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Berlin Brandenburg

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  • 1
    Language: English
    In: Blood, 23 March 2017, Vol.129(12), pp.1702-1706
    Description: Platelets maintain hemostasis after injury, but also during inflammation. Recent studies have shown that platelets prevent inflammatory bleeding through (hem) immunoreceptor tyrosine-based activation motif-dependent mechanisms irrespective of aggregation during skin and lung inflammation. Although the exact mechanisms underlying this process remain unknown, it was speculated that mediators released from platelet granules might be involved. Maintaining cerebral hemostasis during stroke treatment is of high clinical relevance because hemorrhage may aggravate the disease state and increase mortality. Although it was shown that platelets help maintain hemostasis in the ischemic brain, their exact contribution remains ill defined. Here we show that / mice, which lack platelet α- and dense-granule secretion, show no signs of hemorrhage in models of skin or lung inflammation. In stark contrast, lack of platelet granule release resulted in impaired hemostasis in the ischemic brain after transient middle cerebral artery occlusion leading to increased intracranial hemorrhage and mortality. Our results reveal for the first time that platelet granule constituents are essential for maintenance of hemostasis during thrombo-inflammatory brain infarction but not experimental inflammation of the skin or lung, thereby uncovering vascular bed-specific differences in the prevention of inflammatory bleeding.
    Keywords: Blood Platelets -- Metabolism ; Brain Ischemia -- Pathology ; Cerebral Hemorrhage -- Prevention & Control
    ISSN: 00064971
    E-ISSN: 1528-0020
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States, Sept 3, 2013, Vol.110(36), p.14735(6)
    Description: Disruption of the blood--brain barrier (BBB) is a hallmark of acute inflammatory lesions in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis. This disruption may precede and facilitate the infiltration of encephalitogenic T cells. The signaling events that lead to this BBB disruption are incompletely understood but appear to involve dysregulation of tight-junction proteins such as claudins. Pharmacological interventions aiming at stabilizing the BBB in MS might have therapeutic potential. Here, we show that the orally available small molecule LY-317615, a synthetic bisindolylmaleimide and inhibitor of protein kinase C[beta], which is clinically under investigation for the treatment of cancer, suppresses the transmigration of activated T cells through an inflamed endothelial cell barrier, where it leads to the induction of the tight-junction molecules zona occludens-1, claudin 3, and claudin 5 and other pathways critically involved in transendothelial leukocyte migration. Treatment of mice with ongoing experimental autoimmune encephalomyelitis with LY-317615 ameliorates inflammation, demyelination, axonal damage, and clinical symptoms. Although LY-317615 dose-dependently suppresses T-cell proliferation and cytokine production independent of antigen specificity, its therapeutic effect is abrogated in a mouse model requiring pertussis toxin. This abrogation indicates that the anti-inflammatory and clinical efficacy is mainly mediated by stabilization of the BBB, thus suppressing the transmigration of encephalitogenic T cells. Collectively, our data suggest the involvement of endothelial protein kinase C[beta] in stabilizing the BBB in autoimmune neuroinflammation and imply a therapeutic potential of BBB-targeting agents such as LY-317615 as therapeutic approaches for MS. EAE | enzastaurin | CNS www.pnas.org/cgi/doi/10.1073/pnas.1302569110
    Keywords: Protein Kinases -- Physiological Aspects ; Protein Kinases -- Health Aspects ; Blood-brain Barrier -- Physiological Aspects ; Blood-brain Barrier -- Health Aspects ; Encephalomyelitis -- Physiological Aspects
    ISSN: 0027-8424
    Source: Cengage Learning, Inc.
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  • 3
    In: Stroke, 2015, Vol.46(12), pp.3502-3506
    Description: BACKGROUND AND PURPOSE—: Despite the medical and socioeconomic effect of ischemic stroke and extensive preclinical research, treatment options for ischemic stroke are limited. We recently identified and characterized essential steps of thrombus formation in stroke and demonstrated that inhibition of the platelet glycoprotein (GP) receptors Ib and VI, but not IIb/IIIa, protects young and healthy mice from ischemic neurodegeneration. Whether these findings translate to the clinic remains unclear. Considering that the typical stroke patient is elderly with comorbidity, we aimed to analyze the efficacy and safety of novel preclinical antithrombotics in adult and comorbid mice with acute experimental stroke. METHODS—: We subjected adult, healthy, atherosclerotic (Ldlr), diabetic (streptozotocin treated), and hypertensive (RenTgMK) mice to a 60-minute transient middle cerebral artery occlusion. Animals were pretreated with anti-GPVI antibodies or treated 1 hour after stroke induction with anti-GPIb or anti-GPIIb/IIIa antigen–binding fragments, respectively. Isotype treatment served as control. Twenty-four hours after transient middle cerebral artery occlusion, we visually assessed the intracerebral hemorrhage rate and measured infarct volumes (using 2,3,5-triphenyltetrazolium chloride–stained brain slices) and functional outcome (using Bederson and grip-test scores). RESULTS—: GPIb and GPVI inhibition protected the mice from ischemic stroke without increasing bleeding complications. In contrast, GPIIb/IIIa inhibition was not protective but increased the intracerebral hemorrhage rate. CONCLUSIONS—: Inhibition of early steps of thrombus formation protects adult and comorbid mice from ischemic stroke. The use of clinically meaningful mouse strains might improve the translation of preclinical stroke research to the clinic.
