Refine
Has Fulltext
- yes (36)
Is part of the Bibliography
- yes (36)
Year of publication
Document Type
- Journal article (36)
Language
- English (36)
Keywords
- ischemic stroke (12)
- inflammation (5)
- middle cerebral artery occlusion (5)
- blood-brain barrier (4)
- neuroinflammation (4)
- thrombo-inflammation (4)
- blood–brain barrier (3)
- deep brain stimulation (3)
- experimental stroke (3)
- inflammasome (3)
- mechanical thrombectomy (3)
- mesencephalic locomotor region (3)
- neutrophils (3)
- photothrombotic stroke (3)
- stroke (3)
- tight junctions (3)
- B cells (2)
- NLRP3 (2)
- acute ischemic stroke (2)
- biomarker (2)
- endoglin (2)
- glycoprotein receptor Ib (2)
- hypoxia (2)
- immune cells (2)
- immunohistochemistry (2)
- ischemic penumbra (2)
- leukocytes (2)
- lymphocytes (2)
- multiple sclerosis (2)
- platelets (2)
- thrombosis (2)
- transient middle cerebral artery occlusion (2)
- ASC (1)
- C1-inhibitor (1)
- CD105 (1)
- CXCL4 (1)
- CXCL5 (1)
- CXCL7 (1)
- CXCL8 (1)
- CXCR2 (1)
- Cell Index (1)
- Cerebral-ischemia (1)
- EAE (1)
- FTY720-P (1)
- HBMEC (1)
- HMGB1 (1)
- Head-injury (1)
- Hemodynamic depression (1)
- Intravascular coagulation (1)
- K+ channel (1)
- K2P channels (1)
- KCNK5 (1)
- K\(_{2P}\)5.1 (1)
- MCC950 (1)
- Mice (1)
- Model (1)
- Molecular-weight heparin (1)
- NAP-2 (1)
- NETs (1)
- NOAC (1)
- Orai2 (1)
- PF4 (1)
- Rats (1)
- SB332235 (1)
- Schlaganfall (1)
- Sphingosine 1-Phosphate (1)
- T lymphocytes (1)
- T-cells (1)
- TASK2 (1)
- Thrombus formation (1)
- Zonula Occludens-1 (1)
- [18F]FDG positron emission tomography (1)
- adhesion molecules (1)
- alpha-7 nicotinic acetylcholine receptor (1)
- animal model (1)
- autoimmune neuroinflammation (1)
- blood coagulation (1)
- blood flow (1)
- brain endothelium (1)
- cerebral inflammation (1)
- cerebral ischemia (1)
- cerebral small vessel disease (1)
- cerebrovascular disorders (1)
- chemokines (1)
- choline acetyltransferase (1)
- chronic cerebrovascular disease (1)
- collagens (1)
- collateral circulation (1)
- contact-kinin system (1)
- dendric cells (1)
- dimethyl fumarate (1)
- domain potassium channels (1)
- edema (1)
- edoxaban (1)
- endothelial cells (1)
- experimental autoimmune encephalomyelitis (1)
- factor XII (1)
- fullerenes (1)
- glycoprotein VI (1)
- glycoprotein receptor Ibα (1)
- hemorrhagic transformation (1)
- histology (1)
- human brain endothelium (1)
- human cerebral endothelial cells (1)
- hypercholesterolemia (1)
- i.v. thrombolysis (1)
- in-vivo (1)
- infarction (1)
- integrin α2 (1)
- integrins (1)
- interleukin-8 (1)
- intracranial bleeding (1)
- invasive electric stimulation (1)
- ion channels (1)
- ischemia/reperfusion injury (1)
- large vessel occlusion (1)
- matrix metalloproteinases (1)
- monocytes (1)
- mouse brain microvascular endothelial cell cultur (1)
- mouse model (1)
- multiple-sclerosis (1)
- natural killer cells (1)
- neurology (1)
- neuronal apoptosis (1)
- neuronal network (1)
- neuroprotection (1)
- novo renal transplantation (1)
- occlusion (1)
- ph (1)
- photothrombosis (1)
- platelet activation (1)
- platelet aggregation (1)
- potassium channels (1)
- preclinical research (1)
- randomized controlled trial (1)
- rat brain microvascular endothelial cell culture (1)
- recombinant tissue-type plasminogen activator (1)
- regulatory T cells (1)
- relapsing multiple sclerosis (1)
- reoxygenation (1)
- reperfusion injury (1)
- rt-PA (1)
- secondary infarct growth (1)
- serotonin (1)
- shedding (1)
- skilled forelimb movements (1)
- soluble endoglin (1)
- subthalamic nucleus (1)
- tMCAO (1)
- thrombemboli (1)
- thromboemboli (1)
- thromboinflammation (1)
- thrombus formation (1)
- transient middle cerebral artery (1)
- transient middle cerebral artery occlusion model (1)
- traumatic brain injury (1)
- up-regulation (1)
- vascular homeostasis (1)
- vascular permeability (1)
- volume regulation (1)
Institute
- Neurologische Klinik und Poliklinik (36)
