Publications by authors named "Xuefang Ren"

31 Publications

Author Correction: Blood substitution therapy rescues the brain of mice from ischemic damage.

Nat Commun 2021 May 13;12(1):2957. Epub 2021 May 13.

Department of Neuroscience, West Virginia University, Morgantown, WV, USA.

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http://dx.doi.org/10.1038/s41467-021-22615-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119707PMC
May 2021

The Mitochondrial mitoNEET Ligand NL-1 Is Protective in a Murine Model of Transient Cerebral Ischemic Stroke.

Pharm Res 2021 May 12;38(5):803-817. Epub 2021 May 12.

Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, 1 Medical Center Drive, Morgantown, West Virginia, 26506, USA.

Purpose: Therapeutic strategies to treat ischemic stroke are limited due to the heterogeneity of cerebral ischemic injury and the mechanisms that contribute to the cell death. Since oxidative stress is one of the primary mechanisms that cause brain injury post-stroke, we hypothesized that therapeutic targets that modulate mitochondrial function could protect against reperfusion-injury after cerebral ischemia, with the focus here on a mitochondrial protein, mitoNEET, that modulates cellular bioenergetics.

Method: In this study, we evaluated the pharmacology of the mitoNEET ligand NL-1 in an in vivo therapeutic role for NL-1 in a C57Bl/6 murine model of ischemic stroke.

Results: NL-1 decreased hydrogen peroxide production with an IC of 5.95 μM in neuronal cells (N2A). The in vivo activity of NL-1 was evaluated in a murine 1 h transient middle cerebral artery occlusion (t-MCAO) model of ischemic stroke. We found that mice treated with NL-1 (10 mg/kg, i.p.) at time of reperfusion and allowed to recover for 24 h showed a 43% reduction in infarct volume and 68% reduction in edema compared to sham-injured mice. Additionally, we found that when NL-1 was administered 15 min post-t-MCAO, the ischemia volume was reduced by 41%, and stroke-associated edema by 63%.

Conclusion: As support of our hypothesis, as expected, NL-1 failed to reduce stroke infarct in a permanent photothrombotic occlusion model of stroke. This report demonstrates the potential therapeutic benefits of using mitoNEET ligands like NL-1 as novel mitoceuticals for treating reperfusion-injury with cerebral stroke.
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http://dx.doi.org/10.1007/s11095-021-03046-4DOI Listing
May 2021

IL-1β Antibody Protects Brain from Neuropathology of Hypoperfusion.

Cells 2021 Apr 9;10(4). Epub 2021 Apr 9.

Department of Neuroscience, School of Medicine, West Virginia University, Morgantown, WV 26506, USA.

Chronic brain hypoperfusion is the primary cause of vascular dementia and has been implicated in the development of white matter disease and lacunar infarcts. Cerebral hypoperfusion leads to a chronic state of brain inflammation with immune cell activation and production of pro-inflammatory cytokines, including IL-1β. In the present study, we induced chronic, progressive brain hypoperfusion in mice using ameroid constrictor, arterial stenosis (ACAS) surgery and tested the efficacy of an IL-1β antibody on the resulting brain damage. We observed that ACAS surgery causes a reduction in cerebral blood flow (CBF) of about 30% and grey and white matter damage in and around the hippocampus. The IL-1β antibody treatment did not significantly affect CBF but largely eliminated grey matter damage and reduced white matter damage caused by ACAS surgery. Over the course of hypoperfusion/injury, grip strength, coordination, and memory-related behavior were not significantly affected by ACAS surgery or antibody treatment. We conclude that antibody neutralization of IL-1β is protective from the brain damage caused by chronic, progressive brain hypoperfusion.
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http://dx.doi.org/10.3390/cells10040855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069995PMC
April 2021

Intermittent Lipopolysaccharide Exposure Significantly Increases Cortical Infarct Size and Impairs Autophagy.

ASN Neuro 2021 Jan-Dec;13:1759091421991769

Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, United States.

Globally, stroke is a leading cause of death and disability. Traditional risk factors like hypertension, diabetes, and obesity do not fully account for all stroke cases. Recent infection is regarded as changes in systemic immune signaling, which can increase thrombosis formation and other stroke risk factors. We have previously shown that administration of lipopolysaccharide (LPS) 30-minutes prior to stroke increases in infarct volume. In the current study, we found that animals intermittently exposed to LPS have larger cortical infarcts when compared to saline controls. To elucidate the mechanism behind this phenomenon, several avenues were investigated. We observed significant upregulation of tumor necrosis factor-alpha (TNF-α) mRNA, especially in the ipsilateral hemisphere of both saline and LPS exposed groups compared to sham surgery animals. We also observed significant reductions in expression of genes involved in autophagy in the ipsilateral hemisphere of LPS stroke animals. In addition, we assessed DNA methylation of autophagy genes and observed a significant increase in the ipsilateral hemisphere of LPS stroke animals. Intermittent exposure to LPS increases cortical infarct volume, downregulates autophagy genes, and induces hypermethylation of the corresponding CpG islands. These data suggest that intermittent immune activation may deregulate epigenetic mechanisms and promote neuropathological outcomes after stroke.
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http://dx.doi.org/10.1177/1759091421991769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020222PMC
February 2021

Blood substitution therapy rescues the brain of mice from ischemic damage.

Nat Commun 2020 08 25;11(1):4078. Epub 2020 Aug 25.

Department of Neuroscience, West Virginia University, Morgantown, West Virginia, 26506, USA.

Acute stroke causes complex, pathological, and systemic responses that have not been treatable by any single medication. In this study, using a murine transient middle cerebral artery occlusion stroke model, a novel therapeutic strategy is proposed, where blood replacement (BR) robustly reduces infarctions and improves neurological deficits in mice. Our analyses of immune cell subsets suggest that BR therapy substantially decreases neutrophils in blood following a stroke. Electrochemiluminescence detection demonstrates that BR therapy reduces cytokine storm in plasma and ELISA demonstrates reduced levels of matrix metalloproteinase-9 (MMP-9) in the plasma and brains at different time points post-stroke. Further, we have demonstrated that the addition of MMP-9 to the blood diminishes the protective effect of the BR therapy. Our study is the first to show that BR therapy leads to profoundly improved stroke outcomes in mice and that the improved outcomes are mediated via MMP-9. These results offer new insights into the mechanisms of stroke damage.
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http://dx.doi.org/10.1038/s41467-020-17930-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447645PMC
August 2020

The Incidence and Predictors of Postoperative Delirium After Brain Tumor Resection in Adults: A Cross-Sectional Survey.

