The Protective Properties of New Agonists of FPR2 on the Evoked by Bacterial Endotoxin Changes in Microglia Cells (original) (raw)
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Prolonged or excessive microglial activation may lead to disturbances in the resolution of inflammation (RoI). The importance of specialized pro-resolving lipid mediators (SPMs) in RoI has been highlighted. Among them, lipoxins (LXA4) and aspirin-triggered lipoxin A4 (AT-LXA4) mediate beneficial responses through the activation of N-formyl peptide receptor-2 (FPR2). We aimed to shed more light on the time-dependent protective and anti-inflammatory impact of the endogenous SPMs, LXA4, and AT-LXA4, and of a new synthetic FPR2 agonist MR-39, in lipopolysaccharide (LPS)-exposed rat microglial cells. Our results showed that LXA4, AT-LXA4, and MR-39 exhibit a protective and pro-resolving potential in LPS-stimulated microglia, even if marked differences were apparent regarding the time dependency and efficacy of inhibiting particular biomarkers. The LXA4 action was found mainly after 3 h of LPS stimulation, and the AT-LXA4 effect was varied in time, while MR-39′s effect was mainly observed...
Neurobiology of disease, 2017
Maternal infection is a risk factor for periventricular leukomalacia and cerebral palsy (CP) in neonates. We have previously demonstrated hypomyelination and motor deficits in newborn rabbits, as seen in patients with cerebral palsy, following maternal intrauterine endotoxin administration. This was associated with increased microglial activation, primarily involving the periventricular region (PVR). In this study we hypothesized that maternal intrauterine inflammation leads to a pro-inflammatory environment in the PVR that is associated with microglial activation in the first 2 postnatal weeks. Timed pregnant New Zealand white rabbits underwent laparotomy on gestational day 28 (G28). They were randomly divided to receive lipopolysaccharide (LPS; 20μg/kg in 1mL saline) (Endotoxin group) or saline (1mL) (control saline, CS group), administrated along the wall of the uterus. The PVR from the CS and Endotoxin kits were harvested at G29 (1day post-injury), postnatal day1 (PND1, 3day pos...
Journal of Nuclear Medicine, 2007
Intrauterine infection can lead to a fetal inflammatory response syndrome that has been implicated as one of the causes of perinatal brain injury leading to periventricular leukomalacia (PVL) and cerebral palsy. The presence of activated microglial cells has been noted in autopsy specimens of patients with PVL and in models of neonatal hypoxia and ischemia. Activated microglial cells can cause oligodendrocyte damage and white matter injury by release of inflammatory cytokines and production of excitotoxic metabolites. We hypothesized that exposure to endotoxin in utero leads to microglial activation in the fetal brain that can be monitored in vivo by 11 C-(R)-PK11195 (1-[2-chlorophenyl]-N-methyl-N-[1-methylpropyl]-3-isoquinoline carboxamide)-a positron-emitting ligand that binds peripheral benzodiazepine receptor sites in activated microglia-using small-animal PET. Methods: Pregnant New Zealand White rabbits underwent laparotomy and were injected with 20 and 30 mg/kg of Escherichia coli lipopolysaccharide along the length of the uterus on day 28 of gestation. The pups were born spontaneously at term (31 d) and were scanned using small-animal PET after intravenous administration of 11 C-(R)-PK11195 and by MRI on postnatal day 1. The standard uptake values (SUVs) of the tracer were calculated for the whole brain at 10-min intervals for 60 min after tracer injection. The pups were euthanized after the scan, and brains were fixed, sectioned, and stained for microglial cells using biotinylated tomato lectin. Results: There was increased brain retention of 11 C-(R)-PK11195-as determined by a significant difference in the slope of the SUV over time-in the endotoxintreated pups when compared with that of age-matched controls. Immunohistochemical staining showed dose-dependent changes in activated microglia (increased number and morphologic changes) in the periventricular region and hippocampus of the brain of newborn rabbit pups exposed to endotoxin in utero. Conclusion: Intrauterine inflammation leads to activation of microglial cells that may be responsible for the development of brain injury and white matter damage in the perinatal period. PET with the tracer 11 C-(R)-PK11195 can be used as a noninvasive, sensitive tool for determining the presence and progress of neuroinflammation due to perinatal insults in newborns.
2013
Microglial cells express a peculiar plasma membrane receptor for extracellular ATP, named P2Z/P2X 7 purinergic receptor, that triggers massive transmembrane ion fluxes and a reversible permeabilization of the plasma membrane to hydrophylic molecules of up to 900 dalton molecule weight and eventual cell death (Di Virgilio, F. 1995. Immunol. Today. 16:524–528). The physiological role of this newly cloned (Surprenant, A., F. Rassendren, E. Kawashima, R.A. North and G. Buell. 1996. Science (Wash. DC). 272:735–737) cytolytic receptor is unknown. In vitro and in vivo activation of the macrophage and microglial cell P2Z/P2X 7 receptor by exogenous ATP causes a large and rapid release of mature IL-1�. In the present report we investigated the role of microglial P2Z/P2X 7 receptor in IL-1 � release triggered by LPS. Our data suggest that LPS-dependent IL-1 � release involves activation of this purinergic receptor as it is inhibited by the selective P2Z/P2X 7 blocker oxidized ATP and modulate...