- Institut für diagnostische und interventionelle Neuroradiologie (ehem. Abteilung für Neuroradiologie) (10)
- Rudolf-Virchow-Zentrum (9)
- Institut für Experimentelle Biomedizin (7)
- Kinderklinik und Poliklinik (2)
- Neurochirurgische Klinik und Poliklinik (2)
- Deutsches Zentrum für Herzinsuffizienz (DZHI) (1)
- Institut für Anatomie und Zellbiologie (1)
- Institut für Klinische Biochemie und Pathobiochemie (1)
- Institut für Klinische Epidemiologie und Biometrie (1)
Sonstige beteiligte Institutionen
Background:
Ischemic stroke causes a strong inflammatory response that includes T cells, monocytes/macrophages, and neutrophils. Interaction of these immune cells with platelets and endothelial cells facilitates microvascular dysfunction and leads to secondary infarct growth. We recently showed that blocking of platelet glycoprotein (GP) receptor Ib improves stroke outcome without increasing the risk of intracerebral hemorrhage. Until now, it has been unclear whether GPIb only mediates thrombus formation or also contributes to the pathophysiology of local inflammation.
Methods:
Focal cerebral ischemia was induced in C57BL/6 mice by a 60-min transient middle cerebral artery occlusion (tMCAO). Animals were treated with antigen-binding fragments (Fab) against the platelet surface molecules GPIb (p0p/B Fab). Rat immunoglobulin G (IgG) Fab was used as control treatment. Stroke outcome, including infarct size and functional deficits as well as the local inflammatory response, was assessed on day 1 after tMCAO.
Results:
Blocking of GPIb reduced stroke size and improved functional outcome on day 1 after tMCAO without increasing the risk of intracerebral hemorrhage. As expected, disruption of GPIb-mediated pathways in platelets significantly reduced thrombus burden in the cerebral microvasculature. In addition, inhibition of GPIb limited the local inflammatory response in the ischemic brain as indicated by lower numbers of infiltrating T cells and macrophages and lower expression levels of inflammatory cytokines compared with rat IgG Fab-treated controls.
Conclusion:
In acute ischemic stroke, thrombus formation and inflammation are closely intertwined (“thrombo-inflammation”). Blocking of platelet GPIb can ameliorate thrombo-inflammation.
Lymphocytes express potassium channels that regulate physiological cell functions, such as activation, proliferation and migration. Expression levels of K\(_{2P}\)5.1(TASK2; KCNK5) channels belonging to the family of two-pore domain potassium channels have previously been correlated to the activity of autoreactive T lymphocytes in patients with multiple sclerosis and rheumatoid arthritis. In humans, K\(_{2P}\)5.1 channels are upregulated upon T cell stimulation and influence T cell effector functions. However, a further clinical translation of targeting K\(_{2P}\)5.1 is currently hampered by a lack of highly selective inhibitors, making it necessary to evaluate the impact of KCNK5 in established preclinical animal disease models. We here demonstrate that K\(_{2P}\)5.1 knockout (K\(_{2P}\)5.1\(^{-/-}\) mice display no significant alterations concerning T cell cytokine production, proliferation rates, surface marker molecules or signaling pathways. In an experimental model of autoimmune neuroinflammation, K\(_{2P}\)5.1\(^{-/-}\) mice show a comparable disease course to wild-type animals and no major changes in the peripheral immune system or CNS compartment. A compensatory upregulation of the potassium channels K\(_{2P}\)3.1 and K\(_{V}\)1.3 seems to counterbalance the deletion of K\(_{2P}\)5.1. As an alternative model mimicking autoimmune neuroinflammation, experimental autoimmune encephalomyelitis in the common marmoset has been proposed, especially for testing the efficacy of new potential drugs. Initial experiments show that K\(_{2P}\)5.1 is functionally expressed on marmoset T lymphocytes, opening up the possibility for assessing future K\(_{2P}\)5.1-targeting drugs.