    Keywords: Aging–Drug Effects ; Animals–Metabolism ; Disease Models, Animal–Pathology ; Immunoglobulin Fab Fragments–Pharmacology ; Male–Therapeutic Use ; Mice–Metabolism ; Mice, Inbred C57bl–Drug Therapy ; Mice, Knockout–Metabolism ; Mice, Transgenic–Pathology ; Platelet Glycoprotein Gpiib-Iiia Complex–Pathology ; Stroke–Pathology ; Treatment Outcome–Pathology ; Immunoglobulin Fab Fragments ; Platelet Glycoprotein Gpiib-Iiia Complex ; Middle Cerebral Artery Occlusion ; Platelet Aggregation Inhibitors ; Streptozotocin ; Stroke ; Translation;
    ISSN: 0039-2499
    E-ISSN: 15244628
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  • 4
    Language: English
    In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, August 2014, Vol.28(8), pp.3435-45
    Description: CD4(+) T cells expressing the immunotolerizing molecule HLA-G have been described as a unique human thymus-derived regulatory T (tTreg) cell subset involved in immunoregulation and parenchymal homeostasis during infectious and autoimmune inflammation. We compared properties and molecular characteristics of human CD4(+)HLA-G(+) with those of CD4(+)CD25(+)FoxP3-expressing tTreg cells using in vitro studies of T-cell receptor (TCR) signaling, single-cell electrophysiology, and functional in vivo studies. Both tTreg populations are characterized by alterations in proximal-signaling pathways on TCR stimulation and a hyperpolarization of the plasma membrane when compared to conventional CD4(+) T cells. However, both clearly differ in phenotype and pattern of secreted cytokines, which results in distinct mechanisms of suppression: While CD4(+)HLA-G(+) cells secrete high levels of inhibitory molecules (IL-10, soluble HLA-G, IL-35), CD4(+)CD25(+)FoxP3(+) cells express these molecules at significantly lower levels and seem to exert their function mainly in a contact-dependent manner via cyclic adenosine-monophosphate. Finally we demonstrate that human CD4(+)HLA-G(+) tTreg cells significantly ameliorated graft-versus-host disease in a humanized mouse model as a first proof of their in vivo relevance. Our data further characterize and establish CD4(+)HLA-G(+) cells as a potent human tTreg population that can modulate polyclonal adaptive immune responses in vivo and thus being a promising candidate for potential clinical applications in the future.
    Keywords: Human Leukocyte Antigen G ; Humanized Mouse Model ; Immune Tolerance ; Membrane Potential of Ttreg Cells ; Adoptive Transfer ; Cd4-Positive T-Lymphocytes -- Immunology ; Graft Vs Host Disease -- Prevention & Control ; Immunosuppression -- Methods ; Leukocytes, Mononuclear -- Transplantation ; T-Lymphocyte Subsets -- Immunology ; T-Lymphocytes, Regulatory -- Immunology
    ISSN: 08926638
    E-ISSN: 1530-6860
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  • 5
    In: Annals of Neurology, November 2017, Vol.82(5), pp.828-840
    Description: One-third of all stroke survivors are unable to walk, even after intensive physiotherapy. Thus, other concepts to restore walking are needed. Because electrical stimulation of the mesencephalic locomotor region (MLR) is known to elicit gait movements, this area might be a promising target for restorative neurostimulation in stroke patients with gait disability. The present study aims to delineate the effect of high-frequency stimulation of the MLR (MLR-HFS) on gait impairment in a rodent stroke model. Male Wistar rats underwent photothrombotic stroke of the right sensorimotor cortex and chronic implantation of a stimulating electrode into the right MLR. Gait was assessed using clinical scoring of the beam-walking test and video-kinematic analysis (CatWalk) at baseline and on days 3 and 4 after experimental stroke with and without MLR-HFS. Kinematic analysis revealed significant changes in several dynamic and static gait parameters resulting in overall reduced gait velocity. All rats exhibited major coordination deficits during the beam-walking challenge and were unable to cross the beam. Simultaneous to the onset of MLR-HFS, a significantly higher walking speed and improvements in several dynamic gait parameters were detected by the CatWalk system. Rats regained the ability to cross the beam unassisted, showing a reduced number of paw slips and misses. MLR-HFS can improve disordered locomotor function in a rodent stroke model. It may act by shielding brainstem and spinal locomotor centers from abnormal cortical input after stroke, thus allowing for compensatory and independent action of these circuits. Ann Neurol 2017;82:828-840.