World Neurosurg 2020 08 4;140:e129-e139. Epub 2020 May 4.

Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China. Electronic address:

Background: Postoperative delirium (POD) describes a multifactorial disease process occurring after surgery. However, few studies have focused on patients undergoing brain tumor resection, and its influencing factors are unclear.

Methods: We performed a 1-year, single-center, cross-sectional, retrospective survey at Huashan Hospital. Patients were screened using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), Confusion Assessment Method, and Richmond Agitation Sedation Scale by trained bedside nurses. Perioperative data were collected using demographic and disease-related questionnaires. The primary outcome measures were the incidence of POD and subtype of POD. Independent predictors of POD were estimated from multivariate logistic regression models, and receiver operating characteristic analysis was used to compare the predictive performance of the models.

Results: Of the 916 patients included in the study, 893 were analyzed. The overall incidence was 14.78%, 67 had hyperactive delirium (50.76%), 55 had hypoactive delirium (41.67%), and 10 had mixed delirium (7.57%). Age, sex, working status, tobacco use history, comorbidities, physical restraint, axillary temperature (>38.5°C), electrolyte disturbances, duration of anesthesia, pathologic diagnosis, tumor site, length of disease, and duration of operation were risk factors for POD. Conversely, saddle area mass was a protective factor. Age, tobacco use history, electrolyte disturbances, physical restraint, and duration of operation were included in the model.

Conclusions: POD is harmful to patients undergoing brain tumor resection, increasing length of stay in the intensive care unit and hospitalization costs. Intraoperative factors and postoperative factors, in addition to older age and tobacco use history, are associated with POD.
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http://dx.doi.org/10.1016/j.wneu.2020.04.195DOI Listing
August 2020

Mechanisms in blood-brain barrier opening and metabolism-challenged cerebrovascular ischemia with emphasis on ischemic stroke.

Metab Brain Dis 2020 08 15;35(6):851-868. Epub 2020 Apr 15.

Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, USA.

Stroke is the leading cause of disability among adults as well as the 2nd leading cause of death globally. Ischemic stroke accounts for about 85% of strokes, and currently, tissue plasminogen activator (tPA), whose therapeutic window is limited to up to 4.5 h for the appropriate population, is the only FDA approved drug in practice and medicine. After a stroke, a cascade of pathophysiological events results in the opening of the blood-brain barrier (BBB) through which further complications, disabilities, and mortality are likely to threaten the patient's health. Strikingly, tPA administration in eligible patients might cause hemorrhagic transformation and sustained damage to BBB integrity. One must, therefore, delineate upon stroke onset which cellular and molecular factors mediate BBB permeability as well as what key roles BBB rupture plays in the pathophysiology of stroke. In this review article, given our past findings of mechanisms underlying BBB opening in stroke animal models, we elucidate cellular, subcellular, and molecular factors involved in BBB permeability after ischemic stroke. The contribution of each factor to stroke severity and outcome is further discussed. Determinant factors in BBB permeability and stroke include mitochondria, miRNAs, matrix metalloproteinases (MMPs), immune cells, cytokines, chemokines, and adhesion proteins. Once these factors are interrogated and their roles in the pathophysiology of stroke are determined, novel targets for drug discovery and development can be uncovered in addition to novel therapeutic avenues for human stroke management.
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http://dx.doi.org/10.1007/s11011-020-00573-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988906PMC
August 2020

MiR-34a Interacts with Cytochrome c and Shapes Stroke Outcomes.

Sci Rep 2020 02 24;10(1):3233. Epub 2020 Feb 24.

Neuroscience, Center for Basic and Translational Stroke Research; West Virginia University, Morgantown, West Virginia, 26506, USA.

Blood-brain barrier (BBB) dysfunction occurs in cerebrovascular diseases and neurodegenerative disorders such as stroke. Opening of the BBB during a stroke has a negative impact on acute outcomes. We have recently demonstrated that miR-34a regulates the BBB by targeting cytochrome c (CYC) in vitro. To investigate the role of miR-34a in a stroke, we purified primary cerebrovascular endothelial cells (pCECs) from mouse brains following 1 h transient middle cerebral artery occlusion (tMCAO) and measured real-time PCR to detect miR-34a levels. We demonstrate that the miR-34a levels are elevated in pCECs from tMCAO mice at the time point of BBB opening following 1 h tMCAO and reperfusion. Interestingly, knockout of miR-34a significantly reduces BBB permeability, alleviates disruption of tight junctions, and improves stroke outcomes compared to wild-type (WT) controls. CYC is decreased in the ischemic hemispheres and pCECs from WT but not in miR-34a mice following stroke reperfusion. We further confirmed CYC is a target of miR-34a by a dural luciferase reporter gene assay in vitro. Our study provides the first description of miR-34a affecting stroke outcomes and may lead to discovery of new mechanisms and treatments for cerebrovascular and neurodegenerative diseases such as stroke.
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http://dx.doi.org/10.1038/s41598-020-59997-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040038PMC
February 2020

Ischemic stroke alters immune cell niche and chemokine profile in mice independent of spontaneous bacterial infection.

Immun Inflamm Dis 2019 12 5;7(4):326-341. Epub 2019 Nov 5.

Department of Microbiology, Immunology, and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia.

Introduction: Stroke-associated pneumonia (SAP) is a major cause of mortality in patients who have suffered from severe ischemic stroke. Although multifactorial in nature, stroke-induced immunosuppression plays a key role in the development of SAP. Previous studies using a murine model of transient middle cerebral artery occlusion (tMCAO) have shown that focal ischemic stroke induction results in functional defects of lymphocytes in the spleen, thymus, and peripheral blood, leading to spontaneous bacterial infection in the lungs without inoculation. However, how ischemic stroke alters immune cell niche and the expression of cytokines and chemokines in the lungs has not been fully characterized.

