Abstract W P222: Activated Microglia Contribute to Neurovascular Integrity and Limit Brain Injury After Acute Neonatal Focal Stroke

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
David Fernández-López ◽  
Joel Faustino ◽  
Alexander Klibanov ◽  
Nikita Derugin ◽  
katerina Akassoglou ◽  
...  
Keyword(s):  
Brain Injury ◽  
Microglial Activation ◽  
Injury Severity ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Microglial Cells ◽  
Vascular Density ◽  
Relative Role ◽  
Morphological Transformation ◽  
Activated Microglia

It has been recently shown that microglial cells, which for a long time were considered purely injurious in the context of cerebral ischemia, can also exert beneficial effects following stroke in both adults and neonates1,2. Lack of tools to reliably distinguish resident microglia from infiltrated peripheral monocytes has been a major obstacle on the way to understand the relative role of these subpopulations of cells of the monocyte lineage in the pathophysiology of stroke. We subjected postnatal day 10 (P10) transgenic Cx3cr1GFP/-CCr2RFP/- mice, in which resident microglia (Cx3cr1GFP) and infiltrating monocytes (CCr2RFP) can be distinctively identified, to a transient 3 hour middle cerebral artery occlusion MCAO, a model that we recently developed3. Microglial cells were left unperturbed or were selectively depleted before MCAO by intracortical injection of clodronate-encapsulated liposomes. Depletion of microglia exacerbated injury and significantly increased infarct volume (75.9% Vs. 56.3%, p<0.01). Furthermore, compared to mice with unperturbed microglia, depletion of microglia significantly increased the number of hemorrhages in injured regions, adversely affected vascular density and decreased the number of both adherent and infiltrated monocytes. The extent of RFP+ monocyte adhesion to vessels and infiltration in the brain parenchyma was highly variable among individual mice and did not correlate with brain infarct, whereas a significant correlation between the overall extent of microglial activation (measured by morphological transformation) and the number of infiltrated monocytes was observed. The deleterious effect of microglial depletion on vascular integrity and function and on brain injury indicates that activated microglia act as a buffering component that limits vascular degeneration and injury severity after neonatal stroke. Our data also suggest a direct and dynamic relationship between microglial activation and monocyte recruitment into acutely reperfused neonatal brain. Support: NS55915 (ZV), NS76726 (ZV), NS080015 (ZS, KA), AHA POST10980003 (DFL). 1. Faustino J et al. J Neurosci. 2011. 2. Lalancette-Hebert M et al. J Neurosci. 2007. 3. Woo MS et al. Annals of Neurology. 2012.

Abstract TMP69: Endoglin Deficiency Exacerbates Ischemic Brain Injury

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Fanxia Shen ◽  
Vincent Degos ◽  
Zhenying Han ◽  
Eun-Jung Choi ◽  
William L. Young ◽  
...  
Keyword(s):  
Brain Injury ◽  
Infarct Volume ◽  
Paradoxical Embolism ◽  
Artery Occlusion ◽  
Vascular Density ◽  
Ischemic Brain Injury ◽  
Myocardial Repair ◽  
Ischemic Brain ◽  
Removal Time ◽  
Adhesive Removal