    Keywords: Deep Brain Stimulation ; Gait -- Physiology ; Mesencephalon -- Physiology ; Stroke -- Therapy;
    ISSN: 0364-5134
    E-ISSN: 1531-8249
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  • 6
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 03 September 2013, Vol.110(36), pp.14735-40
    Description: Disruption of the blood-brain barrier (BBB) is a hallmark of acute inflammatory lesions in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis. This disruption may precede and facilitate the infiltration of encephalitogenic T cells. The signaling events that lead to this BBB disruption are incompletely understood but appear to involve dysregulation of tight-junction proteins such as claudins. Pharmacological interventions aiming at stabilizing the BBB in MS might have therapeutic potential. Here, we show that the orally available small molecule LY-317615, a synthetic bisindolylmaleimide and inhibitor of protein kinase Cβ, which is clinically under investigation for the treatment of cancer, suppresses the transmigration of activated T cells through an inflamed endothelial cell barrier, where it leads to the induction of the tight-junction molecules zona occludens-1, claudin 3, and claudin 5 and other pathways critically involved in transendothelial leukocyte migration. Treatment of mice with ongoing experimental autoimmune encephalomyelitis with LY-317615 ameliorates inflammation, demyelination, axonal damage, and clinical symptoms. Although LY-317615 dose-dependently suppresses T-cell proliferation and cytokine production independent of antigen specificity, its therapeutic effect is abrogated in a mouse model requiring pertussis toxin. This abrogation indicates that the anti-inflammatory and clinical efficacy is mainly mediated by stabilization of the BBB, thus suppressing the transmigration of encephalitogenic T cells. Collectively, our data suggest the involvement of endothelial protein kinase Cβ in stabilizing the BBB in autoimmune neuroinflammation and imply a therapeutic potential of BBB-targeting agents such as LY-317615 as therapeutic approaches for MS.
    Keywords: CNS ; Eae ; Enzastaurin ; Blood-Brain Barrier -- Drug Effects ; Encephalomyelitis, Autoimmune, Experimental -- Prevention & Control ; Indoles -- Pharmacology ; Protein Kinase C Beta -- Antagonists & Inhibitors
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 7
    In: Stroke, 2014, Vol.45(6), pp.1799-1806
    Description: BACKGROUND AND PURPOSE—: T lymphocytes have recently been identified as key mediators of tissue damage in ischemic stroke. The interaction between very late antigen-4 (VLA-4) and vascular adhesion molecule-1 is crucial for the transvascular egress of T lymphocytes, and inhibition of this interaction by specific antibodies is a powerful strategy to combat autoimmune neuroinflammation. However, whether pharmacological blocking of T-lymphocyte trafficking is also protective during brain ischemia is still unclear. We investigated the efficacy of a monoclonal antibody directed against VLA-4 in mouse models of ischemic stroke. METHODS—: Transient and permanent middle cerebral artery occlusion was induced in male C57Bl/6 mice. Animals treated with a monoclonal anti-CD49d antibody (300 μg) 24 hours before or 3 hours after the onset of cerebral ischemia and stroke outcome, including infarct size, functional status, and mortality, were assessed between day 1 and day 7. The numbers of immune cells invading the ischemic brain were determined by immunocytochemistry and flow cytometry. RESULTS—: Blocking of VLA-4 significantly reduced the invasion of T lymphocytes and neutrophils on day 5 after middle cerebral artery occlusion and inhibited the upregulation of vascular adhesion molecule-1. However, the anti-CD49d antibody failed to influence stroke outcome positively irrespective of the model or the time point investigated. CONCLUSIONS—: Pharmacological inhibition of the VLA-4/vascular adhesion molecule-1 axis in experimental stroke was ineffective in our hands. Our results cast doubt on the effectiveness of anti-CD49d as a stroke treatment. Further translational studies should be performed before testing anti–VLA-4 antibodies in patients with stroke.
