Publications (31)98.24 Total impact
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Article: Pediatric intracranial arteriovenous shunts: a global overview.
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ABSTRACT: INTRODUCTION: Cerebral arteriovenous shunts (CAVS) in the pediatric population cannot be compared to those in adults as they present different anatomical, physiological, and pathological characteristics concerning the arterial and venous vasculature and the cerebrospinal fluid physiology. These lesions develop in a maturing brain, of which expression is difficult to assess, with a potential for recovery different from that in adults. DISCUSSION: Their impact on the brain will be different in the antenatal period, in neonates, in infants, and in children, with variable symptoms according to each age group. We review different classifications of pediatric CAVS (according to the anatomical space in which they develop, their type and architecture, and the age at which they reveal), describe their evolution, and discuss the current role of endovascular treatment in the management of these vascular lesions.Child s Nervous System 04/2013; · 1.54 Impact Factor -
Article: Image-guided method in the rat for inducing cortical or striatal infarction and for controlling cerebral blood flow under MRI.
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ABSTRACT: Experimental models are essential for research on ischemic stroke, the second most common cause of death worldwide. The failure of clinical trials on neuroprotective treatment may be due in part to poor animal models. To push the translation of new therapies, we describe a new rat model that captures key elements of human brain ischemia. The model includes imaging and neurointerventional tools that represent the near future of clinical diagnosis and treatment of stroke. Using Sprague-Dawley rats (n=26), we navigated a microwire with fluoroscopy and MRI guidance from the ventral tail artery to 2 different positions in the middle cerebral artery to establish local occlusion. Animals were scanned with 9.4-T MRI before occlusion, during ischemia, and after reperfusion. We detected stroke lesions, corresponding to the level of occlusion, in all animals by diffusion-weighted and T2 images. We measured lesion volume (mm(3)±SD) on T2 scans at 24 hours to be 23.2±29.8 in the somatosensory cortex group and 107.9±80 in the striatum group. We present a new rat model for focal stroke with the possibility to cause lesions in different regions of the brain under fluoroscopic and MRI control. The model will be highly useful for extended studies on the ischemic penumbra, alterations in neural connectivity, and for investigating neurotransmitter-mediated events and biochemical changes in the hyperacute phase of brain ischemia. Also, the model uses clinical routine microcatheters facilitating superselective administration of therapeutics directly to the cerebral circulation.Stroke 07/2012; 43(9):2437-43. · 5.73 Impact Factor -
Article: Mechanical thrombectomy as the primary treatment for acute basilar artery occlusion: experience from 5 years of practice.
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ABSTRACT: BACKGROUND: Most studies of the treatment for acute basilar occlusion focus on intravenous or intra-arterial thrombolysis whereas data on mechanical thrombectomy as the preferred treatment for acute basilar occlusion are scarce. In this study, data are presented on 28 patients treated with mechanical thrombectomy as the preferred treatment for basilar artery occlusion. METHODS: Retrospective study comprising all patients who were treated for acute basilar occlusion at the Karolinska University Hospital from September 2005 to November 2010. Favorable outcome was defined as a modified Rankin score of ≤2 at 3-8 months after thrombectomy. RESULTS: Of 28 patients treated with mechanical thrombectomy, the proportion reaching a favorable outcome was 57% (95% CI 37% to 75%), and if there were no signs of acute infarction prior to treatment the proportion was 73% (95% CI 50% to 89%). Only 21% died (95% CI 8% to 41%). CONCLUSIONS: The results for mechanical thrombectomy for basilar artery occlusion were superior to those presented previously for intravenous and intra-arterial thrombolysis. The study suggests that mechanical thrombectomy is a method distinct from therapies based on thrombolysis and that any randomized clinical trial on treatment for acute basilar occlusion must consider mechanical thrombectomy as a separate entity.Journal of neurointerventional surgery 03/2012; · 0.92 Impact Factor -
Chapter: Endovascular Methods for Stem Cell Transplantation
02/2012; , ISBN: 978-953-51-0013-3 -
Article: Targeted intra-arterial transplantation of stem cells to the injured CNS is more effective than intravenous administration: engraftment is dependent on cell type and adhesion molecule expression.
