EphB2-dependent signaling promotes neuronal excitotoxicity and inflammation in the acute phase of ischemic stroke
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ABSTRACT:
PROVIDER: PRJNA493579 | ENA |
REPOSITORIES: ENA
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Project description:Local cerebral hypoperfusion causes ischemic stroke while driving multiple cell-specific responses including inflammation, glutamate-NMDAR-mediated neurotoxicity, edema formation and angiogenesis. Despite the relevance of these pathophysiological mechanisms for disease progression and outcome, molecular determinants controlling the onset of these processes are only partially understood. In this context, our study intended to investigate the functional role of EphB2 – a receptor tyrosine kinase that is crucial for synapse function and binds to membrane-associated ephrin-B ligands. Cerebral ischemia was induced in EphB2-deficient mice by transient middle cerebral artery occlusion followed by different times (6, 12, 24 and 48 h) of reperfusion. Histological, neurofunctional and transcriptome analyses indicated an increase in EphB2 phosphorylation under these conditions and attenuated progression of stroke in EphB2-deficient mice. Moreover, while infiltration of microglia/macrophages and astrocytes into the peri-infarct region was not altered, expression of the pro-inflammatory mediators MCP-1 or IL-6 was decreased in these mice. In fact, in vitro analyses indicated that binding of EphB2 to astrocytic ephrin-B ligands stimulates NF-κB-mediated cytokine expression via the MAPK pathway. Further magnetic resonance imaging of the EphB2-deficient ischemic brain revealed a lower level of neuronal cytotoxic edema formation within 6 h upon onset of reperfusion. On the mechanistic level, absence of neuronal EphB2 decreased the mitochondrial Ca2+ load upon activation of NMDAR but not AMPAR. Moreover, activation of EphB2 by ephrin-B2 enhanced the NMDA-evoked excitotoxic neuronal cell death in vitro while neuron-specific loss of ephrin-B2 reduced the extent of cerebral tissue damage in the acute phase of ischemic stroke. Collectively, EphB2 may promote the immediate response to an ischemia-reperfusion event in the central nervous system by (i) pro-inflammatory activation of astrocytes via ephrin-B-dependent signalling and (ii) amplification of the NMDA-evoked neuronal excitotoxicity.
2019-02-13 | GSE120565 | GEO
Project description:Local cerebral hypoperfusion causes ischemic stroke while driving multiple cell-specific responses including inflammation, glutamate-induced neurotoxicity mediated via NMDAR, edema formation and angiogenesis. Despite the relevance of these pathophysiological mechanisms for disease progression and outcome, molecular determinants controlling the onset of these processes are only partially understood. In this context, our study intended to investigate the functional role of EphB2, a receptor tyrosine kinase that is crucial for synapse function and binds to membrane-associated ephrin-B ligands.Cerebral ischemia was induced in Ephb2-/- mice by transient middle cerebral artery occlusion followed by different times (6, 12, 24 and 48 h) of reperfusion. Histological, neurofunctional and transcriptome analyses indicated an increase in EphB2 phosphorylation under these conditions and attenuated progression of stroke in Ephb2-/- mice. Moreover, while infiltration of microglia/macrophages and astrocytes into the peri-infarct region was not altered, expression of the pro-inflammatory mediators MCP-1 and IL-6 was decreased in these mice. In vitro analyses indicated that binding of EphB2 to astrocytic ephrin-B ligands stimulates NF-κB-mediated cytokine expression via the MAPK pathway. Further magnetic resonance imaging of the Ephb2-/- ischemic brain revealed a lower level of cytotoxic edema formation within 6 h upon onset of reperfusion. On the mechanistic level, absence of neuronal EphB2 decreased the mitochondrial Ca2+ load upon specific activation of NMDAR but not during synaptic activity. Furthermore, neuron-specific loss of ephrin-B2 reduced the extent of cerebral tissue damage in the acute phase of ischemic stroke.Collectively, EphB2 may promote the immediate response to an ischemia-reperfusion event in the central nervous system by (i) pro-inflammatory activation of astrocytes via ephrin-B-dependent signaling and (ii) amplification of NMDA-evoked neuronal excitotoxicity.
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Project description:Excitotoxicity is a primary pathological process directing neuronal cell death in both acute neurological disorders and neurodegenerative diseases such as ischemic stroke and Alzheimer’s disease. We use mouse cultured cortical neuron treated with 100uM of Glutamate for a model of excitotoxicity and applied N-terminomics (TAILS) method to identify the neuronal proteins aberrantly modified in excitotoxicity
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Project description:The purpose of this project was to elucidate gene expression in the peripheral whole blood of acute ischemic stroke patients to identify a panel of genes for the diagnosis of acute ischemic stroke. Peripheral blood samples were collected in Paxgene Blood RNA tubes from stroke patients who were >18 years of age with MRI diagnosed ischemic stroke and controls who were non-stroke neurologically healthy. The results suggest a panel of genes can be used to diagnose ischemic stroke, and provide information about the biological pathways involved in the response to acute ischemic stroke in humans. Total RNA extracted from whole blood in n=39 ischemic stroke patients compared to n=24 healthy control subjects.
2010-06-08 | E-GEOD-16561 | biostudies-arrayexpress
Project description:We performed a genome-wide methylation study in whole-blood DNA from 404 ischemic stroke patient cohort, distributed across 3 ischemic stroke subtypes: Large-artery atherosclerosis (n=132), Small-artery disease (n=141) and Cardio embolic (n=127) . Illumina HumanMethylation450 BeadChip array was used to measure DNA methylation in CpG sites. We performed a genome-wide methylation study in whole-blood DNA from 185 ischemic stroke patient cohort. Illumina HumanMethylation450 BeadChip array was used to measure DNA methylation in CpG sites.
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Project description:Analysis of astrocytic gene expression profiles after ischemic stroke. Stroke is a complicated disease caused by the interaction of multiple celltypes. Results provide new insights into the molecular mechanisms underlying astrocytic activation after ischemic stroke.
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Project description:Analysis of microglial gene expression profiles after ischemic stroke. Stroke is a complicated disease caused by the interaction of multiple celltypes. Results provide new insights into the molecular mechanisms underlying microglial activation after ischemic stroke.
2022-01-01 | GSE172456 | GEO
Project description:The purpose of this project was to elucidate gene expression in the peripheral whole blood of acute ischemic stroke patients to identify a panel of genes for the diagnosis of acute ischemic stroke. Peripheral blood samples were collected in Paxgene Blood RNA tubes from stroke patients who were >18 years of age with MRI diagnosed ischemic stroke and controls who were non-stroke neurologically healthy. The results suggest a panel of genes can be used to diagnose ischemic stroke, and provide information about the biological pathways involved in the response to acute ischemic stroke in humans.
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Project description:Ischemic Stroke Genetics Study (ISGS)
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Project description:Intermittent fasting is previously reported to exhibit neuroprotection against experimental ischemic stroke. However, the detailed understanding of protection mechanisms are lacking. By observing the overall transcriptomic changes in each timepoint of ischemic stroke would benefit the understanding of underlying active pathways and mechanisms. Here, we conduct experimental MCAO ischemic stroke on mice exposed to different daily intermittent fasting method to compare not only among the ischemic stroke timepoints but also the efficacy of different intermittent fasting interventions. Our current study presented the transcriptomic changes for the first time in specific timepoints of ischemic stroke as well as under the condition of intermittent fasting. A number of neuroprotective mechanisms-related genes were significantly affected by intermittent fasting conditions in differential manners.
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