scholarly journals A2B Adenosine Receptors: When Outsiders May Become an Attractive Target to Treat Brain Ischemia or Demyelination

2020 ◽  
Vol 21 (24) ◽  
pp. 9697
Author(s):  
Elisabetta Coppi ◽  
Ilaria Dettori ◽  
Federica Cherchi ◽  
Irene Bulli ◽  
Martina Venturini ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Brain Ischemia ◽  
Hippocampal Slices ◽  
Glucose Deprivation ◽  
Inflammatory Cells ◽  
Demyelinating Diseases ◽  
Receptor Subtype ◽  
Functional Impairments

Adenosine is a signaling molecule, which, by activating its receptors, acts as an important player after cerebral ischemia. Here, we review data in the literature describing A2BR-mediated effects in models of cerebral ischemia obtained in vivo by the occlusion of the middle cerebral artery (MCAo) or in vitro by oxygen-glucose deprivation (OGD) in hippocampal slices. Adenosine plays an apparently contradictory role in this receptor subtype depending on whether it is activated on neuro-glial cells or peripheral blood vessels and/or inflammatory cells after ischemia. Indeed, A2BRs participate in the early glutamate-mediated excitotoxicity responsible for neuronal and synaptic loss in the CA1 hippocampus. On the contrary, later after ischemia, the same receptors have a protective role in tissue damage and functional impairments, reducing inflammatory cell infiltration and neuroinflammation by central and/or peripheral mechanisms. Of note, demyelination following brain ischemia, or autoimmune neuroinflammatory reactions, are also profoundly affected by A2BRs since they are expressed by oligodendroglia where their activation inhibits cell maturation and expression of myelin-related proteins. In conclusion, data in the literature indicate the A2BRs as putative therapeutic targets for the still unmet treatment of stroke or demyelinating diseases.

scholarly journals LINGO-1 shRNA protects the brain against ischemia/reperfusion injury by inhibiting the activation of NF-κB and JAK2/STAT3

Human Cell ◽  
2021 ◽  
Author(s):  
Jiaying Zhu ◽  
Zhu Zhu ◽  
Yipin Ren ◽  
Yukang Dong ◽  
Yaqi Li ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Nuclear Translocation ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Mice Model ◽  
Down Regulation

AbstractLINGO-1 may be involved in the pathogenesis of cerebral ischemia. However, its biological function and underlying molecular mechanism in cerebral ischemia remain to be further defined. In our study, middle cerebral artery occlusion/reperfusion (MACO/R) mice model and HT22 cell oxygen–glucose deprivation/reperfusion (OGD/R) were established to simulate the pathological process of cerebral ischemia in vivo and in vitro and to detect the relevant mechanism. We found that LINGO-1 mRNA and protein were upregulated in mice and cell models. Down-regulation LINGO-1 improved the neurological symptoms and reduced pathological changes and the infarct size of the mice after MACO/R. In addition, LINGO-1 interference alleviated apoptosis and promoted cell proliferation in HT22 of OGD/R. Moreover, down-regulation of LINGO-1 proved to inhibit nuclear translocation of p-NF-κB and reduce the expression level of p-JAK2 and p-STAT3. In conclusion, our data suggest that shLINGO-1 attenuated ischemic injury by negatively regulating NF-KB and JAK2/STAT3 pathways, highlighting a novel therapeutic target for ischemic stroke.

scholarly journals The Rapid Decrease in Astrocyte-Associated Dystroglycan Expression by Focal Cerebral Ischemia is Protease-Dependent

2007 ◽  
Vol 28 (4) ◽  
pp. 812-823 ◽  
Author(s):  
Richard Milner ◽  
Stephanie Hung ◽  
Xiaoyun Wang ◽  
Maria Spatz ◽  
Gregory J del Zoppo
Keyword(s):  
Cerebral Ischemia ◽  
Basal Lamina ◽  
Focal Cerebral Ischemia ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Receptor Expression ◽  
Cerebral Microvessels ◽  
The Impact