Methods: Ischemic stroke was induced in mice by tMCAO. Immune cell profiles in the brain and the lungs at 24- and 72-hour time points were compared by flow cytometric analysis. Cytokine and chemokine expression in the lungs were determined by multiplex bead arrays. Tissue damage and bacterial burden in the lungs following tMCAO were evaluated.

Results: Ischemic stroke increases the percentage of alveolar macrophages, neutrophils, and CD11b dendritic cells, but reduces the percentage of CD4 T cells, CD8 T cells, B cells, natural killer cells, and eosinophils in the lungs. The alteration of immune cell niche in the lungs coincides with a significant reduction in the levels of multiple chemokines in the lungs, including CCL3, CCL4, CCL5, CCL17, CCL20, CCL22, CXCL5, CXCL9, and CXCL10. Spontaneous bacterial infection and tissue damage following tMCAO, however, were not observed.

Conclusion: This is the first report to demonstrate a significant reduction of lymphocytes and multiple proinflammatory chemokines in the lungs following ischemic stroke in mice. These findings suggest that ischemic stroke directly impacts pulmonary immunity.
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http://dx.doi.org/10.1002/iid3.277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842816PMC
December 2019

MiR-34a and stroke: Assessment of non-modifiable biological risk factors in cerebral ischemia.

Neurochem Int 2019 07 23;127:73-79. Epub 2018 Oct 23.

Center for Basic and Translational Stroke Research, USA; Rockefeller Neuroscience Institute, USA; Department of Physiology and Pharmacology, West Virginia University, Morgantown, WV, 26505, USA. Electronic address:

Aging of the nervous system, and the occurrence of age-related brain diseases such as stroke, are associated with changes to a variety of cellular processes controlled by many distinct genes. MicroRNAs (miRNAs), short non-coding functional RNAs that can induce translational repression or site-specific cleavage of numerous target mRNAs, have recently emerged as important regulators of cellular senescence, aging, and the response to neurological insult. Here, we focused on the assessment of the role of miR-34a in stroke. We noted increases in miR-34a expression in the blood of stroke patients as well as in blood and brain of mice subjected to experimental stroke. Our methodical genetic manipulation of miR-34a expression substantially impacted stroke-associated preclinical outcomes and we have in vitro evidence that these changes may be driven at least in part by disruptions to blood brain barrier integrity and mitochondrial oxidative phosphorylation in endothelial cells. Finally, aging, independent of brain injury, appears to be associated with shifts in circulating miRNA profiles. Taken together, these data support a role for miRNAs, and specifically miR-34a, in brain aging and the physiological response to age-related neurological insult, and lay the groundwork for future investigation of this novel therapeutic target.
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http://dx.doi.org/10.1016/j.neuint.2018.10.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980108PMC
July 2019

Gradual common carotid artery occlusion as a novel model for cerebrovascular Hypoperfusion.

Metab Brain Dis 2018 12 28;33(6):2039-2044. Epub 2018 Sep 28.

One Medical Center Drive, West Virginia University, Morgantown, WV, 26506, USA.

Chronic cerebrovascular hypoperfusion results in vascular dementia and increases predisposition to lacunar infarcts. However, there are no suitable animal models. In this study, we developed a novel model for chronic irreversible cerebral hypoperfusion in mice. Briefly, an ameroid constrictor was placed on the right carotid artery to gradually occlude the vessel, while a microcoil was placed on the left carotid artery to prevent compensation of the blood flow. This procedure resulted in a gradual hypoperfusion developing over a period of 34 days with no cerebral blood flow recovery. Histological analysis of the brain revealed neuronal and axonal degeneration as well as necrotic lesions. The most severely affected regions were located in the hippocampus and the corpus callosum. Overall, our paradigm is a viable model to study brain pathology resulting from gradual cerebrovascular hypoperfusion.
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http://dx.doi.org/10.1007/s11011-018-0312-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342504PMC
December 2018

Uncoupling of the Electron Transport Chain Compromises Mitochondrial Oxidative Phosphorylation and Exacerbates Stroke Outcomes.

J Neuroinfect Dis 2018 31;9(4). Epub 2018 Dec 31.

Department of Neuroscience, Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, USA.

Objective: Mitochondrial dysfunction is known to be implicated in stroke, but the complex mechanisms of stroke have led to few stroke therapies. The present study to disrupted mitochondrial oxidative phosphorylation through a known electron transport chain (ETC) uncoupler, Carbonyl cyanide-4 (trifluoromethoxy) phenylhydrazone (FCCP). Analyzing the resulting neurological deficits as well as infarct volume could help determine the role of mitochondria in stroke outcome and determine whether uncoupling the ETC could potentially be a strategy for new stroke therapies. The objective of this study was to determine the effects of uncoupling electron flow on mitochondrial oxidative phosphorylation and stroke infarction.

Methods: Cerebral endovascular cells (CECs) were treated with various concentrations of FCCP, and bioenergetics were measured. For the stroke mouse model, FCCP (1 mg/kg, i.p) or vehicle was administered followed by 1-hour transient middle cerebral artery occlusion (tMCAO). Infarct volume was measured after a 23-hour reperfusion, and triphenyl tetrazolium chloride (TTC) staining was used to assess infarct volume.

Results: FCCP significantly decreased basal respiration, ATP turnover, maximal respiration, and spare capacity when the concentration of FCCP was greater than 1000 nM. The mice pretreated with FCCP had a significantly increased infarct volume within the cortex, striatum, and total hemisphere. Mice receiving FCCP had a significantly increased neurological deficit score compared to the vehicle.

Conclusions: FCCP compromised mitochondrial oxidative phosphorylation in CECs in a dose-dependent manner. Uncoupling the electron transport chain with FCCP prior to tMCAO exacerbated stroke infarction in mice.
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http://dx.doi.org/10.4172/2314-7326.1000283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059652PMC
December 2018

Evaluation of Bioenergetic Function in Cerebral Vascular Endothelial Cells.

J Vis Exp 2016 11 19(117). Epub 2016 Nov 19.