Background and Objective: Endoglin (Eng) deficiency causes hereditary hemorrhagic telangiectasia (HHT) and impairs myocardial repair. Pulmonary arteriovenous malformations in HHT patients are associated with a high incidence of paradoxical embolism in the cerebral circulation and ischemic brain injury. We hypothesized that Eng deficiency exacerbates ischemic brain injury. Methods: Eng heterozygous ( Eng +/- ) mice and wild type (WT) mice underwent permanent distal middle cerebral artery occlusion (pMCAO). Infarct volume and CD68 + cells were quantified 3 days and vascular density was determined 60 days after pMCAO. Behavior was assessed by corner test and adhesive removal test at 3, 15, 30 and 60 days after pMCAO. Matrix metalloproteinase 9 (Mmp9) and Notch1 expression in bone marrow (BM)-derived macrophages from Eng +/- and WT were analyzed using real-time RT-PCR. Results: Eng +/- mice had a larger Infarct volume than WT mice (22±6% of the affected hemisphere vs. 16±6%, p=0.04). Eng +/- mice had longer adhesive-removal time (p<0.05) and more frequent turning to the lesion side than WT mice at 15, 30 and 60 days (p<0.05) after pMCAO. Both groups had similar numbers of CD68 + cells in the peri-infarct area at 3 days after pMCAO (370±80 vs 338±44 cells/mm 2 , p=0.37), but Eng +/- mice had lower peri-infarct vessel density (417±69 vs 490±52 vessels/mm 2 , p=0.05) at 60 days after pMCAO. Up-regulation of Mmp9 and Notch1 expression in response to VEGF was attenuated in Eng +/- BM-derived macrophages. Conclusions: Endoglin deficiency exacerbated brain injury and behavior dysfunction in mice after pMCAO and was associated with reduced angiogenesis. Although macrophage homing was not affected, reduced expression of two angiogenic-related genes, Mmp9 and Notch1 , by Eng +/- BM-derived macrophages suggests a potential role of these cells in recovery from an ischemic injury.

scholarly journals Dectin-1/Syk signaling triggers neuroinflammation after ischemic stroke in mice

2019 ◽  
Author(s):  
Xin-chun Ye ◽  
Qi Hao ◽  
Wei-jing Ma ◽  
Qiu-chen Zhao ◽  
Wei-wei Wang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Infarct Volume ◽  
Inos Expression ◽  
Microglial Cells ◽  
Brain Infarct ◽  
Tnf Α ◽  
Bv2 Microglial Cells ◽  
The Brain

Abstract Dendritic cell-associated C-type lectin-1 (Dectin-1) receptor has been reported to be involved in neuroinflammation in Alzheimer's disease and traumatic brain injury. The present study was designed to investigate the role of Dectin-1 and its downstream target spleen tyrosine kinase (Syk) in early brain injury after ischemic stroke using a focal cortex ischemic stroke model. Adult male C57BL/6J mice were subjected to a cerebral focal ischemia model of ischemic stroke. The neurological score, adhesive removal test and foot-fault test were evaluated on days 1, 3, 5 and 7 after ischemic stroke. Dectin-1, Syk, phosphorylated (p)-Syk, tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) expression was analyzed via western blotting in ischemic brain tissue after ischemic stroke and in BV2 microglial cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) injury in vitro. The brain infarct volume and Iba1-positive cells were evaluated using Nissl’s and immunofluorescence staining, respectively. The Dectin-1 antagonist laminarin (LAM) and a selective inhibitor of Syk phosphorylation (piceatannol; PIC) were used for the intervention. Dectin-1, Syk, and p-Syk expression was significantly enhanced on days 3, 5 and 7 and peaked on day 3 after ischemic stroke. The Dectin-1 antagonist LAM or Syk inhibitor PIC decreased the number of Iba1-positive cells and TNF-α and iNOS expression, decreased the brain infarct volume and improved neurological functions on day 3 after ischemic stroke. In addition, the in vitro data revealed that Dectin-1, Syk and p-Syk expression was increased following the 3-h OGD and 0, 3 and 6 h of reperfusion in BV2 microglial cells. LAM and PIC also decreased TNF-α and iNOS expression 3 h after OGD/R induction. Dectin-1/Syk signaling plays a crucial role in inflammatory activation after ischemic stroke, and further investigation of Dectin-1/Syk signaling in stroke is warranted.

scholarly journals Isorhynchophylline Ameliorates Cerebral Ischemia/Reperfusion Injury by Inhibiting CX3CR1-Mediated Microglial Activation and Neuroinflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuanyuan Deng ◽  
Ruirong Tan ◽  
Fei Li ◽  
Yuangui Liu ◽  
Jingshan Shi ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Microglial Activation ◽  
Inflammatory Responses ◽  
Ischemia Reperfusion Injury ◽  
Infarct Volume ◽  
Ischemia Reperfusion ◽  
Underlying Mechanism ◽  
Reperfusion Therapy ◽  
Artery Occlusion ◽  
Cerebral Ischemic