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ABSTRACT: Stem cell transplantation procedures using intraparenchymal injections cause tissue injury in addition to associated surgical risks. Intravenous cell administration give engraftment in parenchymal lesions although the method has low efficacy and specificity. In pathological conditions with inflammation, such as traumatic brain injury, there is a transient up-regulation of ICAM-1 and VCAM-1 which might provide environmental cues for migration of stem cells from blood to parenchyma. The aim of this study was to i) analyze the effect of intra-arterial administration on cellular engraftment, ii) compare engraftment and side effects between three different stem cell systems, and iii) analyze gene expression in these three systems. We performed specific intra-arterial transplantations with human mesenchymal stem cells (hMSCs), human neural progenitor cells (hNPCs), and rat neural progenitor cells (rNPCs) in a rat model of traumatic brain injury. These results were compared to the intravenous route for each cell type, respectively. Analysis of engraftment and recipient characterization was performed by immunohistochemistry. We further characterized the different types of cells by microarray and RT-qPCR analysis. Specific intra-arterial transplantations produced significantly higher engraftment compared to intravenous transplantation with hMSCs and rNPCs. No engraftment was detected after intra-arterial or intravenous administration of hNPCs. Characterization of integrin expression indicated that CD49dVCAM-1 and possibly ICAM-1 interactions through CD18 and CD11a, respectively, are important for engraftment after intravascular cell administration. No side effects, such as thromboembolic complications, were detected. When translating stem cell therapies to clinical practice, the route of transplantation and the properties of the cell lines (homing, diapedesis, and migration) become important. This study supports the use of selective intra-arterial transplantation for improving engraftment after traumatic brain injury. In addition, we conclude that careful analysis of cells intended for local, intra-arterial transplantation with respect to integrin expression is important.Cell Transplantation 06/2011; 21(1):333-43. · 5.13 Impact Factor -
Article: Epidural needle with embedded optical fibers for spectroscopic differentiation of tissue: ex vivo feasibility study.
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ABSTRACT: Epidural injection is commonly used to provide intraoperative anesthesia, postoperative and obstetric analgesia, and to treat acute radicular pain. Identification of the epidural space is typically carried out using the loss of resistance (LOR) technique, but the usefulness of this technique is limited by false LOR and the inability to reliably detect intravascular or subarachnoid needle placement. In this study, we present a novel epidural needle that allows for the acquisition of optical reflectance spectra from tissue close to the beveled surface. This needle has optical fibers embedded in the cannula that deliver and receive light. With two spectrometers, light received from tissue is resolved across the wavelength range of 500 to 1600 nm. To determine the feasibility of optical tissue differentiation, spectra were acquired from porcine tissues during a post mortem laminectomy. The spectra were processed with an algorithm that derives estimates of the hemoglobin and lipid concentrations. The results of this study suggest that the optical epidural needle has the potential to improve the accuracy of epidural space identification.Biomedical Optics Express 06/2011; 2(6):1452-61. · 2.33 Impact Factor -
Article: Long term follow-up of the endovascular trans-vessel wall technique for parenchymal access in rabbit with full clinical integration.
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ABSTRACT: Endovascular techniques are providing options to surgical/percutaneous cell transplantation methods. Some cells, e.g. insulin producing cells, are not suitable for intra-luminal transplantation and for such cells, other options must be found. We have constructed a "nanocatheter" with a penetrating tip for vessel perforation, thereby creating a working channel for parenchymal access by endovascular technique. To finish the procedure safely, the distal tip is detached to provide a securing plug in the vessel wall defect. We have performed interventions with full clinical integration in the superior mesenteric artery (SMA), the subclavian artery and the external carotid artery in rabbits. No hemorrhagic- or thromboembolic events occurred during the procedure. Stenosis formation and distal embolisation were analyzed by angiography and macroscopic inspection during autopsy at five, 30 and 80 days. All animals and implanted devices were also evaluated by micro-dissections and histochemical analysis. In this study we show safety data on the trans-vessel wall technique by behavioral, angiographical and histological analysis. No stenosis formation was observed at any of the follow-up time points. No animals or organs have shown any signs of distress due to the intervention. Histological examination showed no signs of hemorrhage, excellent biocompatibility with no inflammation and a very limited fibrous capsule formation around the device, comparable to titanium implants. Further, no histological changes were detected in the endothelia of the vessels subject to intervention. The trans-vessel wall technique can be applied for e.g. cell transplantations, local substance administration and tissue sampling with low risk for complications during the procedure and low risk for hemorrhage, stenosis development or adverse tissue reactions with an 80 days follow-up time. The benefit should be greatest in organs that are difficult or risky to reach with surgical techniques, such as the pancreas, the CNS and the heart.PLoS ONE 01/2011; 6(8):e23328. · 4.09 Impact Factor -
Article: New endovascular method for transvascular exit of arteries and veins: developed in simulator, in rat and in rabbit with full clinical integration.
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ABSTRACT: Endovascular technique has benefits vis-a-vis surgical access to organs with less accessible anatomical locations. To minimize surgical risk we propose a novel endovascular technique, to create parenchymal access through endovascular methods. We have developed, manufactured and tested an endovascular catheter with a depth limiting collar and a penetrating tip that is used to perforate vessels, thereby creating a working channel to the extra-vascular space. Computer simulations and subsequent interventions have been performed ex vivo and in vivo in both small and large animals by testing different prototypes. All tests were designed for testing extravascular hemostasis and absence of thrombo-embolic complications when exiting the vessels from the inside to the extra vascular space. We have deposited prototypes after intervention in vascular walls over a period of 14 days in rat with no impairment on blood flow and no signs of thrombo-embolic complications upon re-exploration (n = 7). We have also incorporated the catheter system with clinically available systems both in an ex vivo simulator setting and in a full scale clinical angiographical setting in rabbit were no bleeding (0%) in any of the interventions performed (n = 40). To prevent hemorrhage during termination of the procedure, a hollow electrolysis detachment-zone leaves the distal tip in the vessel-wall after the intervention. This has also been tested with absolute hemostasis in large animals (n = 6). We have developed and tested a new system for transvascular tissue access in simulations, ex vivo and in vivo in small and large animals, integrating it with standard clinical catheters and angiographical environment, with absolute hemostasis and without thromboembolic complications. In a clinical setting for stem cell transplantation, local substance administration or tissue sampling, the benefit should be greatest in organs that are difficult or high-risk to access with other techniques, such as the pancreas, the central nervous system (CNS) and the heart.PLoS ONE 01/2010; 5(5):e10449. · 4.09 Impact Factor -
Article: Traumatic brain injury induces relocalization of DNA-methyltransferase 1.
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ABSTRACT: Secondary cerebral damage after traumatic brain injury (TBI) occurs following processes partly initiated by gene expression alterations. DNA methylation in promoter regions is one of several epigenetic modifications, that affect the regulation of gene expression and which is a part of the pathophysiological pathway following TBI. We have investigated expression and cellular localization of DNA-methyltransferase (Dnmts) enzymes by immunohistochemistry (IHC) and confocal microscopy. Nuclear as well as cytoplasmic Dnmt1 was observed in astrocytes, in contrast to its normal neuronal nuclear localization. Interestingly, double staining with Dnmt1 and nestin showed co-localization in some reactive astrocytes in the nucleus alone, while in others this expression pattern was evident both in the nucleus and cytoplasm, in a brain region specific manner. In normal brains, and contralateral to the injury, the great majority of Dnmt1 positive cells were neurons. We also observed cytoplasmic Dnmt1 in peri-ventricular nestin expressing cells. Our findings may form the basis for further epigenetic studies following TBI and new therapeutic strategies to treat TBI patients.Neuroscience Letters 07/2009; 457(1):8-11. · 2.11 Impact Factor -
Article: Endovascular transplantation of stem cells to the injured rat CNS.
