Endogenous level of TIGAR in brain is associated with vulnerability of neurons to ischemic injury.
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ABSTRACT:
SUBMITTER: Cao L
PROVIDER: S-EPMC5563678 | biostudies-other | 2015 Oct
REPOSITORIES: biostudies-other
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Project description:Exposure to low-dose lipopolysaccharide (LPS) before cerebral ischemia is neuroprotective in stroke models, a phenomenon termed preconditioning (PC). Although it is well established that LPS-PC induces central and peripheral immune responses, the cellular mechanisms modulating ischemic injury remain unclear. Here, we investigated the role of immune cells in the brain protection afforded by PC and tested whether monocytes may be reprogrammed by ex vivo LPS exposure, thus modulating inflammatory injury after cerebral ischemia in male mice. We found that systemic injection of low-dose LPS induces a Ly6Chi monocyte response that protects the brain after transient middle cerebral artery occlusion (MCAO) in mice. Remarkably, adoptive transfer of monocytes isolated from preconditioned mice into naive mice 7 h after transient MCAO reduced brain injury. Gene expression and functional studies showed that IL-10, inducible nitric oxide synthase, and CCR2 in monocytes are essential for neuroprotection. This protective activity was elicited even if mouse or human monocytes were exposed ex vivo to LPS and then injected into male mice after stroke. Cell-tracking studies showed that protective monocytes are mobilized from the spleen and reach the brain and meninges, where they suppress postischemic inflammation and neutrophil influx into the brain parenchyma. Our findings unveil a previously unrecognized subpopulation of splenic monocytes capable of protecting the brain with an extended therapeutic window and provide the rationale for cell therapies based on the delivery of autologous or allogeneic protective monocytes in patients after ischemic stroke.SIGNIFICANCE STATEMENT Inflammation is a key component of the pathophysiology of the brain in stroke, a leading cause of death and disability with limited therapeutic options. Here, we investigate endogenous mechanisms of protection against cerebral ischemia. Using lipopolysaccharide (LPS) preconditioning (PC) as an approach to induce ischemic tolerance in mice, we found generation of neuroprotective monocytes within the spleen, from which they traffic to the brain and meninges, suppressing postischemic inflammation. Importantly, systemic LPS-PC can be mimicked by adoptive transfer of in vitro-preconditioned mouse or human monocytes at translational relevant time points after stroke. This model of neuroprotection may facilitate clinical efforts to increase the efficacy of BM mononuclear cell treatments in acute neurological diseases such as cerebral ischemia.
| S-EPMC6067076 | biostudies-literature
Project description:Microglia are resident CNS immune cells that are active sensors in healthy brain and versatile effectors under pathological conditions. Cerebral ischemia induces a robust neuroinflammatory response that includes marked changes in the gene expression and phenotypic profile of a variety of endogenous CNS cell types (astrocytes, neurons, microglia) as well as an influx of leukocytic cells (neutrophils, macrophages, T-cells) from the periphery. Many molecules and conditions can trigger a transformation of ârestingâ (or surveying) microglia to an âactivatedâ (alerted/reactive) state. Here we review recent developments in the literature that relate to microglial activation in the experimental setting of in vitro and in vivo ischemia. We also present new data from our own laboratory demonstrating the direct effects of in vitro ischemic conditions on the microglial phenotype and genomic profile. Emphasis is placed on the role of specific molecular signaling systems such as hypoxia inducible factor-1 (HIF-1) and toll-like receptor-4 (TLR4) in regulating the microglial response in this setting. We then review histological and recent novel radiological data that confirms a key role for microglial activation in the setting of ischemic stroke in humans. We discuss recent progress in the pharmacological and molecular targeting of microglia in acute ischemic stroke. Finally, we explore how recent studies on ischemic preconditioning have increased interest in preemptively targeting microglial activation in order to reduce stroke severity. 12 arrays, 4 experimental groups, 3 replicates in each group, CN is control normoxia, CH is control hypoxia, TN is TLR4 knockout normoxia, TH is TLR4 knockout hypoxia.
2010-10-05 | E-GEOD-18602 | biostudies-arrayexpress
Project description:Gestational hypoxia is a common stress to the fetal development and increases the risk of neonatal morbidity. The present study tested the hypothesis that fetal hypoxia results in heightened brain vulnerability to hypoxic-ischemic (HI) injury in neonatal rats via down-regulation of glucocorticoid receptor (GR) in the developing brain. Time-dated pregnant rats were exposed to hypoxia (10.5% O2) from days 15 to 21 of gestation. Brain HI injury was determined in day 10 pups. Maternal hypoxia resulted in asymmetric intrauterine growth restriction in the fetus. The brain HI injury was significantly increased in maternal hypoxia-treated pups as compared with the normoxia control in both males and females. Activation of brain GR by dexamethasone injection into the right lateral ventricle produced a concentration-dependent reduction of HI-induced brain injury in control pups. Maternal hypoxia significantly decreased GR mRNA and protein abundance in the fetal brain and neonatal hippocampus and abolished the dexamethasone-mediated neuroprotective effect in pup brains. This decreased GR expression was resulted from increased DNA methylation, decreased binding of transcription factors Egr-1 and Sp1 to GR gene exon 17 and 111 promoters, and reduced expression of GR exon 17 and 111 mRNA variants. The results demonstrate that gestational hypoxia causes epigenetic repression of GR gene expression in the developing brain resulting in the heightened brain vulnerability to HI injury in neonatal rats.
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Project description:Neutrophilic inflammation might have a pathophysiological role in both carotid plaque rupture and ischemic stroke injury. Here, we investigated the potential benefits of the CXC chemokine-binding protein Evasin-3, which potently inhibits chemokine bioactivity and related neutrophilic inflammation in two mouse models of carotid atherosclerosis and ischemic stroke, respectively. In the first model, the chronic treatment with Evasin-3 as compared with Vehicle (phosphate-buffered saline (PBS)) was investigated in apolipoprotein E-deficient mice implanted of a 'cast' carotid device. In the second model, acute Evasin-3 treatment (5 minutes after cerebral ischemia onset) was assessed in mice subjected to transient left middle cerebral artery occlusion. Although CXCL1 and CXCL2 were upregulated in both atherosclerotic plaques and infarcted brain, only CXCL1 was detectable in serum. In carotid atherosclerosis, treatment with Evasin-3 was associated with reduction in intraplaque neutrophil and matrix metalloproteinase-9 content and weak increase in collagen as compared with Vehicle. In ischemic stroke, treatment with Evasin-3 was associated with reduction in ischemic brain neutrophil infiltration and protective oxidants. No other effects in clinical and histological outcomes were observed. We concluded that Evasin-3 treatment was associated with reduction in neutrophilic inflammation in both mouse models. However, Evasin-3 administration after cerebral ischemia onset failed to improve poststroke outcomes.
| S-EPMC3618389 | biostudies-literature
Project description:Microglia are resident CNS immune cells that are active sensors in healthy brain and versatile effectors under pathological conditions. Cerebral ischemia induces a robust neuroinflammatory response that includes marked changes in the gene expression and phenotypic profile of a variety of endogenous CNS cell types (astrocytes, neurons, microglia) as well as an influx of leukocytic cells (neutrophils, macrophages, T-cells) from the periphery. Many molecules and conditions can trigger a transformation of “resting” (or surveying) microglia to an “activated” (alerted/reactive) state. Here we review recent developments in the literature that relate to microglial activation in the experimental setting of in vitro and in vivo ischemia. We also present new data from our own laboratory demonstrating the direct effects of in vitro ischemic conditions on the microglial phenotype and genomic profile. Emphasis is placed on the role of specific molecular signaling systems such as hypoxia inducible factor-1 (HIF-1) and toll-like receptor-4 (TLR4) in regulating the microglial response in this setting. We then review histological and recent novel radiological data that confirms a key role for microglial activation in the setting of ischemic stroke in humans. We discuss recent progress in the pharmacological and molecular targeting of microglia in acute ischemic stroke. Finally, we explore how recent studies on ischemic preconditioning have increased interest in preemptively targeting microglial activation in order to reduce stroke severity.
