)-alpha were shown to correlate with severity of HE in chronic liver failure. Here the effects of inflammatory cytokines on protein tyrosine nitration in cultured rat astrocytes and rat brain in vivo were studied. In cultured rat astrocytes TNF-alpha (50 pg/ml-10 ng/ml) within 6h increased protein tyrosine nitration. TNF-alpha-induced tyrosine nitration was related to an increased formation of reactive oxygen and nitrogen intermediates, which was downstream from a NMDA-receptor-dependent increase of intracellular [Ca(2+)](i) and nNOS-catalyzed NO production. Astroglial tyrosine nitration was also elevated in brains of rats receiving a non-lethal injection of lipopolysaccharide, as indicated by colocalization of nitrotyrosine immunoreactivity with glial fibrillary acidic protein and glutamine synthetase, and by identification of the glutamine synthetase among the tyrosine-nitrated proteins. It is concluded that reactive oxygen and nitrogen intermediates as well as protein tyrosine nitration by inflammatory cytokines may alter astrocyte function in an NMDA-receptor-, Ca(2+)-, and NOS-dependent fashion. This may be relevant for the pathogenesis of HE and other conditions involving cytokine exposure the brain.
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PMID:Inflammatory cytokines induce protein tyrosine nitration in rat astrocytes. 1657 53


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