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)

Nitric oxide (NO; 1 microM) or an NO donor (500 microM diethylenetriamine-nitric oxide, DETA-NONOate) caused rapid glutamate and ATP release from cultured rat cortical astrocytes. NO-induced glutamate release was prevented by calcium chelators (EGTA or BAPTA-AM) and an inhibitor of vesicular exocytosis (botulinum neurotoxin C, BoTx-C), but not by a glutamate transport inhibitor, L-trans-pyrrolidine-2,4-dicarboxylate (t-PDC), a cyclooxygenase inhibitor (indomethacin), or an inhibitor of soluble guanylate cyclase 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), and was not induced by mitochondrial respiratory inhibitors (myxothiazol or azide). Similarly to glutamate, NO-induced ATP release was also completely blocked by BAPTA-AM and BoTx-C, suggesting again a vesicular, calcium-dependent mechanism of release. Addition of DETA-NONOate (500 microM) to fura-2-loaded astrocytes induced a rapid, transient increase in intracellular calcium levels followed by a lower, sustained level of calcium entry. The latter was blocked by gadolinium (1 microM), an inhibitor of capacitative Ca(2+) entry. Thus, NO appears to cause rapid exocytosis of vesicular glutamate and ATP from astrocytes by raising intracellular calcium levels. Astrocytes activated by lipopolysaccharide/endotoxin and interferon-gamma to express inducible NO synthase (iNOS) maintained substantially higher extracellular glutamate levels than nonactivated cells or activated cells treated with an iNOS inhibitor (1400W), but the rate of glutamate uptake by these cells was similar. This suggests that NO from inflammatory-activated astrocytes causes release of astrocytic glutamate. NO-induced release of astrocytic glutamate and ATP may be important in physiological or pathological communication between astrocytes and neurons.
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PMID:Nitric oxide induces rapid, calcium-dependent release of vesicular glutamate and ATP from cultured rat astrocytes. 1242 Mar 11

The mrf-1 gene has been isolated from microglia exposed to cultured cerebellar granule neurons undergoing apoptosis. We have shown that mrf-1 is upregulated in response to neuronal death and degeneration both in vitro and in vivo. However, the exact role of MRF-1 remains unknown. Here we show that MRF-1 is released from cultured rat microglia, and its release is greatly enhanced under inflammatory conditions. When microglia were treated with ATP, the amount of MRF-1 that was released increased 10-fold compared to the basal level of release. Enhanced MRF-1 release was induced within 10 min and peaked within 1 h; after approximately 4 h, the MRF-1 release had returned to normal. MRF-1 release was stimulated by 2-methyl-thio-ATP (five-fold) and a P2X(7) selective agonist, 2'- and 3'-O-(4-benzoylbenzoyl)-ATP (ten-fold). Moreover, the ATP-stimulated MRF-1 release was inhibited by a P2X(7) selective antagonist, oxidized ATP (oATP), and also under a Ca(2+)-free condition. These results indicate that the effects of ATP are dependent on Ca(2+) influx through P2X(7) receptors. MRF-1 release was enhanced by Ca(2+)-ionophore A23187 (sixfold), thapsigargin (threefold); however, it was not enhanced by glutamate or lipopolysaccharide. Moreover, a platelet-activating factor enhanced microglial MRF-1 release in a dose-dependent manner. We also showed that a conditioned medium from cerebellar granule neurons undergoing apoptosis markedly increased MRF-1 release from microglia; that effect was significantly inhibited by oATP. These results indicate that selective inflammatory stimulations, including ATP and PAF, enhance MRF-1 release from microglia through a Ca(2+)-dependent mechanism and suggest that MRF-1 may play a role in cell-cell interactions under inflammatory conditions.
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PMID:Selective inflammatory stimulations enhance release of microglial response factor (MRF)-1 from cultured microglia. 1242 Mar 15