Reperfusion therapy is an effective way to rescue cerebral ischemic injury, but this therapy also shows the detrimental risk of devastating disorders and death due to the possible inflammatory responses involved in the pathologies. Hence, the therapy of ischemia/reperfusion (I/R) injury is a great challenge currently. Isorhynchophylline (IRN), a tetracyclic oxindole alkaloid extracted from Uncaria rhynchophylla, has previously shown neuroprotective and anti-inflammatory effects in microglial cells. This study systematically investigates the effect of IRN on I/R injury and its underlying mechanism. The effects of IRN on neuronal injury and microglia-mediated inflammatory response were assessed on a rat model with middle cerebral artery occlusion (MCAO) and reperfusion-induced injury. We found that IRN treatment attenuated the infarct volume and improved the neurological function in I/R injury rats. IRN treatment also reduced the neuronal death rate, brain water content, and aquaporin-4 expression in the ischemic penumbra of I/R injury rats’ brains. Besides, IRN treatment could inhibit the following process, including IκB-α degradation, NF-κB p65 activation, and CX3CR1 expression, as well as the microglial activation and inflammatory response. These findings suggest that IRN is a promising candidate to treat the cerebral I/R injury via inhibiting microglia activation and neuroinflammation.

scholarly journals Activated Microglia in Nociception

2010 ◽  
Vol 3;13 (3;5) ◽  
pp. 295-304
Author(s):  
Howard Smith
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Microglial Activation ◽  
Cell Number ◽  
Vital Role ◽  
Microglial Cells ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Activated Microglia ◽  
C Fiber

Microglial cells appear to play a vital role in the initiation of certain neuropathic pain states. In order to initiate neuropathic pain, microglia need to be activated. Microglia activation in the spinal cord involves both hypertrophy as well as hyperplasia, progressing through a hypertrophic morphology, with thickened and retracted processes (observed within the first 24 hours after nerve injury), and an increase in cell number (observed around 2–3 days after nerve injury). There seems to be at least 5 major paths to activate microglia. These 5 pathways will be discussed and are identified by their main signaling mediator and/or receptor which include fractalkine, interferon-gamma, monocyte chemoattractant protein-1, TLR4, and P2X4. Thus, one or more of these mediators/pathways which lead to microglial activation might contribute to neuropathic pain. A greater appreciation of the roles of various mediators/paths which activate microglia might help lead to future novel therapeutic targets in efforts to ameliorate severe symptoms of neuropathic pain. Key words: microglial cells, glia, C-fiber nociceptors, neuropathic pain, hypertrophy, hyperplasia

scholarly journals INF-β treatment to prolong t-PA treatment window in cerebral ischemia

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Kristopher D. Bosi, BS ◽  
Jui-Hung Yen, PhD
Keyword(s):  
Cerebral Ischemia ◽  
Immune Cell ◽  
Cell Damage ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Microglial Cells ◽  
Therapeutic Window ◽  
Expression Levels ◽  
First Line Therapy ◽  
Acute Cerebral Ischemia