Background
Serotonin (5-hydroxytryptamin, 5-HT) is an indolamine platelet agonist, biochemically derived from tryptophan. 5-HT is secreted from the enterochromaffin cells into the gastrointestinal tract and blood. Blood 5-HT has been proposed to regulate hemostasis by acting as a vasoconstrictor and by triggering platelet signaling through 5-HT receptor 2A (5HTR2A). Although platelets do not synthetize 5-HT, they take 5-HT up from the blood and store it in their dense granules which are secreted upon platelet activation.
Objective
To identify the molecular composite of the 5-HT uptake system in platelets and elucidate the role of platelet released 5-HT in thrombosis and ischemic stroke. Methods: 5-HT transporter knockout mice (5Htt\(^{-/-}\)) were analyzed in different in vitro and in vivo assays and in a model of ischemic stroke.
Results
In 5Htt\(^{-/-}\) platelets, 5-HT uptake from the blood was completely abolished and agonist-induced Ca2+ influx through store operated Ca\(^{2+}\) entry (SOCE), integrin activation, degranulation and aggregation responses to glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC-2) were reduced. These observed in vitro defects in 5Htt\(^{-/-}\) platelets could be normalized by the addition of exogenous 5-HT. Moreover, reduced 5-HT levels in the plasma, an increased bleeding time and the formation of unstable thrombi were observed ex vivo under flow and in vivo in the abdominal aorta and carotid artery of 5Htt\(^{-/-}\) mice. Surprisingly, in the transient middle cerebral artery occlusion (tMCAO) model of ischemic stroke 5Htt\(^{-/-}\) mice showed nearly normal infarct volume and the neurological outcome was comparable to control mice.
Conclusion
Although secreted platelet 5-HT does not appear to play a crucial role in the development of reperfusion injury after stroke, it is essential to amplify the second phase of platelet activation through SOCE and plays an important role in thrombus stabilization.
Immune cells (IC) play a crucial role in murine stroke pathophysiology. However, data are limited on the role of these cells in ischemic stroke in humans. We therefore aimed to characterize and compare peripheral IC subsets in patients with acute ischemic stroke/transient ischemic attack (AIS/TIA), chronic cerebrovascular disease (CCD) and healthy volunteers (HV). We conducted a case-control study of patients with AIS/TIA (n = 116) or CCD (n = 117), and HV (n = 104) who were enrolled at the University Hospital Würzburg from 2010 to 2013. We determined the expression and quantity of IC subsets in the three study groups and performed correlation analyses with demographic and clinical parameters. The quantity of several IC subsets differed between the AIS/TIA, CCD, and HV groups. Several clinical and demographic variables independently predicted the quantity of IC subsets in patients with AIS/TIA. No significant changes in the quantity of IC subsets occurred within the first three days after AIS/TIA. Overall, these findings strengthen the evidence for a pathophysiologic role of IC in human ischemic stroke and the potential use of IC-based biomarkers for the prediction of stroke risk. A comprehensive description of IC kinetics is crucial to enable the design of targeted treatment strategies.
Traumatic brain injury (TBI) induces a strong inflammatory response which includes blood-brain barrier damage, edema formation and infiltration of different immune cell subsets. More recently, microvascular thrombosis has been identified as another pathophysiological feature of TBI. The contact-kinin system represents an interface between inflammatory and thrombotic circuits and is activated in different neurological diseases. C1-Inhibitor counteracts activation of the contact-kinin system at multiple levels. We investigated the therapeutic potential of C1-Inhibitor in a model of TBI. Male and female C57BL/6 mice were subjected to cortical cryolesion and treated with C1-Inhibitor after 1 h. Lesion volumes were assessed between day 1 and day 5 and blood-brain barrier damage, thrombus formation as well as the local inflammatory response were determined post TBI. Treatment of male mice with 15.0 IU C1-Inhibitor, but not 7.5 IU, 1 h after cryolesion reduced lesion volumes by ~75% on day 1. This protective effect was preserved in female mice and at later stages of trauma. Mechanistically, C1-Inhibitor stabilized the blood-brain barrier and decreased the invasion of immune cells into the brain parenchyma. Moreover, C1-Inhibitor had strong antithrombotic effects. C1-Inhibitor represents a multifaceted anti-inflammatory and antithrombotic compound that prevents traumatic neurodegeneration in clinically meaningful settings.
Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox42/2) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox42/2 mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy.