Refine
Has Fulltext
- yes (59)
Is part of the Bibliography
- yes (59)
Year of publication
Document Type
- Journal article (57)
- Report (2)
Language
- English (59) (remove)
Keywords
- ischemic stroke (11)
- B cells (5)
- acute ischemic stroke (4)
- factor XII (4)
- multiple sclerosis (4)
- traumatic brain injury (4)
- MS (3)
- Medizin (3)
- closed head injury (3)
- inflammation (3)
- trial (3)
- EAE (2)
- ELISPOT (2)
- Inflammation (2)
- Mice (2)
- NEUROWIND (2)
- Schlaganfall (2)
- biomarker (2)
- biomarkers (2)
- blood pressure (2)
- blood-brain barrier (2)
- cerebral autoregulation (2)
- chronic cerebrovascular disease (2)
- colony-stimulating factor (2)
- contact-kinin system (2)
- expression (2)
- generalized cerebral edema (2)
- immune cells (2)
- in vivo imaging (2)
- lymphocytes (2)
- neuroinflammation (2)
- neurology (2)
- neuroprotection (2)
- platelets (2)
- predictive value (2)
- relapse (2)
- reversible posterior leukoencephalopathy syndrome (2)
- von Willebrand factor (2)
- Alemtuzumab (1)
- Alzheimer’s disease (1)
- Arterial water (1)
- Brain (1)
- C1-inhibitor (1)
- CD52 (1)
- CNS (1)
- COU254 (1)
- Cerebral small vessel disease (1)
- Cerebral-ischemia (1)
- Coefficient (1)
- Crespi effect (1)
- ERK1/2 (1)
- Experimental stroke (1)
- FTY720 (1)
- FTY720-P (1)
- FXII (1)
- FXIIa inhibitor rHA-Infestin (1)
- Glatiramer acetate (1)
- Head-injury (1)
- Hemodynamic depression (1)
- IBA-1 (1)
- IL-15 (1)
- IntelliCage (1)
- Intravascular coagulation (1)
- Ischemia (1)
- Kaliumkanal (1)
- MIC ligands (1)
- MRI (1)
- Magnetic-resonance (1)
- Maus (1)
- Model (1)
- Molecular-weight heparin (1)
- NADPH oxidase inhibitors (1)
- NKG2D (1)
- NKG2D ligands (1)
- NMO-IGG (1)
- NMR-Tomographie (1)
- Neurodegeneration (1)
- Neurologie (1)
- PET (1)
- Perfusion (1)
- R-715 (1)
- RKIP (1)
- Rats (1)
- SHRSP (1)
- STAIR (1)
- Sphingosine 1-Phosphate (1)
- Stim (1)
- Stroke (1)
- T cell activation (1)
- TBI (1)
- TLO (1)
- TNF-α (1)
- TSPO (1)
- Thrombus (1)
- Thrombus formation (1)
- Vasodilatator-stimuliertes Phosphoprotein (1)
- Vasodilator-Stimulated Phosphoprotein (1)
- Von-Willebrand-factor (1)
- Wissenschaftlicher Nachwuchs (1)
- Zonula Occludens-1 (1)
- accuracy (1)
- acute management of stroke (1)
- acute neurology (1)
- acute stroke imaging (1)
- acute stroke management (1)
- acute stroke outcome (1)
- alias pilot trial (1)
- anti-aquaporin-4 antibody (1)
- antibodies (1)
- anticoagulants (1)
- aquaporin-4 autoantibodies (1)
- astrocyte (1)
- astrocytes (1)
- astrogliosis (1)
- atherosclerosis (1)
- autoradiography (1)
- blood (1)
- blood coagulability (1)
- blood coagulation (1)
- bradykinin (1)
- brain edema (1)
- cardiovascular disease (1)
- celiac disease (1)
- cerebral inflammation (1)
- cerebral ischemia (1)
- cerebral small vessel disease (1)
- cerebrospinal-fluid (1)
- cerebrovascular diseases (1)
- chronic kidney disease (1)
- coagulation (1)
- coagulation factor XIIa (1)
- contact activation system (1)
- cortical pathology (1)
- cutting edge (1)
- damage cool aid (1)
- darbepoetin alpha (1)
- demography (1)
- dendric cells (1)
- developmental signaling (1)
- diabetes mellitus (1)
- diffuse (1)
- dimethyl fumarate (1)
- disability (1)
- disease (1)
- disease-modifying therapy (1)
- echocardiography (1)
- edema (1)
- efficacy (1)
- ejection fraction (1)
- emulsions (1)
- endothelial cells (1)
- endothelin-1 (1)
- experimental autoimmune encephalomyelitis (1)
- experimental stroke (1)
- extensiv transverse myelitis (1)
- factor XI (1)
- feasibility (1)
- fingolimod (1)
- fluorine (1)
- focal (1)
- focal brain lesion (1)
- focal cerebral ischemia (1)
- focal cerebral-ischemia (1)
- free radical scavenger (1)
- glycoprotein Ib (1)
- glycoprotein receptor Ib (1)
- heart failure (1)
- histology (1)