2010-10-05 | GSE18602 | GEO
Project description:Background and purposeMaternal cigarette smoking increases the risk of neonatal morbidity. We tested the hypothesis that perinatal nicotine exposure causes heightened brain vulnerability to hypoxic-ischemic (HI) injury in neonatal rats through aberrant expression patterns of angiotensin II type 1 (AT(1)R) and type 2 (AT(2)R) receptors in the developing brain.MethodsNicotine was administered to pregnant rats through subcutaneous osmotic minipumps. HI brain injury was determined in 10-day-old pups. AT(1)R and AT(2)R expression patterns were assessed through Western blotting, quantitative polymerase chain reaction, immunofluorescence, and confocal imaging.ResultsPerinatal nicotine exposure significantly increased HI brain infarct size in male, but not female, pups. In fetal brains, nicotine caused a decrease in mRNA and protein abundance of AT(2)R but not AT(1)R. The downregulation of AT(2)R persisted in brains of male pups, and nicotine treatment resulted in a significant increase in methylation of CpG locus 3 bases upstream of TATA-box at the AT(2)R gene promoter. In female brains, there was an increase in AT(2)R but a decrease in AT(1)R expression. Both AT(1)R and AT(2)R expressed in neurons but not in astrocytes in the cortex and hippocampus. Central application of AT(1)R antagonist losartan or AT(2)R antagonist PD123319 increased HI brain infarct size in both male and female pups. In male pups, AT(2)R agonist CGP42112 abrogated nicotine-induced increase in HI brain infarction. In females, PD123319 uncovered the nicotine's effect on HI brain infarction.ConclusionsPerinatal nicotine exposure causes epigenetic repression of the AT(2)R gene in the developing brain resulting in heightened brain vulnerability to HI injury in neonatal male rats in a sex-dependent manner.
| S-EPMC3429721 | biostudies-literature
Project description:Microglia are resident CNS immune cells that are active sensors in healthy brain and versatile effectors under pathological conditions. Cerebral ischemia induces a robust neuroinflammatory response that includes marked changes in the gene-expression profile and phenotype of a variety of endogenous CNS cell types (astrocytes, neurons and microglia), as well as an influx of leukocytic cells (neutrophils, macrophages and T-cells) from the periphery. Many molecules and conditions can trigger a transformation of surveying microglia to microglia of an alerted or reactive state. Here we review recent developments in the literature that relate to microglial activation in the experimental setting of in vitro and in vivo ischemia. We also present new data from our own laboratory demonstrating the direct effects of in vitro ischemic conditions on the microglial phenotype and genomic profile. In particular, we focus on the role of specific molecular signaling systems, such as hypoxia inducible factor-1 and Toll-like receptor-4, in regulating the microglial response in this setting. We then review histological and novel radiological data that confirm a key role for microglial activation in the setting of ischemic stroke in humans. We also discuss recent progress in the pharmacologic and molecular targeting of microglia in acute ischemic stroke. Finally, we explore how recent studies on ischemic preconditioning have increased interest in pre-emptively targeting microglial activation in order to reduce stroke severity.