Journal of Experimental Medicine, 1997
Microglial cells express a peculiar plasma membrane receptor for extracellular ATP, named P2Z/P2X7 purinergic receptor, that triggers massive transmembrane ion fluxes and a reversible permeabilization of the plasma membrane to hydrophylic molecules of up to 900 dalton molecule weight and eventual cell death (Di Virgilio, F. 1995. Immunol. Today. 16:524–528). The physiological role of this newly cloned (Surprenant, A., F. Rassendren, E. Kawashima, R.A. North and G. Buell. 1996. Science (Wash. DC). 272:735–737) cytolytic receptor is unknown. In vitro and in vivo activation of the macrophage and microglial cell P2Z/P2X7 receptor by exogenous ATP causes a large and rapid release of mature IL-1β. In the present report we investigated the role of microglial P2Z/P2X7 receptor in IL-1β release triggered by LPS. Our data suggest that LPS-dependent IL-1β release involves activation of this purinergic receptor as it is inhibited by the selective P2Z/P2X7 blocker oxidized ATP and modulated by A...
Neuropharmacological agents modifying endotoxin-induced changes in mice
Journal of the Royal Society of Medicine, 1980
A variety of neuropharmacological agents were tested to elucidate how chlorpromazine influenced an endotoxin-induced reaction. The results obtained, particularly with beta-adrenergic blocking agents, reserpine and fusaric acid, suggested that the primary locus of chlorpromazine's action was mediated by peripheral beta-adrenergic receptor blockade. Such a locus is compatible with the low doses of propranolol which suppress the reaction, and with successful treatment of shock with dopamine.
International Immunopharmacology, 2019
Over-activation of microglia disrupts the physiological homeostasis of the brain, and induces inflammatory response and other processes which are implicated in neurodegenerative diseases. Therefore, theoretically, suppression of neuroinflammation would slow the progression of neurodegenerative disease. In this study, we investigated the possible protective effects of Ferulic acid (FA) against benzo(a)pyrene (BaP)-induced microglial activation using BV2 cells as the model system. Exposure of BV2 cells to BaP (10 μM) significantly increased DNA damage and the production of pro-inflammatory mediators, including nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), reactive oxygen species (ROS), malondialdehyde (MDA), and cytokines (interleukins-1β and −6). On the other hand, when BaP-treated BV2 cells were further incubated with FA (10, 20, 40, or 80 mg/mL) for another 24 h, a significant reduction in BaP-induced DNA damage and the release of multiple pro-inflammatory and cytotoxic factors (including interleukin-1β, interleukin-6, NO, and ROS) was observed in a dose-dependent manner. Further study revealed that the microglial NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) signaling pathway was involved in the protective effect of FA. Taken together, these results suggested that FA suppressed BaP-induced toxicity in microglia, and thus may exert neuroprotective effects by inhibiting microglia-mediated pro-inflammatory response.
Journal of Experimental Medicine, 1997
Microglial cells express a peculiar plasma membrane receptor for extracellular ATP, named P2Z/P2X 7 purinergic receptor, that triggers massive transmembrane ion fluxes and a reversible permeabilization of the plasma membrane to hydrophylic molecules of up to 900 dalton molecule weight and eventual cell death (Di Virgilio, F. 1995. Immunol. Today. 16:524-528). The physiological role of this newly cloned (Surprenant, A., F. Rassendren, E. Kawashima, R.A. North and G. Buell. 1996. Science (Wash. DC). 272:735-737) cytolytic receptor is unknown. In vitro and in vivo activation of the macrophage and microglial cell P2Z/P2X 7 receptor by exogenous ATP causes a large and rapid release of mature IL-1  . In the present report we investigated the role of microglial P2Z/P2X 7 receptor in IL-1  release triggered by LPS. Our data suggest that LPS-dependent IL-1  release involves activation of this purinergic receptor as it is inhibited by the selective P2Z/P2X 7 blocker oxidized ATP and modulated by ATP-hydrolyzing enzymes such as apyrase or hexokinase. Furthermore, microglial cells release ATP when stimulated with LPS. LPS-dependent release of ATP is also observed in monocyte-derived human macrophages. It is suggested that bacterial endotoxin activates an autocrine/paracrine loop that drives ATP-dependent IL-1  secretion.
The Endogenous Estrogen Status Regulates Microglia Reactivity in Animal Models of Neuroinflammation
Endocrinology, 2006
It has been previously demonstrated that 17β-estradiol (E 2 ) inhibits the response of microglia, the resident brain macrophages, to acute injuries in specific brain regions. We here show that the effect of E 2 in acute brain inflammation is widespread and that the hormone reduces the expression of inflammatory mediators, such as MCP-1, MIP-2 and TNF-α, induced by LPS, demonstrating that microglia are a direct target of estrogen action in brain. Using the APP23 mice, an animal model of Alzheimer's Disease reproducing chronic neuroinflammation, we demonstrate that ovary ablation (ovx) increases microglia activation at β-amyloid (Aβ) deposits and facilitates the progression of these cells towards a highly reactive state. Long-term administration of E 2 reverts the effects of ovx and decreases microglia reactivity as compared to control animals. In this animal model, these events do not correlate with a reduced number of Aβ deposits.