Maureen Walberer

University of Cologne, Köln, North Rhine-Westphalia, Germany

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Publications (35)129.97 Total impact

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    ABSTRACT: Neuroinflammation with microglia activation (MA) constitutes a key tissue response in acute stroke. Until now, its course in the chronic stage is less well defined. Here, we investigated (i) neuroinflammation in the chronic stage of a rat model of embolic stroke (n=6), and (ii) whether this process can be visualized in vivo by multimodal imaging using Magnetic Resonance Imaging (MRI) and Positron-Emission-Tomography (PET). Imaging data were verified using histology and immunohistochemistry. Repetitive PET studies until week 6 after stroke reveal poststroke inflammation as a dynamic process that involved the infarct, the surrounding tissue and secondary degenerating areas in a complex fashion. At the end, 7 months after stroke, neuroinflammation had almost completely vanished at the lesion side. In contrast, remote from the primarily infarcted areas, a marked T2⁎- hypointensity was detected in the ipsilateral thalamus. In the corresponding area, [(11)C]PK11195-PET detected microglia activation. Immunohistochemistry confirmed activated microglia in the ipsilateral thalamus with signs of extensive phagocytosis and iron deposition around plaque-like amyloid deposition. Neuronal staining (NeuN) revealed pronounced neuronal loss as an endpoint of neurodegeneration in these areas. In conclusion, the data demonstrate not only ongoing thalamic neuroinflammation but also marked neurodegeneration remote from the lesion site in the chronic phase after stroke in rats. Both, neuroinflammation and neurodegeneration were accessible to (immuno-) histochemical methods as well as to in vivo methods using [(11)C]PK11195-PET and T2⁎-weighted MRI. Although the functional roles of these dynamic processes remain to be elucidated, ongoing destruction of neuronal tissue is conceivable. Its inhibition using anti-inflammatory substances may be beneficial in chronic post-stroke conditions, while multimodal imaging can be used to evaluate putative therapeutic effects in vivo.
    Brain Research 06/2014; · 2.88 Impact Factor
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    ABSTRACT: Focal cerebral ischemia induces cellular responses that may result in secondary tissue damage. We recently demonstrated multi-facetted spatial and temporal patterns of neuroinflammation by multimodal imaging. In the present study, we especially focus on the separation of vital and necrotic tissue, which enabled us to define a demarcation zone. Focal cerebral ischemia was induced via macrosphere embolization of the middle cerebral artery in Wistar rats. Subsequent cellular processes were investigated immunohistochemically from 3 to 56 days after onset of ischemia. We detected several infarct subareas: a necrotic infarct core and its margin adjacent to a nerve/glial antigen 2 (NG2)+ zone delineating it from a vital peri-infarct zone. Initially transition from necrotic to vital tissue was gradual; later on necrosis was precisely separated from vital tissue by a narrow NG2+ belt that was devoid of astrocytes, oligodendrocytes or neurons. Within this demarcation zone NG2+ cells associate with ionized calcium binding adaptor molecule 1 (Iba1) but not with GFAP, neuronal nuclear antigen (NeuN) or 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNPase). During further infarct maturation NG2 seemed to be positioned in the extracellular matrix (ECM) of the demarcation zone, whereas Iba1+ cells invaded the necrotic infarct core and GFAP+ cells built a gliotic containing belt between the lesion and NeuN+ unaffected tissue. Overall, our data suggested that NG2 proteoglycan expression and secretion hallmarked demarcation as a process that actively separated necrosis from vital tissue and therefore decisively impacts secondary neurodegeneration after ischemic stroke.
    Neuropathology 05/2012; · 1.91 Impact Factor
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    ABSTRACT: Minocycline has been reported to reduce infarct size after focal cerebral ischemia, due to an attenuation of microglia activation and prevention of secondary damage from stroke-induced neuroinflammation. We here investigated the effects of minocycline on endogenous neural stem cells (NSCs) in vitro and in a rat stroke model. Primary cultures of fetal rat NSCs were exposed to minocycline to characterize its effects on cell survival and proliferation. To assess these effects in vivo, permanent cerebral ischemia was induced in adult rats, treated systemically with minocycline or placebo. Imaging 7 days after ischemia comprised (i) Magnetic Resonance Imaging (MRI), assessing the extent of infarcts, (ii) Positron Emission Tomography (PET) with [(11)C]PK11195, characterizing neuroinflammation, and (iii) PET with 3'-deoxy-3'-[(18)F]fluoro-L-thymidine ([(18)F]FLT), detecting proliferating endogenous NSCs. Immunohistochemistry was used to verify ischemic damage and characterize cellular inflammatory and repair processes in more detail. In vitro, specific concentrations of minocycline significantly increased NSC numbers without increasing their proliferation, indicating a positive effect of minocycline on NSC survival. In vivo, endogenous NSC activation in the subventricular zone (SVZ) measured by [(18)F]FLT PET correlated well with infarct volumes. Similar to in vitro findings, minocycline led to a specific increase in endogenous NSC activity in both the SVZ as well as the hippocampus. [(11)C]PK11195 PET detected neuroinflammation in the infarct core as well as in peri-infarct regions, with both its extent and location independent of the infarct size. The data did not reveal an effect of minocycline on stroke-induced neuroinflammation. We show that multimodal PET imaging can be used to characterize and quantify complex cellular processes occurring after stroke, as well as their modulation by therapeutic agents. We found minocycline, previously implied in attenuating microglial activation, to have positive effects on endogenous NSC survival. These findings hold promise for the development of novel treatments in stroke therapy.
    Neuroscience 04/2012; 215:174-83. · 3.12 Impact Factor
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    ABSTRACT: Experimental stroke models are essential to study in vivo pathophysiological processes of focal cerebral ischemia. In this study, an embolic stroke model in rats was applied (1) to characterize early development of regional cerebral blood flow and metabolism with positron emission tomography (PET) using [(15)O]H(2)O and [(18)F]-2-fluoro-2-deoxy-D-glucose (FDG); and (2) to identify potential parameters for predicting tissue fate. Remote occlusion of the middle cerebral artery was induced in 10 Wistar rats by injection of 4 TiO(2) macrospheres. Sequential [(15)O]H(2)O-PET (baseline, 5, 30, 60 minutes after middle cerebral artery occlusion) and FDG-PET measurements (75 minutes after middle cerebral artery occlusion) were performed. [(15)O]H(2)O-PET data and FDG kinetic parameters were compared with MRIs and histology at 24 hours. Regional cerebral blood flow decreased substantially within 30 minutes after middle cerebral artery occlusion (41% to 58% of baseline regional cerebral blood flow; P<0.001) with no relevant changes between 30 and 60 minutes. At 60 minutes, regional cerebral blood flow correlated well with the unidirectional transport parameter K1 of FDG in all animals (r=0.86±0.09; P<0.001). Tissue fate could be accurately predicted taking into account K1 and net influx rate constant Ki of FDG. The infarct volume predicted by FDG-PET (375.8±102.3 mm(3)) correlated significantly with the infarct size determined by MRI after 24 hours (360.8±93.7 mm(3); r=0.85). Hypoperfused tissue can be identified by decreased K1 of FDG. Acute ischemic tissue can be well characterized using K1 and Ki allowing for discrimination between infarct core and early viable tissue. Because FDG-PET is widely spread, our findings can be easily translated into clinical application for early diagnoses of ischemia.
    Stroke 01/2012; 43(1):193-8. · 6.16 Impact Factor
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    ABSTRACT: Transcranial direct current stimulation (tDCS) is increasingly being used in human studies as an adjuvant tool to promote recovery of function after stroke. However, its neurobiological effects are still largely unknown. Electric fields are known to influence the migration of various cell types in vitro, but effects in vivo remain to be shown. Hypothesizing that tDCS might elicit the recruitment of cells to the cortex, we here studied the effects of tDCS in the rat brain in vivo. Adult Wistar rats (n = 16) were randomized to either anodal or cathodal stimulation for either 5 or 10 consecutive days (500 µA, 15 min). Bromodeoxyuridine (BrdU) was given systemically to label dividing cells throughout the experiment. Immunohistochemical analyses ex vivo included stainings for activated microglia and endogenous neural stem cells (NSC). Multi-session tDCS with the chosen parameters did not cause a cortical lesion. An innate immune response with early upregulation of Iba1-positive activated microglia occurred after both cathodal and anodal tDCS. The involvement of adaptive immunity as assessed by ICAM1-immunoreactivity was less pronounced. Most interestingly, only cathodal tDCS increased the number of endogenous NSC in the stimulated cortex. After 10 days of cathodal stimulation, proliferating NSC increased by ∼60%, with a significant effect of both polarity and number of tDCS sessions on the recruitment of NSC. We demonstrate a pro-inflammatory effect of both cathodal and anodal tDCS, and a polarity-specific migratory effect on endogenous NSC in vivo. Our data suggest that tDCS in human stroke patients might also elicit NSC activation and modulate neuroinflammation.
    PLoS ONE 01/2012; 7(8):e43776. · 3.53 Impact Factor
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    ABSTRACT: Diseases and dysfunction of the central nervous system are often associated with regional changes in cerebral glucose metabolism, which can be measured in vivo by PET using (18)F-FDG as the tracer. For quantification, the arterial tracer input function must be determined. For rodents in particular, direct measurement of blood radioactivity concentration is scarcely feasible for follow-up of individual animals because of the invasiveness of blood sampling. We show that the whiskers area of the rat's muzzle serves as an extracerebral reference region. The derived model also takes into account local variations of the lumped constant, which is crucial in pathologic tissue. In 11 rats, the reference tissue kinetic parameters were determined from PET data and measured whole blood radioactivity concentration. Parametric images of cerebral kinetic rate constants were calculated using the directly measured input function, the reference tissue time-activity curve with individually fitted reference kinetic parameters, and the reference time-activity curve with fixed reference kinetic parameters calculated from the fitted parameters averaged over all animals. The need for kinetic modeling in disease models is demonstrated in 5 rats subjected to acute focal cerebral ischemia. (18)F-FDG metabolism and transport rate constants and local cerebral glucose metabolic rates were calculated. Cerebral kinetic constants derived from the 3 methods corresponded closely. The maximum difference in whole-brain kinetic parameters observed between the directly measured input function and the reference tissue time-activity curve with individually fitted reference kinetic parameters was less than 5%. Taking fixed reference parameters (the reference time-activity curve with fixed reference kinetic parameters calculated from the fitted parameters averaged over all animals) still provided whole-brain kinetic parameters with an accuracy of approximately 90%. In the rats subjected to focal cerebral ischemia, (18)F-FDG kinetic parameters in healthy tissue were not significantly different from whole-brain kinetic parameters in naive rats. The ischemic region was characterized by preserved glucose metabolism, although (18)F-FDG uptake was elevated significantly-that is, the lumped constant in the ischemic region was different from that of healthy brain tissue. The method presented here allows for the quantitative noninvasive determination of cerebral glucose consumption in rats, takes into account local variations of the lumped constant, and is suitable for follow-up measurements of individuals.
    Journal of Nuclear Medicine 08/2011; 52(8):1252-60. · 5.77 Impact Factor
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    ABSTRACT: Experimental and clinical studies indicate that waves of cortical spreading depolarization (CSD) appearing in the ischemic penumbra contribute to secondary lesion growth. We used an embolic stroke model that enabled us to investigate inverse coupling of blood flow by laser speckle imaging (CBF(LSF)) to CSD as a contributing factor to lesion growth already in the early phase after arterial occlusion. Embolization by macrospheres injected into the left carotid artery of anesthetized rats reduced CBF(LSF) in the territories of the middle cerebral artery (MCA) (8/14 animals), the posterior cerebral artery (PCA) (2/14) or in less clearly defined regions (4/14). Analysis of MCA occlusions (MCAOs) revealed a first CSD wave starting off during ischemic decline at the emerging core region, propagating concentrically over large portions of left cortex. Subsequent recurrent waves of CSD did not propagate concentrically but preferentially circled around the ischemic core. In the vicinity of the core region, CSDs were coupled to waves of predominantly vasoconstrictive CBF(LSF) responses, resulting in further decline of CBF in the entire inner penumbra and in expansion of the ischemic core. We conclude that CSDs and corresponding CBF responses follow a defined spatiotemporal order, and contribute to early evolution of ischemic territories.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 02/2011; 31(2):580-92. · 5.46 Impact Factor
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    ABSTRACT: Neural stem cells reside in two major niches in the adult brain [i.e., the subventricular zone (SVZ) and the dentate gyrus of the hippocampus]. Insults to the brain such as cerebral ischemia result in a physiological mobilization of endogenous neural stem cells. Since recent studies showed that pharmacological stimulation can be used to expand the endogenous neural stem cell niche, hope has been raised to enhance the brain's own regenerative capacity. For the evaluation of such novel therapeutic approaches, longitudinal and intraindividual monitoring of the endogenous neural stem cell niche would be required. However, to date no conclusive imaging technique has been established. We used positron emission tomography (PET) and the radiotracer 3'-deoxy-3'-[(18)F]fluoro-l-thymidine ([(18)F]FLT) that enables imaging and measuring of proliferation to noninvasively detect endogenous neural stem cells in the normal and diseased adult rat brain in vivo. This method indeed visualized neural stem cell niches in the living rat brain, identified as increased [(18)F]FLT-binding in the SVZ and the hippocampus. Focal cerebral ischemia and subsequent damage of the blood-brain barrier did not interfere with the capability of [(18)F]FLT-PET to visualize neural stem cell mobilization. Moreover, [(18)F]FLT-PET allowed for an in vivo quantification of increased neural stem cell mobilization caused by pharmacological stimulation or by focal cerebral ischemia. The data suggest that noninvasive longitudinal monitoring and quantification of endogenous neural stem cell activation in the brain is feasible and that [(18)F]FLT-PET could be used to monitor the effects of drugs aimed at expanding the neural stem cell niche.
    Journal of Neuroscience 05/2010; 30(18):6454-60. · 6.91 Impact Factor
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    ABSTRACT: Subtle cerebral air microembolisation (CAM) is a typical complication of various medical interventions such as open heart surgery or angiography and can cause transient or permanent neurological and neuropsychological deficits. Evaluation of the underlying pathophysiology requires animal models that allow embolisation of air bubbles of defined diameter and number. Herein we present a method for the production of gas bubbles of defined diameter and their injection into the carotid artery of rats. The number of gas microemboli injected is quantified digitally using a high speed optical image capturing system and a custom-made software. In a first pilot study, 0, 50, 100, 400 and 800 gas bubbles of 160 microm in diameter were injected into the carotid artery of rats. Offline evaluation revealed a high constancy of the bubble diameters (mean 159.95+/-9.25 microm, range 144-188 microm) and the number of bubbles injected. First preliminary data indicate that with increasing number of bubbles embolised, more animals revealed neurological deficits and (particularly with higher bubble counts) brain infarctions on TTC-staining. Interestingly, also animals without overt infarcts on TTC-staining displayed neurological deficits in an apparently dose dependent fashion, indicating subtle brain damage by air embolism. In conclusion, the method presented allows injecting air bubbles of defined number and diameter into cerebral arteries of rats. This technique facilitates animal research in the field of air embolisation.
    Journal of neuroscience methods 04/2010; 190(1):10-3. · 2.30 Impact Factor
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    ABSTRACT: Neuroinflammation evolves as a multi-facetted response to focal cerebral ischemia. It involves activation of resident glia cell populations, recruitment of blood-derived leucocytes as well as humoral responses. Among these processes, phagocyte accumulation has been suggested to be a surrogate marker of neuroinflammation. We previously assessed phagocyte accumulation in human stroke by MRI. We hypothesize that phagocyte accumulation in the macrosphere model may resemble the temporal and spatial patterns observed in human stroke. In a rat model of permanent focal ischemia by embolisation of TiO2-spheres we assessed key features of post-ischemic neuroinflammation by the means of histology, immunocytochemistry of glial activation and influx of hematogeneous cells, and quantitative PCR of TNF-α, IL-1, IL-18, and iNOS mRNA. In the boundary zone of the infarct, a transition of ramified microglia into ameboid phagocytic microglia was accompanied by an up-regulation of MHC class II on the cells after 3 days. By day 7, a hypercellular infiltrate consisting of activated microglia and phagocytic cells formed a thick rim around the ischemic infarct core. Interestingly, in the ischemic core microglia could only be observed at day 7. TNF-α was induced rapidly within hours, IL-1β and iNOS peaked within days, and IL-18 later at around 1 week after ischemia. The macrosphere model closely resembles the characteristical dynamics of postischemic inflammation previously observed in human stroke. We therefore suggest that the macrosphere model is highly appropriate for studying the pathophysiology of stroke in a translational approach from rodent to human.
    Experimental and Translational Stroke Medicine 01/2010; 2(1):22.
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    ABSTRACT: Intravenous immunoglobulin (IVIG) is used for treatment of immunodeficiencies and autoimmune disorders. Recently, IVIG has also been shown to reduce infarct size in acute stroke. Since edema treatment can provide secondary neuroprotective effects, we conducted the present study to evaluate whether edema reduction is the underlying cause of the neuroprotective properties of IVIG in experimental stroke. Male Wistar rats received either IVIG or placebo and were subjected to temporary middle cerebral artery occlusion. 24 h after temporary middle cerebral artery occlusion, clinical evaluation and 7.0T magnetic resonance imaging were performed. Ischemic lesion volume was determined on high-resolution T(2) images. T(2) relaxation time and midline shift assessed on magnetic resonance imaging as well as brain water content detected by the wet/dry method after 24 h were measured to quantify edema formation. Pretreatment with IVIG leads to a statistically significant reduction of the ischemic lesion volume by 42% after 24 h, as compared to placebo treatment (p < 0.05). All three methods for quantifying edema formation indicated no differences between IVIG-treated and untreated animals (p > 0.05). These results suggest that the neuroprotective effect of IVIG is not an indirect result of edema reduction, but is caused by direct neuronal protection. Application of IVIG is a promising treatment concept for acute stroke. To further investigate this neuroprotective effect, studies on the efficacy, the safety profile and on the underlying mechanisms are required.
    NeuroImmunoModulation 11/2009; 17(2):97-102. · 1.84 Impact Factor
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    ABSTRACT: Brain edema formation is a serious complication of ischemic stroke and can lead to mechanical compression of adjacent brain structures, cerebral herniation, and death. Furthermore, the space-occupying effect of edema impairs regional cerebral blood flow (rCBF), which is particularly important in the penumbra phase of stroke. In the present study, the authors evaluated the natural course of edema formation in the hyperacute phase of focal cerebral ischemia. Middle cerebral artery occlusion (MCAO) or a sham procedure was performed in rats within an MR imaging unit (in-bore occlusion). Both pre- and postischemic images could be compared on a pixel-by-pixel basis. The T2 relaxation time (T2RT), a marker for brain water content, was measured in regions of interest. A significant increase in the T2RT was detectable as early as 20-45 minutes after MCAO. At this early time point the midline shift (MLS) amounted to 0.214 +/- 0.092 cm in the MCAO group and 0.061 +/- 0.063 cm in the sham group (p < 0.007). The T2RT and MLS increased linearly thereafter. Evans blue dye was intravenously injected in additional animals 20 and 155 minutes after MCAO. Extravasation of the dye was visible in all animals, indicating increased permeability of the blood-brain barrier. Vasogenic brain edema occurs much earlier than expected following permanent MCAO and leads to MLS and mechanical compression of adjacent brain structures. Since compression effects can impair rCBF, early edema formation can significantly contribute to infarct formation and thus represents a promising target for neuroprotection.
    Journal of Neurosurgery 05/2009; 111(5):1036-42. · 3.15 Impact Factor
  • Journal of Cerebral Blood Flow & Metabolism 04/2009; 29(6):1216-1225. · 5.40 Impact Factor
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    ABSTRACT: Focal cerebral ischemia elicits strong inflammatory responses involving activation of resident microglia and recruitment of monocytes/macrophages. These cells express peripheral benzodiazepine receptors (PBRs) and can be visualized by positron emission tomography (PET) using [(11)C]PK11195 that selectively binds to PBRs. Earlier research suggests that transient ischemia in rats induces increased [(11)C]PK11195 binding within the infarct core. In this study, we investigated the expression of PBRs during permanent ischemia in rats. Permanent cerebral ischemia was induced by injection of macrospheres into the middle cerebral artery. Multimodal imaging 7 days after ischemia comprised (1) magnetic resonance imaging that assessed the extent of infarcts; (2) [(18)F]-2-fluoro-2-deoxy-D-glucose ([(18)F]FDG)-PET characterizing cerebral glucose transport and metabolism; and (3) [(11)C]PK11195-PET detecting neuroinflammation. Immunohistochemistry verified ischemic damage and neuroinflammatory processes. Contrasting with earlier data for transient ischemia, no [(11)C]PK11195 binding was found in the infarct core. Rather, permanent ischemia caused increased [(11)C]PK11195 binding in the normoperfused peri-infarct zone (mean standard uptake value (SUV): 1.93+/-0.49), colocalizing with a 60% increase in the [(18)F]FDG metabolic rate constant with accumulated activated microglia and macrophages. These results suggest that after permanent focal ischemia, neuroinflammation occurring in the normoperfused peri-infarct zone goes along with increased energy demand, therefore extending the tissue at risk to areas adjacent to the infarct.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 04/2009; 29(6):1216-25. · 5.46 Impact Factor
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    ABSTRACT: Ischemic stroke causes cell necrosis with the exposure of extracellular ribonucleic acid (RNA) and other intracellular material. As shown recently, extracellular RNA impaired the blood-brain-barrier and contributed to vasogenic edema-formation. Application of ribonuclease 1 (RNase 1) diminished edema-formation and also reduced lesion volume in experimental stroke. Here we investigate whether reduction of lesion volume is due to the reduction of edema or of other neuroprotective means. Neuroprotective and edema protective effects of RNase 1 pretreatment were assessed using a temporary middle cerebral artery occlusion (MCAO) model in rats. Lesion volume was assessed on magnetic resonance imaging (MRI). T2-relaxation-time and midline-shift as well as brain water content (wet-dry-method) were measured to quantify edema formation. The impact of edema formation on infarct volume was evaluated in craniectomized animals. Exogenous RNase 1 was well tolerated and reduced edema-formation and infarct size (26.7% +/- 10.7% vs. 41.0% +/- 10.3%; p<0.01) at an optimal dose of 42 microg/kg as compared to placebo. Craniectomized animals displayed a comparable edema reduction but no reduction in infarct size. The present study introduces a hitherto unrecognized mechanism of ischemic brain damage and a novel neuroprotective approach towards acute stroke treatment.
    Current neurovascular research 03/2009; 6(1):12-9. · 3.23 Impact Factor
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    ABSTRACT: Extracellular RNA has been shown to induce vascular endothelial growth factor (VEGF)-dependent hyperpermeability in vivo as well as in vitro. Studies were performed to investigate the mechanism of these effects. For permeability studies primary cultures of porcine brain-derived microvascular endothelial cells (BMECs) and for all other analytical studies the human brain endothelial cell line HCMEC/D3 or human umbilical vein endothelial cells (HUVECs) were used. RNA, but not DNA, initiated signaling events by binding of VEGF to neuropilin-1, followed by VEGF-R2 phosphorylation, activation of phospholipase C (PLC), and intracellular release of Ca(2+). Activation of these pathways by RNA also resulted in the release of von Willebrand Factor from Weibel-Palade bodies. Pretreatment of cells with heparinase totally abrogated the RNA-induced permeability changes, whereas RNA together with VEGF completely restored VEGF-R2-mediated hyperpermeability. Although poly:IC increased the interleukin-6 release via activation of toll-like receptor-3 (TLR-3), permeability changes mediated by poly:IC or RNA remained unchanged after blocking TLR-3 or NF-kB activation. These results indicate that extracellular RNA serves an important cofactor function to engage VEGF for VEGF-R2-dependent signal transduction, reminiscent of the coreceptor mechanism mediated by proteoglycans, which might be of relevance for the mobilization and cellular activities of RNA-binding cytokines in general.
    The FASEB Journal 03/2009; 23(7):2100-9. · 5.70 Impact Factor
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    ABSTRACT: Ischemic stroke causes cell necrosis with the exposure of extracellular ribonucleic acid (RNA) and other intracellular material. As shown recently, extracellular RNA impaired the blood-brain-barrier and contributed to vasogenic edema-formation. Application of ribonuclease 1 (RNase 1) diminished edema-formation and also reduced lesion volume in experimental stroke. Here we investigate whether reduction of lesion volume is due to the reduction of edema or of other neuroprotective means. Neuroprotective and edema protective effects of RNase 1 pretreatment were assessed using a temporary middle cerebral artery occlusion (MCAO) model in rats. Lesion volume was assessed on magnetic resonance imaging (MRI). T2- relaxation-time and midline-shift as well as brain water content (wet-dry-method) were measured to quantify edema formation. The impact of edema formation on infarct volume was evaluated in craniectomized animals. Exogenous RNase 1 was well tolerated and reduced edema-formation and infarct size (26.7% ± 10.7% vs. 41.0% ± 10.3%; p<0.01) at an optimal dose of 42 μg/kg as compared to placebo. Craniectomized animals displayed a comparable edema reduction but no reduction in infarct size. The present study introduces a hitherto unrecognized mechanism of ischemic brain damage and a novel neuroprotective approach towards acute stroke treatment.
    Current Neurovascular Research 01/2009; 6(1):12-19. · 2.84 Impact Factor
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    ABSTRACT: Early microcirculatory failure is assumed as a key factor in the development of a septic encephalopathy. However, brain edema is also a common finding in sepsis syndromes possibly interfering with the vasoregulative mechanisms of the brain. We assessed the occurrence of brain edema in a rat model of endotoxic shock. Eleven mechanically ventilated male CD-rats. Intravenous application of 5 mg/kg LPS (n = 8) or vehicle (n = 3). Apparent diffusion coefficient (ADC) and T2-relaxation time (T2RT) were quantified on cerebral MRI at baseline and repeatedly for up to 3.5 h after LPS-injection. Change in blood pressure was compensated with norepinephrine. Brain water content was quantified using the wet/dry method. All LPS-treated rats developed endotoxic shock. No significant difference in T2RT or ADC was detectable before and after LPS-injection (T2RT: baseline 60.33 +/- 1.21; after 3.5 h 60.15 +/- 0.59; ADC: baseline 6.86 +/- 0.51; after 3.5 h 6.75 +/- 0.33). Post-mortem analysis did not indicate a difference in brain water content between septic and non-septic animals. Reports of early microcirculatory failure seem not to be related to the occurrence of early (< or =3.5 h) brain edema.
    Inflammation Research 10/2008; 57(10):479-83. · 1.96 Impact Factor
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    ABSTRACT: Recent studies have raised concerns about the safety of low frequency ultrasound in transcranial therapeutic application in cerebral ischemia. This study was designed to evaluate safety aspects and potential deleterious effects of low frequency, 60 kHz ultrasound in treatment of experimental middle cerebral artery occlusion (MCAO) in rats. Forty-five male Wistar rats were submitted to either temporary (90 min; groups I and II) or permanent MCAO (groups III and IV) using the suture technique. All animals received recombinant tissue plasminogen activator (rt-PA) starting 90 min after the beginning of occlusion. Groups I and III were additionally treated with 60 kHz ultrasound (time average acoustic intensity 0.14 W/cm(2), duty cycle 50%). Outcome assessment consisted of magnetic resonance imaging (MRI) and clinical evaluation after 5 and 24 h, and histology (perfusion fixation after 24 h). Overall mortality was higher in animals treated with ultrasound (43% versus 29% in controls). Most animals died during the insonation period (25% in group I, 36% in group III, no animals in the corresponding control groups; p < 0.05). Histology revealed disseminated microscopic intracerebral bleeding and subarachnoid hemorrhage as one possible cause of death. After temporary occlusion, the hemispheric ischemic lesion volume was more than doubled in animals treated with ultrasound (20.3% +/- 14.1% versus 8.6% +/- 5.1% in controls; p < 0.05). No difference in lesion volume was seen after permanent MCAO. Neurological assessment showed impairment of hearing as an additional specific side effect in ultrasound treated animals (65%, no impairment in controls). Although the results are not directly transferable to the human setting, this study clearly demonstrates the potential limitations of low frequency therapeutic ultrasound and the importance of pre-clinical safety assessment.
    Ultrasound in medicine & biology 09/2008; 34(12):2019-27. · 2.46 Impact Factor
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    ABSTRACT: In territorial stroke vasogenic edema formation leads to elevated intracranial pressure (ICP) and can cause herniation and death. Brain swelling further impairs collateral blood flow to the ischemic penumbra and causes mechanical damage to adjacent brain structures. In the present study the authors sought to quantify the impact of this space-occupying effect on ischemic lesion formation. Wistar rats were assigned to undergo bilateral craniectomy or a sham operation and then were subjected to temporary middle cerebral artery occlusion (MCAO) for 90 minutes. A clinical evaluation and 7-T MR imaging studies were performed 5 and 24 hours after MCAO. The absolute brain water content was determined at 24 hours by using the wet/dry method. Bilateral craniectomy before MCAO led to a drastic reduction in lesion volume at both imaging time points (p < 0.0001). Ischemic lesion volume was 2.7- and 2.3-fold larger in sham-operated animals after 5 and 24 hours, respectively. Clinical scores were likewise better in rats that had undergone craniectomy (p < 0.05). After 24 hours the midline shift differed significantly between the 2 groups (p < 0.001), but not after 5 hours. The relation between brain water content and ischemic lesion volume as well as the T2 relaxation time within the infarcted area was not different between the groups (p > 0.05). The data indicated that collateral damage caused by the space-occupying effect of a large MCA territory stroke contributes seriously to ischemic lesion formation. The elimination of increased ICP thus must be regarded as a highly neuroprotective measure, rather than only a life-saving procedure to prevent cerebral herniation. Further clinical trials should reveal the neuroprotective potential of surgical and pharmacological ICP-lowering therapeutic approaches.
    Journal of Neurosurgery 08/2008; 109(2):287-93. · 3.15 Impact Factor

Publication Stats

478 Citations
129.97 Total Impact Points

Institutions

  • 2009–2014
    • University of Cologne
      • Department of Neurology
      Köln, North Rhine-Westphalia, Germany
  • 2011
    • Max Planck Institute for Metabolism Research
      Köln, North Rhine-Westphalia, Germany
  • 2005–2008
    • Justus-Liebig-Universität Gießen
      • Department of Internal Medicine
      Gieben, Hesse, Germany