- human muscle-cells (1)
- hypercholesterolemia (1)
- idiopathic inflammatory myopathies (1)
- immune-response (1)
- immunoglobulin-G (1)
- immunohistochemistry (1)
- in-vivo (1)
- increased risk (1)
- infarction (1)
- injection site reactions; (1)
- interleukin-1 receptor antagonist (1)
- intractable hiccup (1)
- intravenous thrombolysis (1)
- ischemia (1)
- ischemic cascade (1)
- kallikrein–kinin system (1)
- kinin receptor (1)
- kinin receptors (1)
- lesions (1)
- leukocytes (1)
- lymphokine-activated killer (1)
- macrophages (1)
- magnetic resonance imaging (1)
- matrix metalloproteinases (1)
- mechanical thrombectomy (1)
- mechanisms (1)
- mice (1)
- mice impact (1)
- microglia (1)
- microsphere/macrosphere (1)
- mitochondria (1)
- monocytes (1)
- mouse (1)
- mouse model (1)
- myasthenia gravis (1)
- natural history (1)
- neurobehavioural deficits (1)
- neurons (1)
- neurorepair (1)
- novo renal transplantation (1)
- object recognition memory (1)
- occlusion (1)
- oxidative stress (1)
- pathology section (1)
- permanent and transient middle cerebral artery occlusion (1)
- photothrombosis (1)
- placebo-controlled (1)
- point-of-care echocardiography (1)
- polymorphisms inflammation (1)
- polymyositis (1)
- prefrontal cortex (1)
- quality of life (1)
- randomized controlled trial (1)
- rat (1)
- rat brain microvascular endothelial cell culture (1)
- receptor (1)
- regulatory T cells (1)
- relapsing multiple sclerosis (1)
- relapsing-remitting multiple sclerosis (1)
- search filter (1)
- sex addiction (1)
- small vessel disease (1)
- stress (1)
- stroke (1)
- stroke unit (1)
- subcutaneous injection (1)
- systolic dysfunction (1)
- tMCAO (1)
- therapy (1)
- thrombo-inflammation (1)
- thromboembolic clot model (1)
- thromboembolic stroke (1)
- thromboinflammation (1)
- thrombosis (1)
- thrombus formation (1)
- tight junctions (1)
- tissue-plasminogen activator (1)
- transient middle cerebral artery (1)
- transient middle cerebral artery occlusion (1)
- transient middle cerebral artery occlusion model (1)
- translation (1)
- translational research (1)
- translational stroke research (1)
- troponin (1)
- tumor immunity (1)
- vascular dementia (1)
- vascular permeability (1)
- weight drop (1)
- β-APP (1)
Institute
- Neurologische Klinik und Poliklinik (59) (remove)
Dimethyl fumarate attenuates lymphocyte infiltration and reduces infarct size in experimental stroke
(2023)
Ischemic stroke is associated with exacerbated tissue damage caused by the activation of immune cells and the initiation of other inflammatory processes. Dimethyl fumarate (DMF) is known to modulate the immune response, activate antioxidative pathways, and improve the blood–brain barrier (BBB) after stroke. However, the specific impact of DMF on immune cells after cerebral ischemia remains unclear. In our study, male mice underwent transient middle cerebral artery occlusion (tMCAO) for 30 min and received oral DMF (15 mg/kg) or a vehicle immediately after tMCAO, followed by twice-daily administrations for 7 days. Infarct volume was assessed on T2-weighted magnetic resonance images on days 1 and 7 after tMCAO. Brain-infiltrating immune cells (lymphocytes, monocytes) and microglia were quantified using fluorescence-activated cell sorting. DMF treatment significantly reduced infarct volumes and brain edema. On day 1 after tMCAO, DMF-treated mice showed reduced lymphocyte infiltration compared to controls, which was not observed on day 7. Monocyte and microglial cell counts did not differ between groups on either day. In the acute phase of stroke, DMF administration attenuated lymphocyte infiltration, probably due to its stabilizing effect on the BBB. This highlights the potential of DMF as a therapeutic candidate for mitigating immune cell-driven damage in stroke.