Department of Physiology and Pharmacology, West Virginia University; Experimental Stroke Core, West Virginia University; Center for Basic and Translational Stroke Research, West Virginia University;

The integrity of the blood-brain-barrier (BBB) is critical to prevent brain injury. Cerebral vascular endothelial (CVE) cells are one of the cell types that comprise the BBB; these cells have a very high-energy demand, which requires optimal mitochondrial function. In the case of disease or injury, the mitochondrial function in these cells can be altered, resulting in disease or the opening of the BBB. In this manuscript, we introduce a method to measure mitochondrial function in CVE cells by using whole, intact cells and a bioanalyzer. A mito-stress assay is used to challenge the cells that have been perturbed, either physically or chemically, and evaluate their bioenergetic function. Additionally, this method also provides a useful way to screen new therapeutics that have direct effects on mitochondrial function. We have optimized the cell density necessary to yield oxygen consumption rates that allow for the calculation of a variety of mitochondrial parameters, including ATP production, maximal respiration, and spare capacity. We also show the sensitivity of the assay by demonstrating that the introduction of the microRNA, miR-34a, leads to a pronounced and detectable decrease in mitochondrial activity. While the data shown in this paper is optimized for the bEnd.3 cell line, we have also optimized the protocol for primary CVE cells, further suggesting the utility in preclinical and clinical models.
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http://dx.doi.org/10.3791/54847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226249PMC
November 2016

Deciphering the Blood-Brain Barrier Damage in Stroke: Mitochondrial Mechanism.

J Neuroinfect Dis 2015 Oct 22;6(Suppl 2). Epub 2015 Aug 22.

Department of Physiology and Pharmacology, Experimental Stroke Core, Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, West Virginia, USA.

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http://dx.doi.org/10.4172/2314-7326.S2-e002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873162PMC
October 2015

Geissoschizine methyl ether protects oxidative stress-mediated cytotoxicity in neurons through the 'Neuronal Warburg Effect'.

J Ethnopharmacol 2016 Jul 22;187:249-58. Epub 2016 Apr 22.

Department of Physiology and Pharmacology, Center for Basic and Translational Stroke Research, West Virginia University, 1 Medical Center Drive, Morgantown, WV 26506, United States. Electronic address:

Ethnopharmacological Relevance: The rate of production of reactive oxygen species (ROS) is determined by mitochondrial metabolic rate. In turn, excessive ROS damage mitochondrial function, which is linked to aging and neurodegenerative conditions. One possible path to prevent oxidative stress could be achieved by reducing mitochondrial respiration in favor of less efficient ATP production via glycolysis. Such a shift in energy metabolism is known as the 'Warburg effect'. Geissoschizine methyl ether (GM) is one of the active components responsible for the psychotropic effects of Yokukansan, an herbal preparation widely used in China and Japan.

Aim Of The Study: GM protects neurons from glutamate-induced oxidative cytotoxicity through regulating mitochondrial function and suppressing ROS generation. We investigated the protective mechanism of GM against glutamate-induced oxidative stress in neuronal cells.

Materials And Methods: The current study was performed on primary neurons and HT22 cells, a hippocampus neuronal cell line. Cell viability was measured by Calcein AM assay. H2DCFDA staining was used for intracellular ROS measurement. GSH level was measured using the GSH-Glo™ luminescence-based assay. Mitochondrial respiration and glycolysis were measured by the Seahorse Bioscience XFe 96 Extracellular Flux Analyzer. Protein levels were analyzed by western blot analysis.

Results: GM prevented glutamate-induced cytotoxicity in an HT-22 neuronal cell line even with a 9-hour exposure delay. GM blocked glutamate-induced intracellular ROS accumulation through suppressing mitochondrial respiration. Further, we found that GM up-regulated glycolysis and the pentose-phosphate pathway, which is involved in the production of intracellular reducing agent, NADPH. In addition, GM protected primary cortical neurons from both glutamate and buthioninesulfoximine toxicity.

Conclusion: GM prevents glutamate-induced oxidative damage through reducing mitochondrial respiration, which further suppresses ROS generation. In addition, GM up-regulates glycolysis which compensate for the energy depletion induced by mitochondrial respiration inhibition. Overall, our study is the first to report that GM protects neurons from oxidative toxicity by shifting energy metabolism from mitochondrial respiration to glycolysis.
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http://dx.doi.org/10.1016/j.jep.2016.04.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887292PMC
July 2016

Impacts of prenatal nanomaterial exposure on male adult Sprague-Dawley rat behavior and cognition.

J Toxicol Environ Health A 2016 19;79(11):447-52. Epub 2016 Apr 19.

a Department of Physiology and Pharmacology , West Virginia University , Morgantown , West Virginia , USA.

It is generally accepted that gestational xenobiotic exposures result in systemic consequences in the adult F1 generation. However, data on detailed behavioral and cognitive consequences remain limited. Using our whole-body nanoparticle inhalation facility, pregnant Sprague-Dawley rats (gestational day [GD] 7) were exposed 4 d/wk to either filtered air (control) or nano-titanium dioxide aerosols (nano-TiO2; count median aerodynamic diameter of 170.9 ± 6.4 nm, 10.4 ± 0.4 mg/m(3), 5 h/d) for 7.8 ± 0.5 d of the remaining gestational period. All rats received their final exposure on GD 20 prior to delivery. The calculated daily maternal deposition was 13.9 ± 0.5 µg. Subsequently, at 5 mo of age, behavior and cognitive functions of these pups were evaluated employing a standard battery of locomotion, learning, and anxiety tests. These assessments revealed significant working impairments, especially under maximal mnemonic challenge, and possible deficits in initial motivation in male F1 adults. Evidence indicates that maternal engineered nanomaterial exposure during gestation produces psychological deficits that persist into adulthood in male rats.
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http://dx.doi.org/10.1080/15287394.2016.1164101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899177PMC
May 2017

Tert-butylhydroquinone compromises survival in murine experimental stroke.

Neurotoxicol Teratol 2016 Mar-Apr;54:15-21. Epub 2016 Jan 28.