    Keywords: Medicine;
    ISSN: 0039-2499
    E-ISSN: 15244628
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  • 8
    Language: English
    In: International Journal of Molecular Sciences, 01 August 2017, Vol.18(8), p.1783
    Description: Fullerenols, water-soluble C60-fullerene derivatives, have been shown to exert neuroprotective effects in vitro and in vivo, most likely due to their capability to scavenge free radicals. However, little is known about the effects of fullerenols on the blood–brain barrier (BBB), especially on cerebral endothelial cells under inflammatory conditions. Here, we investigated whether the treatment of primary mouse brain microvascular endothelial cells with fullerenols impacts basal and inflammatory blood–brain barrier (BBB) properties in vitro. While fullerenols (1, 10, and 100 µg/mL) did not change transendothelial electrical resistance under basal and inflammatory conditions, 100 µg/mL of fullerenol significantly reduced erk1/2 activation and resulted in an activation of NFκB in an inflammatory milieu. Our findings suggest that fullerenols might counteract oxidative stress via the erk1/2 and NFκB pathways, and thus are able to protect microvascular endothelial cells under inflammatory conditions.
    Keywords: Fullerenes ; Blood-Brain Barrier ; Mouse Brain Microvascular Endothelial Cell Culture ; Inflammation ; Tight Junctions ; Adhesion Molecules ; Biology
    E-ISSN: 1422-0067
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  • 9
    Language: English
    In: Blood, 01 January 2015, Vol.125(1), pp.185-94
    Description: Glycoprotein VI and C-type lectin-like receptor 2 are essential platelet activating receptors in hemostasis and thrombo-inflammatory disease, which signal through a (hem)immunoreceptor tyrosine-based activation motif (ITAM)-dependent pathway. The adapter molecules Src-like adapter proteins (SLAP and SLAP2) are involved in the regulation of immune cell surface expression and signaling, but their function in platelets is unknown. In this study, we show that platelets expressed both SLAP isoforms and that overexpression of either protein in a heterologous cell line almost completely inhibited glycoprotein VI and C-type lectin-like receptor 2 signaling. In mice, single deficiency of SLAP or SLAP2 had only moderate effects on platelet function, whereas double deficiency of both adapters resulted in markedly increased signal transduction, integrin activation, granule release, aggregation, procoagulant activity, and thrombin generation in response to (hem)ITAM-coupled, but not G protein-coupled, receptor activation. In vivo, constitutive SLAP/SLAP2 knockout mice displayed accelerated occlusive arterial thrombus formation and a dramatically worsened outcome after focal cerebral ischemia. This was attributed to the absence of both adapter proteins in platelets, as demonstrated by adoptive transfer of Slap(-/-)/Slap2(-/-) platelets into wild-type mice. Our results establish SLAP and SLAP2 as critical inhibitors of platelet (hem)ITAM signaling in the setting of arterial thrombosis and ischemic stroke.
    Keywords: Signal Transduction ; Adaptor Proteins, Signal Transducing -- Metabolism ; Brain Infarction -- Metabolism ; Proto-Oncogene Proteins Pp60(C-Src) -- Metabolism ; Thrombosis -- Metabolism
    ISSN: 00064971
    E-ISSN: 1528-0020
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  • 10
    Language: English
    In: Blood, 24 January 2013, Vol.121(4), pp.679-91
    Description: We have recently identified T cells as important mediators of ischemic brain damage, but the contribution of the different T-cell subsets is unclear. Forkhead box P3 (FoxP3)-positive regulatory T cells (Tregs) are generally regarded as prototypic anti-inflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. In the present study, we examined the role of Tregs after experimental brain ischemia/reperfusion injury. Selective depletion of Tregs in the DEREG mouse model dramatically reduced infarct size and improved neurologic function 24 hours after stroke and this protective effect was preserved at later stages of infarct development. The specificity of this detrimental Treg effect was confirmed by adoptive transfer experiments in wild-type mice and in Rag1(-/-) mice lacking lymphocytes. Mechanistically, Tregs induced microvascular dysfunction in vivo by increased interaction with the ischemic brain endothelium via the LFA-1/ICAM-1 pathway and platelets and these findings were confirmed in vitro. Ablation of Tregs reduced microvascular thrombus formation and improved cerebral reperfusion on stroke, as revealed by ultra-high-field magnetic resonance imaging at 17.6 Tesla. In contrast, established immunoregulatory characteristics of Tregs had no functional relevance. We define herein a novel and unexpected role of Tregs in a primary nonimmunologic disease state.
    Keywords: Brain Ischemia -- Immunology ; Microvessels -- Physiopathology ; Stroke -- Metabolism ; T-Lymphocytes, Regulatory -- Metabolism
    ISSN: 00064971
    E-ISSN: 1528-0020
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