Background
Troponin elevation is common in ischemic stroke (IS) patients. The pathomechanisms involved are incompletely understood and comprise coronary and non-coronary causes, e.g. autonomic dysfunction. We investigated determinants of troponin elevation in acute IS patients including markers of autonomic dysfunction, assessed by heart rate variability (HRV) time domain variables.
Methods
Data were collected within the Stroke Induced Cardiac FAILure (SICFAIL) cohort study. IS patients admitted to the Department of Neurology, Würzburg University Hospital, underwent baseline investigation including cardiac history, physical examination, echocardiography, and blood sampling. Four HRV time domain variables were calculated in patients undergoing electrocardiographic Holter monitoring. Multivariable logistic regression with corresponding odds ratios (OR) and 95% confidence intervals (CI) was used to investigate the determinants of high-sensitive troponin T (hs-TnT) levels ≥14 ng/L.
Results
We report results from 543 IS patients recruited between 01/2014–02/2017. Of those, 203 (37%) had hs-TnT ≥14 ng/L, which was independently associated with older age (OR per year 1.05; 95% CI 1.02–1.08), male sex (OR 2.65; 95% CI 1.54–4.58), decreasing estimated glomerular filtration rate (OR per 10 mL/min/1.73 m2 0.71; 95% CI 0.61–0.84), systolic dysfunction (OR 2.79; 95% CI 1.22–6.37), diastolic dysfunction (OR 2.29; 95% CI 1.29–4.02), atrial fibrillation (OR 2.30; 95% CI 1.25–4.23), and increasing levels of C-reactive protein (OR 1.48 per log unit; 95% CI 1.22–1.79). We did not identify an independent association of troponin elevation with the investigated HRV variables.
Conclusion
Cardiac dysfunction and elevated C-reactive protein, but not a reduced HRV as surrogate of autonomic dysfunction, were associated with increased hs-TnT levels in IS patients independent of established cardiovascular risk factors.
Ischemic disorders are the leading cause of death worldwide. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) are thought to affect the outcome of ischemic stroke. However, it is under debate whether activation or inhibition of ERK1/2 is beneficial. In this study, we report that the ubiquitous overexpression of wild-type ERK2 in mice (ERK2\(^{wt}\)) is detrimental after transient occlusion of the middle cerebral artery (tMCAO), as it led to a massive increase in infarct volume and neurological deficits by increasing blood–brain barrier (BBB) leakiness, inflammation, and the number of apoptotic neurons. To compare ERK1/2 activation and inhibition side-by-side, we also used mice with ubiquitous overexpression of the Raf-kinase inhibitor protein (RKIP\(^{wt}\)) and its phosphorylation-deficient mutant RKIP\(^{S153A}\), known inhibitors of the ERK1/2 signaling cascade. RKIP\(^{wt}\) and RKIP\(^{S153A}\) attenuated ischemia-induced damages, in particular via anti-inflammatory signaling. Taken together, our data suggest that stimulation of the Raf/MEK/ERK1/2-cascade is severely detrimental and its inhibition is rather protective. Thus, a tight control of the ERK1/2 signaling is essential for the outcome in response to ischemic stroke.
Based on recent findings that show that depletion of factor XII (FXII) leads to better posttraumatic neurological recovery, we studied the effect of FXII-deficiency on post-traumatic cognitive and behavioral outcomes in female and male mice. In agreement with our previous findings, neurological deficits on day 7 after weight-drop traumatic brain injury (TBI) were significantly reduced in FXII\(^{−/−}\) mice compared to wild type (WT) mice. Also, glycoprotein Ib (GPIb)-positive platelet aggregates were more frequent in brain microvasculature of WT than FXII\(^{−/−}\) mice 3 months after TBI. Six weeks after TBI, memory for novel object was significantly reduced in both female and male WT but not in FXII\(^{−/−}\) mice compared to sham-operated mice. In the setting of automated home-cage monitoring of socially housed mice in IntelliCages, female WT mice but not FXII\(^{−/−}\) mice showed decreased exploration and reacted negatively to reward extinction one month after TBI. Since neuroendocrine stress after TBI might contribute to trauma-induced cognitive dysfunction and negative emotional contrast reactions, we measured peripheral corticosterone levels and the ration of heart, lung, and spleen weight to bodyweight. Three months after TBI, plasma corticosterone levels were significantly suppressed in both female and male WT but not in FXII\(^{−/−}\) mice, while the relative heart weight increased in males but not in females of both phenotypes when compared to sham-operated mice. Our results indicate that FXII deficiency is associated with efficient post-traumatic behavioral and neuroendocrine recovery.