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Project description:AimsBone morphogenetic proteins (BMPs) are a group of proteins related to bone morphogenesis. BMP-binding endothelial regulator (BMPER), a secreted protein that interacts with BMPs, is known to be involved in ischemic injuries. Here, we explored the effects of BMPER on cerebral ischemia and its mechanism of action.MethodsA mouse model of brain ischemia was induced by middle cerebral artery occlusion (MCAO). An in vitro ischemic model was established by subjecting primary cultured neurons to oxygen-glucose deprivation/reperfusion (OGD/R). Serum levels of BMPs/BMPER were measured in MCAO mice and in patients with acute ischemic stroke (AIS). Brain damages were compared between BMPER- and vehicle-treated mice. Quantitative polymerase chain reaction (qPCR), immunohistochemistry, and immunofluorescence staining were performed to examine neuroinflammation and cell death. BMPER-related pathways were assessed by Western blotting.ResultsBMPER level was elevated in MCAO mice and AIS patients. BMPER administration reduced mortality, infarct size, brain edema, and neurological deficit after MCAO. Neuroinflammation and cell death after ischemia were alleviated by BMPER both in vivo and in vitro. BMPER activated the Smad3/Akt/Nrf2 pathway in OGD/R-challenged neurons.ConclusionBMPER is a neuroprotective hormone that alleviates ischemic brain injury via activating the Smad3/Akt/Nrf2 pathway. These findings may provide potential therapeutic strategies for stroke.
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Project description:Peripheral nerve injury results in dramatic upregulation in pituitary adenylate cyclase activating polypeptide (PACAP) expression in adult rat dorsal root ganglia and spinal motor neurons mirroring that described for the neurotrophin brain derived neurotrophic factor (BDNF). Thus, we posited that injury-associated alterations in BDNF expression regulate the changes in PACAP expression observed in the injured neurons. The role of endogenous BDNF in induction and/or maintenance of PACAP mRNA expression in injured adult rat motor and sensory neurons was examined by intrathecally infusing or intraperitoneally injecting BDNF-specific antibodies or control IgGs immediately at the time of L4-L6 spinal nerve injury, or in a delayed fashion one week later for 3 days followed by analysis of impact on PACAP expression. PACAP mRNA in injured lumbar sensory and motor neurons was detected using in situ hybridization, allowing quantification of relative changes between experimental groups, with ATF-3 immunofluorescence serving to identify the injured subpopulation of motor neurons. Both the incidence and level of PACAP mRNA expression were dramatically reduced in injured sensory and motor neurons in response to immediate intrathecal anti-BDNF treatment. In contrast, neither intraperitoneal injections nor delayed intrathecal infusions of anti-BDNF had any discernible impact on PACAP expression. This impact on PACAP expression in response to BDNF immunoneutralization in DRG was confirmed using qRT-PCR or by using BDNF selective siRNAs to reduce neuronal BDNF expression. Collectively, our findings support that endogenous injury-associated BDNF expression is critically involved in induction, but not maintenance, of injury-associated PACAP expression in sensory and motor neurons.
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Project description:Hepatic grafts from non-heartbeating donors may alleviate the organ shortage, but they inherently suffer from warm ischemia. In the present study, we tested our hypothesis that augmentation of endogenous adenosine by inhibition of nucleoside transport with R75231 attenuates ischemic liver injury. Adult female beagle dogs underwent 2-hr hepatic vascular exclusion with venovenous bypass. R75231 was given to the animals by continuous intravenous infusion for 30 min before ischemia at a dose of 0.1 mg/kg (Group 2, n=6), 0.05 mg/kg (Group 3, n=6), or 0.025 mg/kg (Group 4, n=6). Nontreated animals were used as the control (Group 1, n= 10). Animal survival, hepatic tissue blood flow, liver function, and histopathology were analyzed. Two-week animal survival was 30% in Group 1, 83% in Group 2, 100% in Group 3, and 100% in Group 4. Postreperfusion hepatic tissue blood flow was markedly improved by the treatment. Treatment significantly attenuated liver enzyme release, lipid peroxidation, and changes in adenine nucleotides and purine catabolites. Structural abnormality of the liver after reperfusion was markedly improved by R75231 treatment, showing better architecture and less neutrophil infiltration. Preischemic administration of a nucleoside transport inhibitor ameliorated ischemic liver injury due to the positive effects of augmented endogenous adenosine, and is applicable clinically when the liver is procured from a controlled non-heartbeating donor.
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