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ABSTRACT: Transplantation procedures using intraparenchymal injection of stem cells result in tissue injury in addition to associated surgical risks. Intravenous injection of mesenchymal stem cells gives engraftment to lesions, but the method has low efficiency and specificity. In traumatic brain injuries (TBI), there is a transient breakdown of the blood-brain barrier and an inflammatory response, which increase migration of cells from blood to parenchyma. The aim of this investigation was to analyze the effect of intra-arterial administration on cellular engraftment. Experimental TBI was produced in a rat model. Endovascular technique was used to administer human mesenchymal stem cells in the ipsilateral internal carotid artery. Evaluation of engraftment and side effects were performed by immunohistochemical analysis of the brain and several other organs. The results were compared to intravenous administration of stem cells. Intra-arterial transplantation of mesenchymal stem cells resulted in central nervous system (CNS) engraftment without thromboembolic ischemia. We observed a significantly higher number of transplanted cells in the injured hemisphere after intra-arterial compared to intravenous administration both 1 day (p < 0.01) and 5 days (p < 0.05) after the transplantation. Some cells were also detected in the spleen but not in the other organs analyzed. Selective intra-arterial administration of mesenchymal stem cells to the injured CNS is a minimally invasive method for transplantation. The method is significantly more efficient than the intravenous route and causes no side effects in the current model. The technique can potentially be used for repeated transplantation to the CNS after TBI and in other diseases.Neuroradiology 07/2009; 51(10):661-7. · 2.82 Impact Factor -
Article: Differences in cell death between high and low energy brain injury in adult rats.
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ABSTRACT: Traumatic brain damage is dependent on energy transfer to the brain at impact. Different injury mechanisms may cause different types of brain injury. It is, however, unknown if the relative distribution between apoptotic cell-death and necrotic cell- death in different populations of brain cells varies depending on energy transfer. Experimental contusions were produced with a modified weight drop onto the exposed dura of rats. Animals were divided into two groups. They received a weight drop from two different heights to vary energy transfer to be higher or lower. Animals were sacrificed at 24 hours post injury (1 DPI) or 6 days (6 DPI); brains were frozen and processed for TUNEL (TdT mediated dUTP nick end labelling), light microscopy and immunochemistry. The total number of TUNEL positive cells was higher in the higher energy group on the first day after the injury. At the same time point, relatively fewer cells were apoptotic than necrotic, while relatively more glial cells than neurons were TUNEL-positive in higher energy trauma. At 6 day after the injury fewer cells were TUNEL positive and there were no longer significant differences between the high and low energy groups. Increasing energy transfer in a model for brain contusion demonstrated qualitative and quantitative changes in the pattern of cell death. This complexity must be considered when evaluating brain-protection as treatment results may vary depending on which cellular population and which mechanism of cell death is treated under the exact experimental and clinical conditions.Acta Neurochirurgica 12/2008; 150(12):1269-75;discussion 1275. · 1.52 Impact Factor -
Article: Natural history of dural arteriovenous shunts.
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ABSTRACT: Dural arteriovenous shunts with cortical venous reflux or drainage may cause neurological symptoms and death with or without intracranial hemorrhage. Present knowledge about the natural history of these lesions is limited, however. We investigated the incidences of intracranial hemorrhage, progressive dementia syndrome, and death in patients diagnosed in our neurovascular center. We evaluated the records of 85 patients with dural arteriovenous shunts with cortical venous drainage or reflux hospitalized in our institution from 1978 to 2007. The annual incidences of intracranial hemorrhage, progressive dementia syndrome, and death were calculated. Fifty-three patients did not have an intracranial hemorrhage as the presenting event. One of these patients bled after diagnosis. Thirty-two patients had an intracranial hemorrhage as the presenting event. Three patients bled after diagnosis. One of these patients died. Apart from deficits caused by hemorrhage, no patient reported adverse neurological symptoms. In patients presenting with an intracranial hemorrhage the annual risk for hemorrhage is approximately 7.4% and in those not presenting with a hemorrhage it is approximately 1.5%. The risk of intracranial hemorrhage from a dural arteriovenous shunt with cortical venous drainage is most likely smaller than previously proposed. Presentation with hemorrhage is a risk factor for hemorrhage. The risks of developing neurological symptoms not related to hemorrhage are also less than previously reported.Stroke 07/2008; 39(6):1735-9. · 5.73 Impact Factor -
Article: Intradural saccular aneurysms treated by Guglielmi detachable bare coils at a single institution between 1993 and 2005: clinical long-term follow-up for a total of 1810 patient-years in relation to morphological treatment results.
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ABSTRACT: The aim of this study was to analyze the clinical results of Guglielmi detachable bare coil (GDC) embolization of intradural saccular aneurysms (AAs) at a single center and to relate the morphological results at various time points to the clinical situation. All intradural saccular AAs treated with GDCs between 1993 and April 2005 were prospectively entered into a database completed by retrospective analysis of charts and images and a long-term clinical outcome questionnaire. In 413 consecutive patients, there were 466 treated AAs, of which 68.7% were ruptured and 31.1% were unruptured. The periprocedural thromboembolic event rate, retreatment procedures included, was 5.4%, causing permanent neurologic deficits in 2.2% of patients. One patient (0.2%) bled during a mean+/-SD clinical follow-up of 64.3+/-39.9 months (93 AAs were followed up for >8 years and 45 AAs were followed up for >10 years) for a total of 1810 patient-years. The modified Rankin Scale score was 0 in 54.7%, 1 in 21.0%, 2 in 12.1%, 3 in 7.1%, 4 in 2.1%, 5 in 0.3%, and 6 (death from unrelated causes) in 2.7% of patients. If an aneurysm, with or without a remnant, was unchanged for 12 months, then the risk for future morphological loss was 4.8%, whereas if an aneurysm showed a morphological loss during the earlier 12-month interval, the risk for additional late loss was 38.3% (P<0.001, odds ratio=12.4). Embolization of saccular AAs entails a prolonged management period. A stable angiographic result during a 12-month interval predicts a low risk for morphological deterioration. This regimen, aiming for a stable angiographic result rather than complete aneurysm occlusion, gives a low rebleed rate and excellent clinical long-term results.Stroke 06/2008; 39(8):2288-97. · 5.73 Impact Factor -
Article: Cerebral proliferative angiopathy: clinical and angiographic description of an entity different from cerebral AVMs.
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ABSTRACT: The purpose of this article is to describe "cerebral proliferative angiopathy" (CPA) as a clinical entity, which may be regarded as separate from "classical" brain AVMs in angioarchitecture, natural history, clinical presentation, and, therefore, treatment and which can be discerned from other cerebral AVMs by characteristic imaging features. In a prospectively entered databank encompassing 1434 patients with brain AVMs, a subgroup of 49 patients harboring specific angiographic characteristics were identified. Their charts and imaging films were retrospectively reviewed. We found a preponderance of CPA in young (mean age: 22) females (67%). Clinical symptoms were seizures, disabling headaches, and stroke-like symptoms; hemorrhagic presentations were exceptional. On cross-sectional imaging, CPA demonstrated as a diffuse network of densely enhancing vascular spaces with intermingled normal brain parenchyma. The discrepancy between the large size of the nidus and the small shunting volume, the absence of flow-related aneurysms, the presence of diffuse angiogenesis (eg, transdural supply, progressive arterial occlusion), and the small calibre of a multitude of feeding arteries and draining veins were the angiographic hallmarks of this disease. The diffuse angiogenetic activity is presumably related to reduced perinidal perfusion and subsequent chronic cortical ischemia. Natural history demonstrates a low risk of hemorrhage. CPA may be regarded as a separate clinical entity different to "classical" cerebral AVMs, because normal brain is interspersed with the abnormal vascular channels increasing the risk of neurological deficit in aggressive treatments, which in the light of the natural history does not seem to be indicated.Stroke 04/2008; 39(3):878-85. · 5.73 Impact Factor -
Article: Neuroprotection by selective inhibition of inducible nitric oxide synthase after experimental brain contusion.
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ABSTRACT: The inflammatory response is thought to be important for secondary damage following traumatic brain injury (TBI). The inducible nitric oxide synthase (iNOS) isoform is a mediator in inflammatory reactions and may catalyze substantial synthesis of NO in the injured brain. This study was undertaken to analyze neuronal degeneration and survival, cellular apoptosis and formation of nitrotyrosine following treatment with the iNOS-inhibitor L-N-iminoethyl-lysine (L-NIL) in a model of brain contusion. A brain contusion was produced using a weight-drop device in 30 rats. The animals received treatment with L-NIL or NaCl at 15 min and 12 h after the injury and were sacrificed at 24 h or 6 days after trauma. iNOS activity was measured at 24 h post-trauma by the conversion of L-[U- ( 14 )C]arginine to L-[U-( 14 )C]citrulline and immunohistochemistry for iNOS. Peroxynitrite formation was indirectly assessed by nitrotyrosine (NT) immunohistochemistry. Neuronal degeneration and survival were assessed by Fluoro-Jade (FJ) and NeuN stainings, and cellular death by TUNEL staining. iNOS activity but not iNOS immunoreactivity was significantly reduced in animals that received L-NIL. Neuronal degeneration (FJ) and NT immunoreactivity were significantly reduced at 24 h. Neuronal survival was unchanged at 24 h but increased at 6 days in L-NIL-treated animals. Cellular apoptosis of ED-1 and NeuN positive cells was significantly reduced following L-NIL treatment at 6 days after trauma. We demonstrated neuroprotection by selective inhibition of iNOS after trauma. L-NIL appeared to protect the injured brain by limiting peroxynitrite formation. Our findings support a putative harmful role of iNOS induction early after TBI.Journal of Neurotrauma 10/2006; 23(9):1343-54. · 3.65 Impact Factor -
Article: Sustained survival of xenografted human neural stem/progenitor cells in experimental brain trauma despite discontinuation of immunosuppression.
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ABSTRACT: Neural stem cells have emerged as a promising therapeutic tool in CNS disease and injuries. In the clinical setting, cultured human neural stem/progenitor cells (hNSC) are an attractive possibility for transplantation to the damaged brain. However, transplantation of hNSC requires toxic immunosuppressive treatment to avoid rejection. The aim of the current study was to evaluate if shortening the duration of immunosuppression by cyclosporin A would affect hNSC survival and differentiation after transplantation to the site of a focal brain injury in the rat. hNSC were xenografted to the hippocampus and the medial limit of an experimentally induced cortical contusion. The animals received immunosuppression for either 6 or 3 weeks or no immunosuppression. The status of the grafted human cells was analysed by immunohistochemistry. No statistically significant differences were observed between the two immunosuppressed groups regarding graft survival, migration or proliferation at 6 weeks post-transplantation. In contrast, the graft survival was extremely poor in the non-immunosuppressed group. Furthermore, the expression of the differentiation markers nestin, neuronal nuclei (NeuN) and glial fibrillary acidic protein (GFAP) in the transplanted cells did not differ significantly between the two immunosuppressed groups. Moreover, a fourth group of eight animals that were immunosuppressed for 3 weeks were allowed to survive for 6 months. Five of these rats demonstrated robust graft survival in the hippocampus and scattered cells in the cortex. This study demonstrates the importance of immunosuppression but also the possibility of shortening immunosuppression without impacting on the phenotype of the grafted hNSC.Experimental Neurology 07/2006; 199(2):339-47. · 4.70 Impact Factor -
Article: Inhibition of vascular endothelial growth factor receptor 2 activity in experimental brain contusions aggravates injury outcome and leads to early increased neuronal and glial degeneration.
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ABSTRACT: Angiogenesis following traumatic brain injuries (TBIs) may be of importance for post-traumatic reparative processes and the development of secondary injuries. We have previously shown expression of vascular endothelial growth factor (VEGF), a major regulator of endothelial cell proliferation, angiogenesis and vascular permeability, and VEGF receptors (VEGFR1 and 2) after TBI in rat. In the present work we tried to further elucidate the role of VEGF after TBI by performing specific VEGFR2 activity inhibition. In rats subjected to VEGFR2 blockage we report an increased haemorrhagic area (P < 0.05), early increase in serum levels of neural injury marker neuron-specific enolase (P < 0.05) and glial injury marker S100beta (P < 0.05), and increased numbers of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labelling- (TUNEL-) and FluoroJade B- (P < 0.05) positive cells, all increases preceding the known VEGF/VEGFR vascular response in brain trauma. An increase in lesion area, as measured by decreased microtubuli-associated protein 2 expression (P < 0.05) and increased glial fibrillary acidic protein reactivity (P < 0.05), could also be demonstrated. In addition, vascular density, as measured by von Willebrandt factor-positive cells, was decreased (P < 0.05). No differences in post-traumatic inflammatory response, as measured by stainings for macrophages, granulocytes and intracellular adhesion molecules, were shown between the groups. Taken together, our findings point towards VEGF/VEGFR2 up-regulation after TBI as being an important endogenous cytoprotective mechanism in TBI. The possible importance of VEGF on the vascular, neuronal and glial compartments of the neurovascular unit after TBI is discussed.European Journal of Neuroscience 01/2006; 23(1):21-34. · 3.63 Impact Factor -
Article: Reduced neuronal injury after treatment with NG-nitro-L-arginine methyl ester (L-NAME) or 2-sulfo-phenyl-N-tert-butyl nitrone (S-PBN) following experimental brain contusion.
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ABSTRACT: Nitric oxide (NO) and oxygen free radicals are implicated in the pathophysiology of traumatic brain injury (TBI). Peroxynitrite formation from NO and superoxide contributes to secondary neuronal injury but the neuroprotective effects of nitric oxide synthase (NOS)-inhibitors have been contradictory. This study was undertaken to examine whether PTtic administration of the (NOS)-inhibitor N-nitro-l-arginine methyl ester (L-NAME), and a combination of L-NAME and the nitrone radical scavenger 2-sulfo-phenyl-N-tert-butyl nitrone (S-PBN) favorable affects neuronal injury in a model of TBI. A weight-drop model of TBI was used. The animals received L-NAME, S-PBN or a combination of the drugs 15 minutes prothrombin time (PT) and sacrificed after 24 hours or six days. NOS activity was measured by the conversion of L-[U-C]arginine to L-[U-C]citrulline. Peroxynitrite formation, cellular apoptosis, neuronal degeneration and survival were assessed by nitrotyrosine-, TUNEL-, Fluoro-Jade- and NeuN-stainings. eNOS and nNOS activity was significantly reduced in animals that received L-NAME alone or the combination with S-PBN. iNOS activity or iNOS immunoreactivity was not affected. All treatments significantly reduced neuronal degeneration and nitrotyrosine immunoreactivity at 24 hours and increased neuronal survival at six days PT. No differences were detected between L-NAME and L-NAME + S-PBN groups. NO from NOS contributes to secondary neuronal injury in this TBI-model. PTtic treatment does not inhibit early beneficial NO-related effects. L-NAME and S-PBN limit peroxynitrite formation, promoting neuronal survival. The combination of L-NAME and S-PBN was neuroprotective; surprisingly no additive effects were found on nitrotyrosine formation, apoptosis or neuronal survival.Neurosurgery 01/2006; 57(6):1272-81; discussion 1272-81. · 2.79 Impact Factor -
Article: Experimental subarachnoid hemorrhage induces changes in the levels of hippocampal NMDA receptor subunit mRNA.