During focal cerebral ischemia, the detachment of astrocytes from the microvascular basal lamina is not completely explained by known integrin receptor expression changes. Here, the impact of experimental ischemia (oxygen—glucose deprivation (OGD)) on dystroglycan expression by murine endothelial cells and astrocytes grown on vascular matrix laminin, perlecan, or collagen and the impact of middle cerebral artery occlusion on αβ-dystroglycan within cerebral microvessels of the nonhuman primate were examined. Dystroglycan was expressed on all cerebral microvessels in cortical gray and white matter, and the striatum. Astrocyte adhesion to basal lamina proteins was managed in part by α-dystroglycan, while ischemia significantly reduced expression of dystroglycan both in vivo and in vitro. Furthermore, dystroglycan and integrin α6β4 expressions on astrocyte end-feet decreased in parallel both in vivo and in vitro. The rapid loss of astrocyte dystroglycan during OGD appears protease-dependent, involving an matrix metalloproteinase-like activity. This may explain the rapid detachment of astrocytes from the microvascular basal lamina during ischemic injury, which could contribute to significant changes in microvascular integrity.

scholarly journals Mechanism of antrocytic connexin-43 autophagy degradation in oxygen-glucose deprivation and its effect on neuroinflammation

2019 ◽  
Author(s):  
Xinyu Wang ◽  
Liangshu Feng ◽  
Meiying Xin ◽  
Yulei Hao ◽  
Xu Wang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Connexin 43 ◽  
Cell Communication ◽  
Glucose Deprivation ◽  
In Vivo Model ◽  
Oxygen Glucose Deprivation ◽  
Cx43 Protein ◽  
Protein Levels

Abstract Background : Connexin 43 (Cx43) are the most widely distributed gap junction proteins in the nervous system. Cx43 enables cell-to-cell communication and plays an important role in ion transport, substrate exchange and delivery of information , which have been implicated in cerebral ischemia injury. Our previous work revealed the relationships between Cx43 and glia-mediated neuroinflammation through the release of ATP in oxygen-glucose deprivation (OGD), which means degradation of Cx43 may improve neuroinflammatory damage during OGD injury . However, the roles of Cx43 degradation and neuroinflammation caused by OGD remain unclear. Methods: We used primary cultured astrocytes treated with OGD as an in vitro model of cerebral ischemia injury and we used middle cerebral artery occlusion (MCAO) model as an in vivo model of cerebral ischemia. HeLa cells were used in overexpression experiments. Cx43 protein levels were determined by western blotting. The interaction between Cx43 and related autophagy receptors was determined by co-immunoprecipitation and immunofluorescence. The gene knockdown (KD) of ATG5, OPTN, NDP52, PINK1 and Cx43 was applied by siRNA transfection. Related cytokines were detected by cytometric bead assay. Results: We found that Cx43 protein levels increased after ischemia in gene KD of ATG5, OPTN, NDP52 and PINK1 primary astrocytes. The interaction of Cx43 with OPTN, NDP52 and PINK1 was increased after cerebral ischemia injury in vitro and vivo. While the interaction was weakened after point mutation of Cx43 at Ser368, Tyr265 and Tyr247. Meanwhile, IL-10 upregulated during OGD after KD of ATG5, OPTN, NDP52 and PINK1 in astrocytes , while TNF downregulated during OGD after KD of ATG5, OPTN, NDP52 and PINK1 in astrocytes. Conclusions: Our results suggest that degradation of Cx43 is caused by selective autophagy during ischemia injury and the autophagy degradation of Cx43 plays important roles in neuroinflammation mediated by OGD injury. Treatment targeting Cx43 degradation pathway can improve neuroinflammation responses induced by OGD injury , which provide novel therapeutic strategies and crosstalk between autophagy and neuroinflammation.

scholarly journals EphrinB2-EphB2 signaling for dendrite protection after neuronal ischemia in vivo and oxygen-glucose deprivation in vitro

2020 ◽  
pp. 0271678X2097311
Author(s):  
Zhanyang Yu ◽  
Wenlu Li ◽  
Jing Lan ◽  
Kazuhide Hayakawa ◽  
Xunming Ji ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Mouse Model ◽  
Therapeutic Potential ◽  
Focal Cerebral Ischemia ◽  
Ischemic Injury ◽  
Glucose Deprivation ◽  
Oxygen Glucose Deprivation ◽  
Neuron Soma