Department of Physiology and Pharmacology, Center for Basic and Translational Stroke Research, West Virginia University, 1 Medical Center Drive, Morgantown, WV 26506, United States.. Electronic address:

Tert-butylhydroquinone (tBHQ), an Nrf2 signaling pathway inducer that is widely used as a food additive in the U.S., prevents oxidative stress-induced cytotoxicity in neurons. This study assesses the effects of tBHQ on ischemic stroke outcomes in mice. We measured infarct size, neurological deficits, and brain volume after tBHQ treatments in murine permanent middle cerebral artery occlusion (pMCAO) model in vivo. Further, we evaluated the regulation of tBHQ on mitochondrial function in cerebrovascular endothelial cells in vitro, which is critical to the blood-brain barrier (BBB) permeability. Our results demonstrated that tBHQ increased post-stroke mortality and worsened stroke outcomes. Mitochondrial function was suppressed by tBHQ treatment of cerebrovascular endothelial cells, and this suppression was potentiated by co-treatment with lipopolysaccharide (LPS), the bacterial mimic. These data indicate that tBHQ-exacerbated stroke damage might due to the compromised BBB permeability in permanent stroke.
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http://dx.doi.org/10.1016/j.ntt.2016.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789102PMC
December 2016

Mitochondrial Impairment in Cerebrovascular Endothelial Cells is Involved in the Correlation between Body Temperature and Stroke Severity.

Aging Dis 2016 Jan 2;7(1):14-27. Epub 2016 Jan 2.

1 Department of Physiology and Pharmacology,; 2 Experimental Stroke Core, Center for Basic and Translational Stroke Research.

Stroke is the second leading cause of death worldwide. The prognostic influence of body temperature on acute stroke in patients has been recently reported; however, hypothermia has confounded experimental results in animal stroke models. This work aimed to investigate how body temperature could prognose stroke severity as well as reveal a possible mitochondrial mechanism in the association of body temperature and stroke severity. Lipopolysaccharide (LPS) compromises mitochondrial oxidative phosphorylation in cerebrovascular endothelial cells (CVECs) and worsens murine experimental stroke. In this study, we report that LPS (0.1 mg/kg) exacerbates stroke infarction and neurological deficits, in the mean time LPS causes temporary hypothermia in the hyperacute stage during 6 hours post-stroke. Lower body temperature is associated with worse infarction and higher neurological deficit score in the LPS-stroke study. However, warming of the LPS-stroke mice compromises animal survival. Furthermore, a high dose of LPS (2 mg/kg) worsens neurological deficits, but causes persistent severe hypothermia that conceals the LPS exacerbation of stroke infarction. Mitochondrial respiratory chain complex I inhibitor, rotenone, replicates the data profile of the LPS-stroke study. Moreover, we have confirmed that rotenone compromises mitochondrial oxidative phosphorylation in CVECs. Lastly, the pooled data analyses of a large sample size (n=353) demonstrate that stroke mice have lower body temperature compared to sham mice within 6 hours post-surgery; the body temperature is significantly correlated with stroke outcomes; linear regression shows that lower body temperature is significantly associated with higher neurological scores and larger infarct volume. We conclude that post-stroke body temperature predicts stroke severity and mitochondrial impairment in CVECs plays a pivotal role in this hypothermic response. These novel findings suggest that body temperature is prognostic for stroke severity in experimental stroke animal models and may have translational significance for clinical stroke patients - targeting endothelial mitochondria may be a clinically useful approach for stroke therapy.
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http://dx.doi.org/10.14336/AD.2015.0906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4723230PMC
January 2016

MiR-34a regulates blood-brain barrier permeability and mitochondrial function by targeting cytochrome c.

J Cereb Blood Flow Metab 2016 Feb 30;36(2):387-92. Epub 2015 Sep 30.

Department of Physiology and Pharmacology, West Virginia University, Morgantown, West Virginia, USA Experimental Stroke Core, Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, West Virginia, USA

The blood-brain barrier is composed of cerebrovascular endothelial cells and tight junctions, and maintaining its integrity is crucial for the homeostasis of the neuronal environment. Recently, we discovered that mitochondria play a critical role in maintaining blood-brain barrier integrity. We report for the first time a novel mechanism underlying blood-brain barrier integrity: miR-34a mediated regulation of blood-brain barrier through a mitochondrial mechanism. Bioinformatics analysis suggests miR-34a targets several mitochondria-associated gene candidates. We demonstrated that miR-34a triggers the breakdown of blood-brain barrier in cerebrovascular endothelial cell monolayer in vitro, paralleled by reduction of mitochondrial oxidative phosphorylation and adenosine triphosphate production, and decreased cytochrome c levels.
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http://dx.doi.org/10.1177/0271678X15606147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759667PMC
February 2016

Lipopolysaccharide exacerbates infarct size and results in worsened post-stroke behavioral outcomes.

Behav Brain Funct 2015 Oct 13;11(1):32. Epub 2015 Oct 13.

Department of Physiology and Pharmacology, Center for Basic and Translational Stroke Research, West Virginia University Health Science Center, 1 Medical Center Drive, Morgantown, WV, 26506-9229, USA.

Background: A third of ischemic stroke cases have no traditional underlying causes such as hypertension, diabetes, atherosclerosis, obesity, or age. Moreover, thirty to forty percent of strokes occur during or acutely after an active infection and the incidence of stroke increases during flu season. We and others have shown that the combination of a minor bacterial infection mimic, 100 μg/kg of lipopolysaccharide (LPS) prior to a minor stroke-30 min transient middle cerebral artery occlusion (tMCAO)-exacerbates infarct volume in a mouse model. Thus, experimental and epidemiological data strongly suggest that infection and/or inflammation play a role in stroke occurrence and severity. However, to date, long-term outcomes of stroke during an active infection has not been studied.

Methods: 3-4 month old C57Bl6/J mice were treated with saline or LPS 30 min prior to a 30 min tMCAO or sham surgery. A behavioral battery was administered to assess health status/sickness behavior, neurological deficits, motor, cognitive, and affective behaviors.

Results: We show for the first time that exposure to a low dose of LPS prior to a mild stroke significantly worsens neurological deficits and sickness scores. Motor, cognitive, and affective behaviors were assessed post-stroke and while stroke significantly affected motor behavior on rotarod, LPS did not increase the motor deficits. We did not observe any effects of stroke or LPS on cognitive and affective behaviors.