Background and Hypothesis: Cerebral ischemia is the 2nd leading cause of death worldwide. The pathological hallmarks of cerebral ischemia are cell damage, degradation of the blood brain barrier (BBB), and inflammation followed by resident microglia activation, peripheral immune cell infiltration and subsequent secondary neurodegeneration. The first line therapy for ischemic stroke is the thrombolytic, tPA. However, only ten percent of patients are eligible for this treatment – primarily due to the risk of cerebral hemorrhage, secondary to BBB breakdown. Less than ten percent of individuals with acute cerebral ischemia are eligible for tPA. The objective of this study is to establish whether matrix metalloproteinase (MMP) activity, implicated in exacerbating the cerebral infarct volume seen with delayed tPA treatment, can be suppressed with Interferon-β (IFN-β) and thus extend the therapeutic window of tPA. Experimental Design: We first investigated the therapeutic effect of IFN-β co-administered with t-PA in the mouse model of transient middle cerebral artery occlusion/reperfusion. Second, using immunoblotting technique we investigated the expression levels of MMPs in brain endothelial and microglial cells following various treatment combinations of TNFα and PGE2, t-PA, and INF-β. Results: First, we demonstrated that IFN-β coadministered with tPA reduces the infarct size in ischemic brains. Second, we demonstrated in microglial cells that MMP-9 expression induced by TNFα, PGE2, and tPA can be suppressed by IFN-β treatment. Our experiments to demonstrate the expression levels of MMP-3 and MMP-9 in brain endothelial cells require further optimization. Conclusion and Potential Impact: Overall these data indicate that IFN-β treatment is a viable therapeutic candidate to suppress the deleterious effects seen in delayed tPA treatment in the setting of acute cerebral ischemia. Furthermore, our preliminary data indicate that the molecular target of IFN-β, in this setting, belong to the MMP family of proteins.

Abstract TP109: Impact of ATP-Induced Mild Hypothermia on Focal Cerebral Ischemia in Rats

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Meijuan Zhang ◽  
Wenjin Li ◽  
Rehana K Leak ◽  
Jun Chen ◽  
Feng Zhang
Keyword(s):  
Brain Injury ◽  
Cerebral Ischemia ◽  
Body Temperature ◽  
Mild Hypothermia ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Core Body Temperature ◽  
Artery Occlusion ◽  
Dependent Manner

Brain ischemia is a devastating disorder without effective therapies. One of the most promising approaches to attenuate ischemic brain injury is mild hypothermia. Recent studies show that adenosine nucleotides can induce hypothermia in mice. The purpose of the present study was to test the hypothesis that ATP, a common form of energy currency, induces mild hypothermia in rats and reduces brain injury following focal cerebral ischemia. ATP solution was dissolved in water and intraperitoneally injected; and focal stroke was induced by a suture model of middle cerebral artery occlusion and ischemic outcomes were evaluated within 24 hr. We found that injections of ATP lowered core body temperature in a dose-dependent manner; the dose appropriate for subsequent experiments was 2 g/kg as it reduced temperature to the range of mild hypothermia for approximately 7 hours. While intravenous injection of ATP was less effective in lowering body temperature. However, when ATP-induced hypothermia was applied to stroke, a neuroprotective effect was not observed. In contrast, the infarct volume grew even larger in ATP-treated rats. Not surprisingly, this was accompanied by an increased rate of seizure events, hemorrhagic transformation, and higher mortality. Continuous monitoring of physiological parameters revealed that ATP severely reduced heartbeat rate and blood pressure. ATP also raised blood glucose to dangerous levels and this was accompanied by severe acidosis and hypocalcemia. Western blotting showed that ATP treatment decreased levels of both phospho-Akt and total-Akt in the ischemic cortex. Our results reveal that, despite inducing hypothermia, ATP is not appropriate for protecting the brain against stroke, as it is associated with exaggerated ischemic outcomes and dangerous systemic side effects.

scholarly journals Dectin-1/Syk signaling triggers neuroinflammation after ischemic stroke in mice

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Xin-Chun Ye ◽  
Qi Hao ◽  
Wei-Jing Ma ◽  
Qiu-Chen Zhao ◽  
Wei-Wei Wang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Infarct Volume ◽  
Inos Expression ◽  
Microglial Cells ◽  
Brain Infarct ◽  
Tnf Α ◽  
Bv2 Microglial Cells ◽  
The Brain