In order to rescue neuronal function, neuroprotection should be required not only for the neuron soma but also the dendrites. Here, we propose the hypothesis that ephrin-B2-EphB2 signaling may be involved in dendritic degeneration after ischemic injury. A mouse model of focal cerebral ischemia with middle cerebral artery occlusion (MCAO) method was used for EphB2 signaling test in vivo. Primary cortical neuron culture and oxygen-glucose deprivation were used to assess EphB2 signaling in vitro. siRNA and soluble ephrin-B2 ectodomain were used to block ephrin-B2-Ephb2 signaling. In the mouse model of focal cerebral ischemia and in neurons subjected to oxygen-glucose deprivation, clustering of ephrin-B2 with its receptor EphB2 was detected. Phosphorylation of EphB2 suggested activation of this signaling pathway. RNA silencing of EphB2 prevented neuronal death and preserved dendritic length. To assess therapeutic potential, we compared the soluble EphB2 ectodomain with the NMDA antagonist MK801 in neurons after oxygen-glucose deprivation. Both agents equally reduced lactate dehydrogenase release as a general marker of neurotoxicity. However, only soluble EphB2 ectodomain protected the dendrites. These findings provide a proof of concept that ephrin-B2-EphB2 signaling may represent a novel therapeutic target to protect both the neuron soma as well as dendrites against ischemic injury.

scholarly journals TGFα preserves oligodendrocyte lineage cells and improves white matter integrity after cerebral ischemia

2019 ◽  
Vol 40 (3) ◽  
pp. 639-655 ◽  
Author(s):  
Xuejiao Dai ◽  
Jie Chen ◽  
Fei Xu ◽  
Jingyan Zhao ◽  
Wei Cai ◽  
...  
Keyword(s):  
Cell Death ◽  
White Matter ◽  
Cerebral Ischemia ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Glucose Deprivation ◽  
White Matter Integrity ◽  
Functional Impairments ◽  
Transforming Growth Factor Α

Transforming growth factor α (TGF-α) has been reported to play important roles in neurogenesis and angiogenesis in the injured brain. The present study characterizes a novel role for TGFα in oligodendrocyte lineage cell survival and white matter integrity after ischemic stroke. Three days after transient (60 min) middle cerebral artery occlusion (tMCAO), TGFα expression was significantly increased in microglia/macrophages and neurons. Expression of the receptor of TGFα—epidermal growth factor receptor (EGFR)—was increased in glial cells after ischemia, including in oligodendrocyte lineage cells. TGFα knockout enlarged brain infarct volumes and exacerbated cell death in oligodendrocyte precursor cells (OPCs) and oligodendrocytes three days after tMCAO. TGFα-deficient mice displayed long-term exacerbation of sensorimotor deficits after tMCAO, and these functional impairments were accompanied by loss of white matter integrity and impaired oligodendrocyte replacement. In vitro studies confirmed that 5 or 10 ng/mL TGFα directly protected OPCs and oligodendrocytes against oxygen and glucose deprivation (OGD)-induced cell death, but exerted no effects on OPC differentiation. Further studies identified STAT3 as a key transcription factor mediating the effects of TGFα on OPCs and oligodendrocytes. In conclusion, TGFα provides potent oligodendrocyte protection against cerebral ischemia, thereby maintaining white matter integrity and improving neurological recovery after stroke.

scholarly journals A novel therapeutic approach using peripheral blood mononuclear cells preconditioned by oxygen-glucose deprivation

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Masahiro Hatakeyama ◽  
Masato Kanazawa ◽  
Itaru Ninomiya ◽  
Kaoru Omae ◽  
Yasuko Kimura ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Therapeutic Strategy ◽  
Mononuclear Cells ◽  
Focal Cerebral Ischemia ◽  
Glucose Deprivation ◽  
Oxygen Glucose Deprivation ◽  
Peripheral Blood Mononuclear ◽  
Novel Therapeutic