Conclusions: Our observations of the association between infection, stroke, and worse sickness and neurological outcomes identify (1) a clinical need to aggressively treat infections in people with risk factors for stroke and (2) the need to understand the mechanism(s) of the association between infections and stroke.
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http://dx.doi.org/10.1186/s12993-015-0077-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604642PMC
October 2015

Sequential Upregulation of Superoxide Dismutase 2 and Heme Oxygenase 1 by tert-Butylhydroquinone Protects Mitochondria during Oxidative Stress.

Mol Pharmacol 2015 Sep 16;88(3):437-49. Epub 2015 Jun 16.

Department of Physiology and Pharmacology, Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, West Virginia

Oxidative stress is linked to mitochondrial dysfunction in aging and neurodegenerative conditions. The transcription factor nuclear factor E2-related factor 2 (Nrf2)-antioxidant response element (ARE) regulates intracellular antioxidative capacity to combat oxidative stress. We examined the effect of tert-butylhydroquinone (tBHQ), an Nrf2-ARE signaling pathway inducer, on mitochondrial function during oxidative challenge in neurons. tBHQ prevented glutamate-induced cytotoxicity in an HT-22 neuronal cell line even with an 8-hour exposure delay. tBHQ blocked glutamate-induced intracellular reactive oxygen species (ROS) and mitochondrial superoxide accumulation. It also protected mitochondrial function under glutamate toxicity, including maintaining mitochondrial membrane potential, mitochondrial Ca(2+) hemostasis, and mitochondrial respiration. Glutamate-activated, mitochondria-mediated apoptosis was inhibited by tBHQ as well. In rat primary cortical neurons, tBHQ protected cells from both glutamate and buthionine sulfoximine toxicity. We found that tBHQ scavenged ROS and induced a rapid upregulation of superoxide dismutase 2 (SOD2) expression and a delayed upregulation of heme oxygenase 1 (HO-1) expression. In HT-22 cells with a knockdown of SOD2 expression, delayed treatment with tBHQ failed to prevent glutamate-induced cell death. Briefly, tBHQ rescues mitochondrial function by sequentially increasing SOD2 and HO-1 expression during glutamate-mediated oxidative stress. This study is the first to demonstrate the role of tBHQ in preserving mitochondrial function during oxidative challenge and provides a clinically relevant argument for using tBHQ against acute neuron-compromising conditions.
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http://dx.doi.org/10.1124/mol.115.098269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4551047PMC
September 2015

Mitochondrial crisis in cerebrovascular endothelial cells opens the blood-brain barrier.

Stroke 2015 Jun 28;46(6):1681-9. Epub 2015 Apr 28.

From the Department of Neurobiology and Anatomy (D.N.D.), Experimental Stroke Core, Center for Basic and Translational Stroke Research (H.H., S.E.L., J.W.S., X.R.), and Department of Physiology and Pharmacology (H.H., J.S., S.E.L., J.W.S., X.R.), West Virginia University, Morgantown.

Background And Purpose: The blood-brain barrier (BBB) is a selectively permeable cerebrovascular endothelial barrier that maintains homeostasis between the periphery and the central nervous system. BBB disruption is a consequence of ischemic stroke and BBB permeability can be altered by infection/inflammation, but the complex cellular and molecular changes that result in this BBB alteration need to be elucidated to determine mechanisms.

Methods: Infection mimic (lipopolysaccharide) challenge on infarct volume, BBB permeability, infiltrated neutrophils, and functional outcomes after murine transient middle cerebral artery occlusion in vivo; mitochondrial evaluation of cerebrovascular endothelial cells challenged by lipopolysaccharide in vitro; pharmacological inhibition of mitochondria on BBB permeability in vitro and in vivo; the effects of mitochondrial inhibitor on BBB permeability, infarct volume, and functional outcomes after transient middle cerebral artery occlusion.

Results: We report here that lipopolysaccharide worsens ischemic stroke outcome and increases BBB permeability after transient middle cerebral artery occlusion in mice. Furthermore, we elucidate a novel mechanism that compromised mitochondrial function accounts for increased BBB permeability as evidenced by: lipopolysaccharide-induced reductions in oxidative phosphorylation and subunit expression of respiratory chain complexes in cerebrovascular endothelial cells, a compromised BBB permeability induced by pharmacological inhibition of mitochondrial function in cerebrovascular endothelial cells in vitro and in an in vivo animal model, and worsened stroke outcomes in transient middle cerebral artery occlusion mice after inhibition of mitochondrial function.

Conclusions: We concluded that mitochondria are key players in BBB permeability. These novel findings suggest a potential new therapeutic strategy for ischemic stroke by endothelial cell mitochondrial regulation.
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http://dx.doi.org/10.1161/STROKEAHA.115.009099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4418219PMC
June 2015

Rapid mitochondrial dysfunction mediates TNF-alpha-induced neurotoxicity.

J Neurochem 2015 Feb 29;132(4):443-51. Epub 2015 Jan 29.

Neurobiology and Anatomy, West Virginia University, Morgantown, West Virginia, USA; Center for Neuroscience, Morgantown, WV, USA; Center for Basic and Translational Stroke Research, Morgantown, WV, USA.