Abstract Background Dendritic cell-associated C-type lectin-1 (Dectin-1) receptor has been reported to be involved in neuroinflammation in Alzheimer’s disease and traumatic brain injury. The present study was designed to investigate the role of Dectin-1 and its downstream target spleen tyrosine kinase (Syk) in early brain injury after ischemic stroke using a focal cortex ischemic stroke model. Methods Adult male C57BL/6 J mice were subjected to a cerebral focal ischemia model of ischemic stroke. The neurological score, adhesive removal test, and foot-fault test were evaluated on days 1, 3, 5, and 7 after ischemic stroke. Dectin-1, Syk, phosphorylated (p)-Syk, tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS) expression was analyzed via western blotting in ischemic brain tissue after ischemic stroke and in BV2 microglial cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) injury in vitro. The brain infarct volume and Iba1-positive cells were evaluated using Nissl’s and immunofluorescence staining, respectively. The Dectin-1 antagonist laminarin (LAM) and a selective inhibitor of Syk phosphorylation (piceatannol; PIC) were used for the intervention. Results Dectin-1, Syk, and p-Syk expression was significantly enhanced on days 3, 5, and 7 and peaked on day 3 after ischemic stroke. The Dectin-1 antagonist LAM or Syk inhibitor PIC decreased the number of Iba1-positive cells and TNF-α and iNOS expression, decreased the brain infarct volume, and improved neurological functions on day 3 after ischemic stroke. In addition, the in vitro data revealed that Dectin-1, Syk, and p-Syk expression was increased following the 3-h OGD and 0, 3, and 6 h of reperfusion in BV2 microglial cells. LAM and PIC also decreased TNF-α and iNOS expression 3 h after OGD/R induction. Conclusion Dectin-1/Syk signaling plays a crucial role in inflammatory activation after ischemic stroke, and further investigation of Dectin-1/Syk signaling in stroke is warranted.

scholarly journals Gingko biloba Extract (EGb 761) Prevents Ischemic Brain Injury by Activation of the Akt Signaling Pathway

2009 ◽  
Vol 37 (03) ◽  
pp. 547-555 ◽  
Author(s):  
Jae-Hyeon Cho ◽  
Jin-Hee Sung ◽  
Eun-Hae Cho ◽  
Chung-Kil Won ◽  
Hyo-Jong Lee ◽  
...  
Keyword(s):  
Brain Injury ◽  
Infarct Volume ◽  
Artery Occlusion ◽  
Male Rats ◽  
Ischemic Brain Injury ◽  
Protective Effects ◽  
Egb 761 ◽  
Neuroprotective Effects ◽  
Ischemic Brain ◽  
Gingko Biloba

EGb 761 is a standardized extract of Gingko biloba that exerts protective effects against ischemic brain injury. This study investigated whether EGb 761 modulates the neuroprotective effects through Akt and its downstream targets, Bad and FKHR. Adult male rats were treated with EGb 761 (100 mg/kg) or vehicle prior to middle cerebral artery occlusion (MCAO). Brains were collected 24 hours after MCAO and infarct volumes were analyzed. EGb 761 significantly reduced infarct volume. Potential activation was mearsured by phosphorylation of Akt at Ser473, Bad at Ser136, and FKHR at Ser256 using Western blot analysis. EGb 761 prevented the injury-induced decrease of pAkt and its down stream targets, pBad and pFKHR. Furthermore, EGb 761 prevented the injury-induced increase of cleaved caspase-3 levels. In conclusion, this study suggests that EGb 761 prevents cell death due to brain injury and that EGb 761 protection is affected by preventing the injury-induce decrease of Akt phosphorylation.

scholarly journals Neuroprotective Effects of Collagen-Glycosaminoglycan Matrix Implantation following Surgical Brain Injury

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Jia-Hui Chen ◽  
Wei-Cherng Hsu ◽  
Kuo-Feng Huang ◽  
Chih-Huang Hung
Keyword(s):  
Brain Injury ◽  
Microglial Activation ◽  
Tissue Concentration ◽  
Neurological Deficits ◽  
Surgical Trauma ◽  
Neurosurgical Procedures ◽  
Neuroprotective Effects ◽  
Activated Microglia ◽  
Surgical Brain Injury ◽  
Anti Inflammatory