AbstractCell therapies that invoke pleiotropic mechanisms may facilitate functional recovery in patients with stroke. Based on previous experiments using microglia preconditioned by oxygen-glucose deprivation, we hypothesized that the administration of peripheral blood mononuclear cells (PBMCs) preconditioned by oxygen-glucose deprivation (OGD-PBMCs) to be a therapeutic strategy for ischemic stroke. Here, OGD-PBMCs were identified to secrete remodelling factors, including the vascular endothelial growth factor and transforming growth factor-β in vitro, while intra-arterial administration of OGD-PBMCs at 7 days after focal cerebral ischemia prompted expression of such factors in the brain parenchyma at 28 days following focal cerebral ischemia in vivo. Furthermore, administration of OGD-PBMCs induced an increasing number of stage-specific embryonic antigen-3-positive cells both in vitro and in vivo. Finally, it was found to prompt angiogenesis and axonal outgrowth, and functional recovery after cerebral ischemia. In conclusion, the administration of OGD-PBMCs might be a novel therapeutic strategy against ischemic stroke.

scholarly journals Altered Biosynthesis of Neuropeptide Processing Enzyme Carboxypeptidase E after Brain Ischemia: Molecular Mechanism and Implication

2004 ◽  
Vol 24 (6) ◽  
pp. 612-622 ◽  
Author(s):  
An Zhou ◽  
Manabu Minami ◽  
Xiaoman Zhu ◽  
Sylvia Bae ◽  
John Minthorne ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Brain Ischemia ◽  
Cortical Neurons ◽  
Focal Cerebral Ischemia ◽  
Proteolytic Processing ◽  
Carboxypeptidase E ◽  
Processing Enzyme ◽  
The Impact

In this study, using both in vivo and in vitro ischemia models, the authors investigated the impact of brain ischemia on the biosynthesis of a key neuropeptide-processing enzyme, carboxypeptidase E (CPE). The response to brain ischemia of animals that lacked an active CPE was also examined. Combined in situ hybridization and immunocytochemical analyses for CPE showed reciprocal changes of CPE mRNA and protein, respectively, in the same cortical cells in rat brains after focal cerebral ischemia. Western blot analysis revealed an accumulation of the precursor protein of CPE in the ischemic cortex in vivo and in ischemic cortical neurons in vitro. Detailed metabolic labeling experiments on ischemic cortical neurons showed that ischemic stress caused a blockade in the proteolytic processing of CPE. When mice lacking an active CPE protease were subjected to a sublethal episode of focal cerebral ischemia, abundant TUNEL-positive cells were seen in the ischemic cortex whereas only a few were seen in the cortex of wild-type animals. These findings suggest that ischemia has an adverse impact on the neuropeptide-processing system in the brain and that the lack of an active neuropeptide-processing enzyme exacerbates ischemic brain injury.

scholarly journals Xingnaojing Injection Protects against Cerebral Ischemia Reperfusion Injury via PI3K/Akt-Mediated eNOS Phosphorylation

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Yue-Ming Zhang ◽  
Xiao-Yu Qu ◽  
Jing-Hui Zhai ◽  
Li-Na Tao ◽  
Huan Gao ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Underlying Mechanism ◽  
Dapi Staining ◽  
Pi3k Inhibitor Ly294002 ◽  
Cerebral Ischemic

Xingnaojing (XNJ) injection, derived from traditional Chinese medicine formulation, has a protective effect against stroke, but the underlying mechanism is unclear, which severely limited its clinical application. This research aims to elucidate the role and mechanism of XNJ in reducing cerebral ischemic reperfusion (I/R) injury. Rats received 2 h cerebral ischemia followed by reperfusion of 24 h and were intraperitoneally given 5, 10, or 15 ml/kg XNJ 24 h before ischemia and at the onset of reperfusion, respectively. TTC staining, HE staining, and neurological score were implied to evaluate the effectiveness of XNJ. The protein expressions of PI3K/Akt and eNOS signaling were measured. Experiments were further performed in human brain microvascular endothelial cells (HBMECs) to investigate the protective mechanisms of XNJ. HBMECs were subjected to 3 h oxygen and glucose deprivation following 24 h of reoxygenation (OGD) to mimic cerebral I/R in vitro. PI3K inhibitor LY294002 was added with or without the preconditioning of XNJ. Multiple methods including western blot, immunofluorescence, DAPI staining, JC-1, and flow cytometry were carried out to evaluate the effect of XNJ on HBMECs. XNJ could improve rat cerebral ischemic injury and OGD induced HBMECs apoptosis. In vivo and in vitro researches indicated that the mechanism might be relevant to the activation of PI3K/Akt/eNOS signaling.

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