Background:
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) for which several new treatment options were recently introduced. Among them is the monoclonal anti-CD52 antibody alemtuzumab that depletes mainly B cells and T cells in the immune periphery. Considering the ongoing controversy about the involvement of B cells and in particular the formation of B cell aggregates in the brains of progressive MS patients, an in-depth understanding of the effects of anti-CD52 antibody treatment on the B cell compartment in the CNS itself is desirable.
Methods:
We used myelin basic protein (MBP)-proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 (B6) mice as B cell-dependent model of MS. Mice were treated intraperitoneally either at the peak of EAE or at 60 days after onset with 200 μg murine anti-CD52 vs. IgG2a isotype control antibody for five consecutive days. Disease was subsequently monitored for 10 days. The antigen-specific B cell/antibody response was measured by ELISPOT and ELISA. Effects on CNS infiltration and B cell aggregation were determined by immunohistochemistry. Neurodegeneration was evaluated by Luxol Fast Blue, SMI-32, and Olig2/APC staining as well as by electron microscopy and phosphorylated heavy neurofilament serum ELISA.
Results:
Treatment with anti-CD52 antibody attenuated EAE only when administered at the peak of disease. While there was no effect on the production of MP4-specific IgG, the treatment almost completely depleted CNS infiltrates and B cell aggregates even when given as late as 60 days after onset. On the ultrastructural level, we observed significantly less axonal damage in the spinal cord and cerebellum in chronic EAE after anti-CD52 treatment.
Conclusion:
Anti-CD52 treatment abrogated B cell infiltration and disrupted existing B cell aggregates in the CNS.
Background:
Standard echocardiography (SE) is an essential part of the routine diagnostic work-up after ischemic stroke (IS) and also serves for research purposes. However, access to SE is often limited. We aimed to assess feasibility and accuracy of point-of-care (POC) echocardiography in a stroke unit (SU) setting.
Methods:
IS patients were recruited on the SU of the University Hospital Würzburg, Germany. Two SU team members were trained in POC echocardiography for a three-month period to assess a set of predefined cardiac parameters including left ventricular ejection fraction (LVEF). Diagnostic agreement was assessed by comparing POC with SE executed by an expert sonographer, and intraclass correlation coefficient (ICC) or kappa (κ) with 95% confidence intervals (95% CI) were calculated.
Results:
In the 78 patients receiving both POC and SE agreement for cardiac parameters was good, with ICC varying from 0.82 (95% CI 0.71–0.89) to 0.93 (95% CI 0.87–0.96), and κ from 0.39 (−95% CI 0.14–0.92) to 0.79 (95% CI 0.67–0.91). Detection of systolic dysfunction with POC echocardiography compared to SE was very good, with an area under the curve of 0.99 (0.96–1.00). Interrater agreement for LVEF measured by POC echocardiography was good with κ 0.63 (95% CI 0.40–0.85).
Conclusions:
POC echocardiography in a SU setting is feasible enabling reliable quantification of LVEF and preliminary assessment of selected cardiac parameters that might be used for research purposes. Its potential clinical utility in triaging stroke patients who should undergo or do not necessarily require SE needs to be investigated in larger prospective diagnostic studies.
Background:
Traumatic brain injury (TBI) is a devastating neurological condition and a frequent cause of permanent disability. Posttraumatic inflammation and brain edema formation, two pathological key events contributing to secondary brain injury, are mediated by the contact-kinin system. Activation of this pathway in the plasma is triggered by activated factor XII. Hence, we set out to study in detail the influence of activated factor XII on the abovementioned pathophysiological features of TBI.
Methods:
Using a cortical cryogenic lesion model in mice, we investigated the impact of genetic deficiency of factor XII and inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused Infestin-4 on the release of bradykinin, the brain lesion size, and contact-kinin system-dependent pathological events. We determined protein levels of bradykinin, intracellular adhesion molecule-1, CC-chemokine ligand 2, and interleukin-1β by enzyme-linked immunosorbent assays and mRNA levels of genes related to inflammation by quantitative real-time PCR. Brain lesion size was determined by tetrazolium chloride staining. Furthermore, protein levels of the tight junction protein occludin, integrity of the blood-brain barrier, and brain water content were assessed by Western blot analysis, extravasated Evans Blue dye, and the wet weight-dry weight method, respectively. Infiltration of neutrophils and microglia/activated macrophages into the injured brain lesions was quantified by immunohistological stainings.