Tumor necrosis factor alpha (TNF-α) is known to exacerbate ischemic brain injury; however, the mechanism is unknown. Previous studies have evaluated the effects of TNF-α on neurons with long exposures to high doses of TNF-α, which is not pathophysiologically relevant. We characterized the rapid effects of TNF-α on basal respiration, ATP production, and maximal respiration using pathophysiologically relevant, post-stroke concentrations of TNF-α. We observed a reduction in mitochondrial function as early as 1.5 h after exposure to low doses of TNF-α, followed by a decrease in cell viability in HT-22 cells and primary neurons. Subsequently, we used the HT-22 cell line to determine the mechanism by which TNF-α causes a rapid and profound reduction in mitochondrial function. Pre-treating with TNF-R1 antibody, but not TNF-R2 antibody, ameliorated the neurotoxic effects of TNF-α, indicating that TNF-α exerts its neurotoxic effects through TNF-R1. We observed an increase in caspase 8 activity and a decrease in mitochondrial membrane potential after exposure to TNF-α which resulted in a release of cytochrome c from the mitochondria into the cytosol. These novel findings indicate for the first time that an acute exposure to pathophysiologically relevant concentrations of TNF-α has neurotoxic effects mediated by a rapid impairment of mitochondrial function. This study focuses on the neurotoxic mechanism of a pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-α). We demonstrate a prompt mitochondrial dysfunction followed by nerve cell loss after exposure to TNF-α. These studies may provide evidence that the immune system can rapidly and adversely affect brain function and that TNF-α signaling may be a target for neuroprotection.
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http://dx.doi.org/10.1111/jnc.13008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459129PMC
February 2015

NF-κB is involved in brain repair by stem cell factor and granulocyte-colony stimulating factor in chronic stroke.

Exp Neurol 2015 Jan 2;263:17-27. Epub 2014 Oct 2.

Department of Neurosurgery, State University of New York, Upstate Medical University, Syracuse, NY 13210, USA; Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA; Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA. Electronic address:

Chronic stroke is the phase of brain recovery and repair generally beginning 3 months after stroke onset. No pharmaceutical approach is currently available to enhance brain repair in chronic stroke. We have previously determined the therapeutic effects of stem cell factor (SCF) and granulocyte-colony stimulating factor (G-CSF) alone or in combination (SCF+G-CSF) in an animal model of chronic stroke and demonstrated that only SCF+G-CSF induces long-term functional recovery. However, the mechanism underlying the SCF+G-CSF-induced brain repair in chronic stroke remains largely elusive. In the present study, we determined the role of nuclear factor-kappa B (NF-κB) in neurovascular network remodeling and motor function improvement by SCF+G-CSF treatment in chronic stroke. SCF+G-CSF was subcutaneously administered for 7 days beginning 17 weeks after induction of experimental stroke. To inhibit NF-κB activation, NF-κB inhibitor was infused into the brain before SCF+G-CSF treatment. We observed that NF-κB inhibitor abolished the SCF+G-CSF-induced axonal sprouting, synaptogenesis and angiogenesis in the ipsilesional somatosensorimotor cortex. In addition, blockage of NF-κB activation resulted in elimination of the SCF+G-CSF-induced motor functional restoration in chronic stroke. These data suggest that NF-κB is required for the SCF+G-CSF-induced neuron-vascular network remodeling in the ipsilesional somatosensorimotor cortex and motor functional recovery in chronic stroke.
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http://dx.doi.org/10.1016/j.expneurol.2014.08.026DOI Listing
January 2015

Implementation of the best practice in nasogastric tube feeding of critically ill patients in a neurosurgical intensive care unit.

Int J Evid Based Healthc 2013 Jun;11(2):128-33

Huashan Hospital affiliated to Fudan University, Shanghai, China.

Objectives: This project was designed to implement the best practice in nasogastric tube feeding of critically ill patients in a neurosurgical intensive care unit.

Methods: Clinical audit software programmes of the Joanna Briggs Institute (Practical Application of Clinical Evidence System and Getting Research Into Practice) were used in this project. A baseline audit, feedback, follow-up audit cycle was followed. The audit team analysed the results of the baseline audit, conducted a situational analysis and formulated and implemented a strategic plan to improve the nasogastric tube care.

Results: Initially, the compliance with the criteria varied from 0% to 87%. The Getting Research Into Practice phase of the project identified several barriers of each criterion. After implementation of best practice, the following audit showed an improvement in all criteria, ranging from 33% to 95%. Marked improvement was achieved in the criteria that were not strictly required by local standards, such as rechecking the tube position, assessing the gastric residual volume and maintaining the airway cuff pressure.

Conclusion: The project had some success in improving the practice of nasogastric tube feeding. Collaboration, education, monitoring and a reward system were the key elements used to drive the project. Further actions and changes are expected to produce 100% compliance.
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http://dx.doi.org/10.1111/1744-1609.12020DOI Listing
June 2013

Myelin specific cells infiltrate MCAO lesions and exacerbate stroke severity.

Metab Brain Dis 2012 Mar 12;27(1):7-15. Epub 2011 Oct 12.

Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR, USA.

Although inflammatory responses increase stroke severity, the role of immune cells specific for central nervous system (CNS) antigens remains controversial. Disruption of the blood-brain barrier (BBB) during stroke allows CNS antigens to leak into the peripheral circulation and enhances access of circulating leukocytes to the brain, including those specific for CNS antigens such as myelin oligodendrocyte glycoprotein (MOG) that can induce experimental autoimmune encephalomyelitis (EAE). We here demonstrate for the first time that myelin reactive splenocytes specific for MOG transferred into severe combined immunodeficient (SCID) mice can migrate into the infarct hemisphere of recipients subjected to 60 min middle cerebral artery occlusion (MCAO) and 96 h reperfusion; moreover these cells exacerbate infarct volume and worsen neurological deficits compared to animals transferred with naïve splenocytes. These findings indicate that autoimmunity in the CNS can exert detrimental injury on brain cells and worsen the damage from ischemic stroke.
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http://dx.doi.org/10.1007/s11011-011-9267-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3270145PMC
March 2012

Recombinant T cell receptor ligands improve outcome after experimental cerebral ischemia.

Transl Stroke Res 2011 Sep;2(3):404-10

Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA.

A key target for novel stroke therapy is the regulation of post-ischemic inflammatory mechanisms. Recent evidence emphasizes the role of T lymphocytes of differing subtypes in the evolution is ischemic brain damage. We have recently demonstrated the benefit of myelin antigen-specific immunodulatory agents known as recombinant T cell receptor ligands (RTLs) in a standard murine model of focal stroke. The aim of the current study was to extend this initial observation to RTL treatment in a therapeutically relevant timing after middle cerebral artery occlusion (MCAO) and verify functional benefit to complement histological outcome measures. We observed that the administration of mouse-specific RTL551 reduced infarct size and improved sensorimotor outcome when administered within a 3 h post-ischemic therapeutic window. RTL551 treatment reduced cortical, caudate putamen, and total infarct volume as compared to vehicle-treated mice. Using a standard behavioral testing repertoire, we observed that RTL551 reduced sensorimotor impairment 3 days after MCAO. Humanized RTL1000 (HLA-DR2 moiety linked to hMOG-35-55 peptide) also reduced infarct size in HLA-DR2 transgenic mice. These data indicate that this neuroantigen-specific immunomodulatory agent reduces damage when administered in a therapeutically relevant reperfusion timeframe.
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http://dx.doi.org/10.1007/s12975-011-0085-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181103PMC
September 2011

Programmed death-1 pathway limits central nervous system inflammation and neurologic deficits in murine experimental stroke.

Stroke 2011 Sep 7;42(9):2578-83. Epub 2011 Jul 7.

DrMed, Neuroimmunology Research, R&D-31, Portland Veterans Affairs Medical Center, 3710 SW US Veterans Hospital Road, Portland, OR 97239, USA.

Background And Purpose: Evaluation of infarct volumes and infiltrating immune cell populations in mice after middle cerebral artery occlusion strongly implicates a mixture of both pathogenic and regulatory immune cell subsets that affect stroke outcome. Our goal was to evaluate the contribution of the well-described coinhibitory pathway, programmed death (PD)-1, to the development of middle cerebral artery occlusion.

Methods: Infarct volumes, functional outcomes, and effects on infiltrating immune cell populations were compared in wild-type C57BL/6 versus PD-1-deficient mice after 60 minutes middle cerebral artery occlusion and 96 hours reperfusion.

Results: The results clearly demonstrate a previously unrecognized activity of the PD-1 pathway to limit infarct volume, recruitment of inflammatory cells from the periphery, activation of macrophages and central nervous system microglia, and functional neurological deficits. These regulatory functions were associated with increased percentages of circulating PD-ligand-1 and PD-ligand-2 expressing CD19(+) B-cells in blood, the spleen, and central nervous system with the capacity to inhibit activation of inflammatory T-cells and central nervous system macrophages and microglial cells through upregulated PD-1.

Conclusions: Our novel observations are the first to implicate PD-1 signaling as a major protective pathway for limiting central nervous system inflammation in middle cerebral artery occlusion. This inhibitory circuit would likely be pivotal in reducing stroke-associated Toll-like receptor-2- and Toll like receptor-4-mediated release of neurotoxic factors by activated central nervous system microglia.
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http://dx.doi.org/10.1161/STROKEAHA.111.613182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164218PMC
September 2011

Regulatory B cells limit CNS inflammation and neurologic deficits in murine experimental stroke.

J Neurosci 2011 Jun;31(23):8556-63

Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, Oregon 97239, USA.

Evaluation of infarct volumes and infiltrating immune cell populations in mice after middle cerebral artery occlusion (MCAO) strongly implicates a mixture of both pathogenic and regulatory immune cell subsets in stroke pathogenesis and recovery. Our goal was to evaluate the contribution of B cells to the development of MCAO by comparing infarct volumes and functional outcomes in wild-type (WT) versus B-cell-deficient μMT(-/-) mice. The results clearly demonstrate larger infarct volumes, higher mortality, more severe functional deficits, and increased numbers of activated T cells, macrophages, microglial cells, and neutrophils in the affected brain hemisphere of MCAO-treated μMT(-/-) versus WT mice. These MCAO-induced changes were completely prevented in B-cell-restored μMT(-/-) mice after transfer of highly purified WT GFP(+) B cells that were detected in the periphery, but not the CNS. In contrast, transfer of B cells from IL-10(-/-) mice had no effect on infarct volume when transferred into μMT(-/-) mice. These findings strongly support a previously unrecognized activity of IL-10-secreting WT B cells to limit infarct volume, mortality rate, recruitment of inflammatory cells, and functional neurological deficits 48 h after MCAO. Our novel observations are the first to implicate IL-10-secreting B cells as a major regulatory cell type in stroke and suggest that enhancement of regulatory B cells might have application as a novel therapy for this devastating neurologic condition.
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http://dx.doi.org/10.1523/JNEUROSCI.1623-11.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3111929PMC
June 2011

Therapy with recombinant T-cell receptor ligand reduces infarct size and infiltrating inflammatory cells in brain after middle cerebral artery occlusion in mice.

Metab Brain Dis 2011 Jun 7;26(2):123-33. Epub 2011 Apr 7.

Department of Anesthesiology & Peri-Operative Medicine, Oregon Health & Science University, Portland, USA.

Stroke induces a biphasic effect on the peripheral immune response that involves early activation of peripheral leukocytes followed by severe immunosuppression and atrophy of the spleen. Peripheral immune cells, including T lymphocytes, migrate to the brain and exacerbate the developing infarct. Recombinant T-cell receptor (TCR) Ligand (RTL)551 is designed as a partial TCR agonist for myelin oligodendrocyte glycoprotein (MOG)-reactive T cells and has demonstrated the capacity to limit infarct volume and inflammation in brain when administered to mice undergoing middle cerebral artery occlusion (MCAO). The goal of this study was to determine if RTL551 could retain protection when given within the therapeutically relevant 4 h time window currently in clinical practice for stroke patients. RTL551 was administered subcutaneously 4 h after MCAO, with repeated doses every 24 h until the time of euthanasia. Cell numbers were assessed in the brain, blood, spleen and lymph nodes and infarct size was measured after 24 and 96 h reperfusion. RTL551 reduced infarct size in both cortex and striatum at 24 h and in cortex at 96 h after MCAO and inhibited the accumulation of inflammatory cells in brain at both time points. At 24 h post-MCAO, RTL551 reduced the frequency of the activation marker, CD44, on T-cells in blood and in the ischemic hemisphere. Moreover, RTL551 reduced expression of the chemokine receptors, CCR5 in lymph nodes and spleen, and CCR7 in the blood and lymph nodes. These data demonstrate effective treatment of experimental stroke with RTL551 within a therapeutically relevant 4 h time window through immune regulation of myelin-reactive inflammatory T-cells.
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http://dx.doi.org/10.1007/s11011-011-9241-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3111858PMC
June 2011