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ABSTRACT: NMDA receptors may play a crucial role in nerve cell death following subarachnoid hemorrhage (SAH). Changes in NMDA receptor-mediated transmission appear before neuronal death in rodent models of transient ischemia, and NMDA receptor function is known to be dependent on subunit composition. Here, we have investigated whether mRNA expression of the NMDA receptor subunits is altered in the hippocampal formation 3-5 h following experimental SAH, and correlated these early alterations to subsequent delayed cell death. SAH was induced by intraluminal perforation of the internal carotid artery intracranially, and cerebral blood flow (CBF) was bilaterally monitored by laser-Doppler flowmetry. Early changes in NMDA receptor subunit mRNA and early nerve cell death were analyzed at 3-5 h after SAH, and delayed nerve cell death was analyzed at 2-7 days after SAH. Duration of ipsilateral CBF reduction below 30% of baseline (CBF30) was predictive of ipsilateral delayed nerve cell death in the CA1 2-7 days after SAH. At CBF30 > 9 min, we found downregulation of mRNA for NR2A, NR2B, and NR3B at 3-5 h after SAH, whereas the levels of NR1 mRNA were unaffected. The downregulation of NR2A and NR2B mRNA may result in a reduced NMDA receptor function. Such reduction may be sufficient to provide neuroprotection in the dentate gyrus, where no cell death appears, but insufficient to rescue neurons in the hippocampus proper following SAH.Molecular Brain Research 06/2005; 137(1-2):119-25. · 2.00 Impact Factor -
Article: VEGF and VEGF receptor expression after experimental brain contusion in rat.
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ABSTRACT: Angiogenesis following traumatic brain injury (TBI) may be of importance not only for post-traumatic reparative processes but also for the development of secondary injuries. Vascular endothelial growth factor (VEGF) is a major regulator of endothelial cell proliferation, angiogenesis, and vascular permeability, though its possible involvement in secondary injuries after TBI is largely unknown. This study was undertaken to analyze the expression of VEGF and the VEGF receptors in experimental brain contusion in rat. Twenty-three adult female Sprague-Dawley rats were subjected to a focal cerebral contusion injury by use of a weight-drop model. Four additional rats underwent craniotomy only. The animals were sacrificed 6 h, or 1, 2, 4, 6, 8, or 16 days post-injury. Expression of VEGF and the VEGF receptors VEGFR1 (Flt-1) and VEGFR2 (Flk-1) were studied by in situ hybridization and immunohistochemistry. VEGF messenger (m)RNA and protein expression were detected in astrocytes, neutrophils, and macrophages in or adjacent to the injury from 1 day after injury, with a peak expression after 4-6 days. Flt-1 and Flk-1 mRNA and protein were detected in vessels adjacent to the lesion from 1 day after injury throughout day 6 after injury. It was also noted that Flt-1/Flk-1 and VEGF-positive vessels often were negative for SMI-71, a marker for vessels in areas with blood-brain barrier (BBB). In conclusion, we have demonstrated that TBI leads to an upregulation of VEGF, Flt-1, and Flk-1 mRNA and protein in and around the lesion. The data provide a foundation for future pharmacological intervention studies focusing on posttraumatic angiogenesis and possible injury repair effects of the VEGF system in TBI.Journal of Neurotrauma 04/2005; 22(3):353-67. · 3.65 Impact Factor
Top co-authors
Top Journals
- Stroke (4)
- Neuroscience Letters (2)
- Journal of Neurotrauma (2)
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Institutions
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2004–2012
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Karolinska University Hospital
Stockholm, Stockholm, Sweden
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2002–2012
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Karolinska Institutet
- • Institutionen för klinisk neurovetenskap
- • Institutionen för neurovetenskap
Solna, Stockholm, Sweden
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2003–2004
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Karolinska Institute
- Institutionen för klinisk neurovetenskap
Stockholm, Stockholm, Sweden
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