Results:
We show that both genetic deficiency of factor XII and inhibition of activated factor XII in mice diminish brain injury-induced bradykinin release by the contact-kinin system and minimize brain lesion size, blood-brain barrier leakage, brain edema formation, and inflammation in our brain injury model.
Conclusions:
Stimulation of bradykinin release by activated factor XII probably plays a prominent role in expanding secondary brain damage by promoting brain edema formation and inflammation. Pharmacological blocking of activated factor XII could be a useful therapeutic principle in the treatment of TBI-associated pathologic processes by alleviating posttraumatic inflammation and brain edema formation.
Background
While hypercholesterolemia plays a causative role for the development of ischemic stroke in large vessels, its significance for cerebral small vessel disease (CSVD) remains unclear. We thus aimed to understand the detailed relationship between hypercholesterolemia and CSVD using the well described Ldlr\(^{−/-}\) mouse model.
Methods
We used Ldlr\(^{−/-}\) mice (n = 16) and wild-type (WT) mice (n = 15) at the age of 6 and 12 months. Ldlr\(^{−/-}\) mice develop high plasma cholesterol levels following a high fat diet. We analyzed cerebral capillaries and arterioles for intravascular erythrocyte accumulations, thrombotic vessel occlusions, blood-brain barrier (BBB) dysfunction and microbleeds.
Results
We found a significant increase in the number of erythrocyte stases in 6 months old Ldlr\(^{−/-}\) mice compared to all other groups (P < 0.05). Ldlr\(^{−/-}\) animals aged 12 months showed the highest number of thrombotic occlusions while in WT animals hardly any occlusions could be observed (P < 0.001). Compared to WT mice, Ldlr\(^{−/-}\) mice did not display significant gray matter BBB breakdown. Microhemorrhages were observed in one Ldlr\(^{−/-}\) mouse that was 6 months old. Results did not differ when considering subcortical and cortical regions.
Conclusions
In Ldlr\(^{−/-}\) mice, hypercholesterolemia is related to a thrombotic CSVD phenotype, which is different from hypertension-related CSVD that associates with a hemorrhagic CSVD phenotype. Our data demonstrate a relationship between hypercholesterolemia and the development of CSVD. Ldlr\(^{−/-}\) mice appear to be an adequate animal model for research into CSVD.
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.
Differential effects of FTY720 on the B cell compartment in a mouse model of multiple sclerosis.
(2017)
Background:
MP4-induced experimental autoimmune encephalomyelitis (EAE) is a mouse model of multiple sclerosis (MS), which enables targeted research on B cells, currently much discussed protagonists in MS pathogenesis. Here, we used this model to study the impact of the S1P1 receptor modulator FTY720 (fingolimod) on the autoreactive B cell and antibody response both in the periphery and the central nervous system (CNS).
Methods:
MP4-immunized mice were treated orally with FTY720 for 30 days at the peak of disease or 50 days after EAE onset. The subsequent disease course was monitored and the MP4-specific B cell/antibody response was measured by ELISPOT and ELISA. RNA sequencing was performed to determine any effects on B cell-relevant gene expression. S1P\(_{1}\) receptor expression by peripheral T and B cells, B cell subset distribution in the spleen and B cell infiltration into the CNS were studied by flow cytometry. The formation of B cell aggregates and of tertiary lymphoid organs (TLOs) was evaluated by histology and immunohistochemistry. Potential direct effects of FTY720 on B cell aggregation were studied in vitro.
Results:
FTY720 significantly attenuated clinical EAE when treatment was initiated at the peak of EAE. While there was a significant reduction in the number of T cells in the blood after FTY720 treatment, B cells were only slightly diminished. Yet, there was evidence for the modulation of B cell receptor-mediated signaling upon FTY720 treatment. In addition, we detected a significant increase in the percentage of B220\(^{+}\) B cells in the spleen both in acute and chronic EAE. Whereas acute treatment completely abrogated B cell aggregate formation in the CNS, the numbers of infiltrating B cells and plasma cells were comparable between vehicle- and FTY720-treated mice. In addition, there was no effect on already developed aggregates in chronic EAE. In vitro B cell aggregation assays suggested the absence of a direct effect of FTY720 on B cell aggregation. However, FTY720 impacted the evolution of B cell aggregates into TLOs.
Conclusions:
The data suggest differential effects of FTY720 on the B cell compartment in MP4-induced EAE.