Inducible nitric oxide synthase (iNOS) plays a significant role in the pathology of central nervous system diseases. Inducible NOS expression is regulated by intracellular adenosine 3',5'-cyclic monophosphate (cAMP) signaling, and astrocytes contain both iNOS and adenylate cyclase-coupled neurotransmitter receptors. The data obtained from the present study indicated that acetylcholine, lambda-amino-n-butyric acid, glutamate, quinolinic acid, N-methyl-D-aspartate and aspartate have no effect on NO(2)(-) production in C6 glioma cells stimulated by lipopolysaccharide and interferon-gamma. However, dopamine (DA) caused inhibition of NO(2)(-) production and iNOS transcription. The effects of DA were not due to homovanillic acid/3,4-dihydroxyphenylacetic acid, the autoxidative products superoxide (O(2)(-))/hydrogen peroxide (H(2)O(2)) or direct reactions with NO(2)(-). Forskolin, adenylate cyclase activator, dose-dependently reduced NO(2)(-). Meanwhile, (+/-) SKF-38393 D(1) receptor agonist attenuated iNOS in a similar fashion to DA. In addition, the results indicated that DA attenuation of iNOS was significantly impeded by the adenylate cyclase inhibitor MDL-12,330A, the D(1) antagonist SCH-23390, the beta2 adrenergic receptor antagonist ICI-118,551 and the beta1 adrenergic receptor antagonist atenolol. In conclusion, it appears that DA attenuates iNOS through a D(1), beta1 and beta2 adrenergic receptor-linked adenylate cyclase-mediated cAMP cascade.
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PMID:Characterization of neurotransmitters and dopamine attenuation of inducible nitric oxide synthase in glioma cells. 1245 38

Bacterial endotoxin lipopolysaccharide (LPS) treatment of neuron-rich cells and glia-rich cells exhibited significant cell damage 12 hr after incubation, although no severe or significant cell damage induced by LPS appeared in neuron-glia co-cultured cells. Moreover, severe and significant time-dependent cell damage was induced by a larger dose treatment (10 mM) of glutamate (Glu), and this damage was seen in neuron-rich cells, neuron-glia co-cultured cells, and glia-rich cells. Examining extracellular tumor necrosis factor alpha (TNFalpha) induced by either LPS or Glu treatment, the levels of extracellular TNFalpha induced by LPS were significantly higher than those induced by Glu. These significant increases of TNFalpha were measured within 2 hr after LPS treatment in neuron-glia co-cultured cells and glia-rich cells, although no significant changes were detected in the neuron-rich cells. With Glu treatment, a significant increase in TNFalpha levels was detected after 6 hr of Glu treatment only in glia-rich cells. Our results indicate that cerebral TNFalpha is mainly produced in glia cells and that its production is dependently regulated by each stimulant. In addition, the production of TNFalpha is not directly related to the trigger of cell injury.
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PMID:Regulation of brain cell environment on neuronal protection: role of TNFalpha in glia cells. 1246 97

Glutamate release from microglial cells may cause neuronal damage. To elucidate the mechanism of glutamate release, we examined the possible regulation by nitric oxide and protein kinase C. Cultured microglia prepared from the whole brains of newborn rats released glutamate by the stimulation with lipopolysaccharide (LPS) dose dependently. The time course study revealed that glutamate release showed a long lag time about 6 h after LPS stimulation, whereas about 3 h lag time was observed in LPS-induced NO production. An inhibitor for NO synthase, N(G)-nitro-L-arginine, could effectively inhibit the glutamate release. Glutamate release induced by LPS was enhanced by 1 nM phorbol myristate acetate (PMA). Furthermore, high concentrations of PMA (>10 nM) induced glutamate release even without LPS stimulation. Glutamate release stimulated either by 100 ng/ml LPS or 100 nM PMA was inhibited by staurosporine, and also by alpha-aminoadipate. These results provide insight into the pathways regulating microglial pathological activation by protein kinase C and may be a base for the protection against microglia-evoked neurotoxicity.
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PMID:Involvement of protein kinase C in glutamate release from cultured microglia. 1254 62

Although glucose and protein metabolism have been investigated extensively in experimental models of hypodynamic sepsis, relatively little information is available regarding the compensated stage of sepsis. We investigated interorgan amino acid and glucose metabolism in a porcine model of compensated hyperdynamic sepsis. Fasting catheterized pigs received endotoxin ( Escherichia coli lipopolysaccharide; 3 microg.h(-1).kg(-1); intravenous) or saline (controls) and volume resuscitation over 24 h to reproduce hyperdynamic sepsis. Primed-constant infusions of p -aminohippurate and (3)H-labelled isotopes were used to measure glucose, amino acid and protein metabolism across the portal-drained viscera, liver and hindquarters (to represent muscle) at 0 and 24 h of endotoxaemia. Whole-body protein and glucose flux were increased during hyperdynamic compensated sepsis. In endotoxaemic pigs, visceral protein was conserved, and hindquarter protein breakdown exceeded the increase in liver protein synthesis, resulting in net whole-body protein loss. Endotoxaemia increased hindquarter and visceral glycolysis and branched-chain amino acid transamination. The rate of efflux of glutamine and alanine from the hindquarters was higher than anticipated from protein breakdown, indicating de novo synthesis of these amino acids during endotoxaemia. In addition to the hindquarters, the portal-drained viscera provided substantial gluconeogenic amino acids and lactate to the liver. Although increased liver glutamate release constitutes an important nitrogen-sparing mechanism and carbon skeletons are effectively being cycled in glucose, net body protein is lost through increased ureagenesis during the hyperdynamic stage of sepsis. Specific amino acid requirements may develop in compensated hyperdynamic sepsis that is characterized by maintained organ perfusion and increased substrate utilization at the expense of body protein.
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PMID:Aspects of organ protein, amino acid and glucose metabolism in a porcine model of hypermetabolic sepsis. 1254 35

A reduction in microglial activation and subsequent neurotoxicity may prove critical for neuroprotection in neurodegenerative diseases. We examined the expression and functionality of group III metabotropic glutamate (mGlu) receptors on microglia. Rat microglia express mRNA and receptor protein for group III mGlu receptors mGlu4, mGlu6, and mGlu8 but not mGlu7. Activation of these receptors on microglia with the specific group III agonists (L)-2-amino-4-phosphono-butyric acid (l-AP-4) or (R,S)-phosphonophenylglycine (RS-PPG) inhibited forskolin-induced cAMP production, linking these receptors to the negative inhibition of adenylate cyclase. These agonists did not induce a fall in mitochondrial membrane potential or apoptosis in the microglia, suggesting that activation of these receptors is not in itself toxic to microglia. Fluorescence-activated cell sorting analysis revealed that activation of group III mGlu receptors induces a mild activation of the microglia, as evidence by their enhanced staining with ED1. However, this activation is not neurotoxic. Agonists of group III mGlu receptors reduced microglial reactivity when they were activated with lipopolysaccharide (LPS), chromogranin A (CGA) or amyloid beta peptide 25-35 (Abeta25-35). Furthermore, l-AP-4 or RS-PPG treatment of microglia reduced their neurotoxicity after microglial stimulation with LPS or CGA but not Abeta25-35. Similar results were obtained with microglial conditioned medium or in coculture, suggesting that the activation of microglial group III mGlu receptors may modulate the production of stable neurotoxins from the microglia. These results suggest that selective modulation of microglial group III mGlu receptors may provide a therapeutic target in neuroinflammatory diseases such as Alzheimer's disease.
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PMID:Activation of microglial group III metabotropic glutamate receptors protects neurons against microglial neurotoxicity. 1265 74

It is presently unknown what types of neuronal signals maintain microglial cells resting in the normal brain or control their activation in neuropathology. Recent data suggest that microglia activation induces apoptosis and that healthy neurons are controllers of the activation state and immune functions of microglia. In the present study we have evaluated, on microglial cells in cultures, whether neurons are able to affect their survival in resting conditions or upon activation with the bacterial endotoxin, lipopolysaccharide (LPS). We report that neuron-conditioned culture media induced apoptosis of LPS-stimulated, but not of unstimulated, microglia. This effect was, however, only present when conditioned media had been exposed to differentiated neurons and not to immature ones, and was absent when glutamate receptors had been pharmacologically blocked in neuronal cultures. The effect was also blocked by heat-inactivation of the conditioned media. Media conditioned with either differentiated or undifferentiated cerebellar granule neurons positively affected the survival of unstimulated microglial cells when the standard concentration of fetal bovine serum (10%) was included in the culture media. Our results highlight the ability of differentiated neurons to maintain a controlled inflammatory state through production of factor(s) favoring the apoptotic elimination of activated microglia. They also suggest that immature neurons may, on the contrary, favor the survival of microglia during development.
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PMID:Neuron-conditioned media differentially affect the survival of activated or unstimulated microglia: evidence for neuronal control on apoptotic elimination of activated microglia. 1272 27

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


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