Background. Neurological deficits following neurosurgical procedures are inevitable; however, there are still no effective clinical treatments. Earlier reports revealed that collagen-glycosaminoglycan (CG) matrix implantation promotes angiogenesis, neurogenesis, and functional recovery following surgical brain injury (SBI). The present study was conducted to further examine the potential neuroprotective effects of collagen-glycosaminoglycan (CG) matrix implantation following neurosurgery. Methods. CG implantation was performed in the lesion cavity created by surgical trauma. The Sprague-Dawley rat model of SBI was used as established in the previous study by the author. The rats were divided into three groups as follows: (1) sham (SHAM), (2) surgery-induced lesion cavity (L), and (3) CG matrix implantation following surgery-induced lesion cavity (L+CG). Proinflammatory (tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells)) and anti-inflammatory (IL-10 and granulocyte-macrophage colony-stimulating factor (GMCSF)) cytokine expression was evaluated by enzyme-linked immunosorbent assays. Microglial activation was evaluated by immunohistochemistry, and the neuroprotective effect of CG matrix implantation was evaluated by an immunohistochemical study of microglia ED-1 and IBA-1 (activated microglia) and myeloperoxidase (MPO) and by the analysis of IL-6, IL-10, TNF-α, NF-κB, and GMCSF cytokine levels. Apoptosis was also assessed using a TUNEL assay. Results. The results showed that CG matrix implantation following surgically induced lesions significantly decreased the density of ED-1, IBA-1, and MPO (activated microglia). The tissue concentration of proinflammatory cytokines, such as TNF-α, IL-6, and NF-κB was significantly decreased. Conversely, the anti-inflammatory cytokines GMCSF and IL-10 were significantly increased. Conclusions. Implantation of the CG matrix following SBI has neuroprotective effects, including the suppression of microglial activation and the production of inflammatory-related cytokines.

scholarly journals Attenuation of Stroke Size in Rats Using an Adenoviral Vector to Induce Overexpression of Interleukin-1 Receptor Antagonist in Brain

1995 ◽  
Vol 15 (4) ◽  
pp. 547-551 ◽  
Author(s):  
A. Lorris Betz ◽  
Guo-Yuan Yang ◽  
Beverly L. Davidson
Keyword(s):  
Brain Injury ◽  
Receptor Antagonist ◽  
Recombinant Adenovirus ◽  
Infarct Volume ◽  
Interleukin 1 ◽  
Adenovirus Vector ◽  
Histochemical Staining ◽  
Artery Occlusion ◽  
Central Administration ◽  
Interleukin 1 Receptor Antagonist

Adenoviruses have been proposed as potential vectors for gene therapy in the central nervous system, but there are no reports of their use in the treatment of a brain disease. Because central administration of interleukin-1 receptor antagonist protein (IL-1ra) reduces ischemic brain damage, we determined whether a recombinant adenovirus vector carrying the human IL-1ra cDNA (Ad.RSV IL-1ra) could be used to ameliorate brain injury in permanent focal ischemia. Groups of six rats received intraventricular injections of Ad.RSV IL-1ra or a control adenovirus containing the Escherichia coli β-galactosidase gene (Ad.RSV lacZ). Histochemical staining for β-galactosidase 5 days after virus injection indicated that transgene expression was confined primarily to the cells lining the ventricle. The concentrations of IL-1ra were fivefold to 50-fold higher in the Ad.RSV IL-1ra-injected animals, achieving levels of 9.1 ± 3.3 ng/g in brain and 23.7 ± 22.5 ng/ml in CSF. In these animals, cerebral infarct volume resulting from 24 h of permanent middle cerebral artery occlusion was reduced 64%. These studies demonstrate that adenoviral vectors can be used to deliver genes that attenuate brain injury.

Sign in / Sign up

Export Citation Format

Share Document