The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Tiit Mathiesen - One of the best experts on this subject based on the ideXlab platform.
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inos mediated secondary inflammatory response differs between rat strains following experimental Brain Contusion
Acta Neurochirurgica, 2012Co-Authors: Mattias Gunther, Caroline Gahm, Faiez Al Nimer, Fredrik Piehl, Tiit MathiesenAbstract:Background Nitric oxide is a key mediator of post-traumatic inflammation in the Brain. We examined the expressions of iNOS, nNOS, and eNOS in inbred DA and PVGa rat strains where DA is susceptible to autoimmune neuroinflammation and PVGa-resistant.
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neuroprotection by selective inhibition of inducible nitric oxide synthase after experimental Brain Contusion
Journal of Neurotrauma, 2006Co-Authors: Caroline Gahm, Staffan Holmin, Peter Wiklund, Lou Brundin, Tiit MathiesenAbstract: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.
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autoreactive antibodies against neurons and basal lamina found in serum following experimental Brain Contusion in rats
Acta Neurochirurgica, 2006Co-Authors: S Rudehill, Staffan Holmin, S Muhallab, Andre Wennersten, C Von Gertten, Al F Nimer, A C Sandbergnordqvist, Tiit MathiesenAbstract:Background. Brain trauma is a risk factor for delayed CNS degeneration which may be attenuated by anti-inflammatory treatment. CNS injuries may cause anti-Brain reactivity. This study was undertaken to analyze the pattern of delayed post-traumatic anti-Brain immunity in experimental Brain Contusion.
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neuronal degeneration and inos expression in experimental Brain Contusion following treatment with colchicine dexamethasone tirilazad mesylate and nimodipine
Acta Neurochirurgica, 2005Co-Authors: Caroline Gahm, S Rudehill, Staffan Holmin, Tiit MathiesenAbstract:Background. The pathophysiological mechanisms of secondary neurological injury after traumatic Brain injury are complex. Post-traumatic biochemical reactions include parenchymal inflammation, free radical production, increased intracellular calcium and lipid peroxidation and nitric oxide production. The relative importance of each mechanism is unknown in Brain Contusions. This study was undertaken to investigate protection by the neuroprotective and/or anti-inflammatory drugs that have different putative mechanisms of action: colchicine, dexamethasone, tirilazad mesylate and nimodipine.
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vegf and vegf receptor expression after experimental Brain Contusion in rat
Journal of Neurotrauma, 2005Co-Authors: Mattias K Skold, Tiit Mathiesen, Christina Von Gertten, Annchristin Sandbergnordqvist, Staffan HolminAbstract: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.
Staffan Holmin - One of the best experts on this subject based on the ideXlab platform.
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neuroprotection by selective inhibition of inducible nitric oxide synthase after experimental Brain Contusion
Journal of Neurotrauma, 2006Co-Authors: Caroline Gahm, Staffan Holmin, Peter Wiklund, Lou Brundin, Tiit MathiesenAbstract: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.
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autoreactive antibodies against neurons and basal lamina found in serum following experimental Brain Contusion in rats
Acta Neurochirurgica, 2006Co-Authors: S Rudehill, Staffan Holmin, S Muhallab, Andre Wennersten, C Von Gertten, Al F Nimer, A C Sandbergnordqvist, Tiit MathiesenAbstract:Background. Brain trauma is a risk factor for delayed CNS degeneration which may be attenuated by anti-inflammatory treatment. CNS injuries may cause anti-Brain reactivity. This study was undertaken to analyze the pattern of delayed post-traumatic anti-Brain immunity in experimental Brain Contusion.
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neuronal degeneration and inos expression in experimental Brain Contusion following treatment with colchicine dexamethasone tirilazad mesylate and nimodipine
Acta Neurochirurgica, 2005Co-Authors: Caroline Gahm, S Rudehill, Staffan Holmin, Tiit MathiesenAbstract:Background. The pathophysiological mechanisms of secondary neurological injury after traumatic Brain injury are complex. Post-traumatic biochemical reactions include parenchymal inflammation, free radical production, increased intracellular calcium and lipid peroxidation and nitric oxide production. The relative importance of each mechanism is unknown in Brain Contusions. This study was undertaken to investigate protection by the neuroprotective and/or anti-inflammatory drugs that have different putative mechanisms of action: colchicine, dexamethasone, tirilazad mesylate and nimodipine.
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vegf and vegf receptor expression after experimental Brain Contusion in rat
Journal of Neurotrauma, 2005Co-Authors: Mattias K Skold, Tiit Mathiesen, Christina Von Gertten, Annchristin Sandbergnordqvist, Staffan HolminAbstract: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.
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in situ detection of intracerebral cytokine expression after human Brain Contusion
Neuroscience Letters, 2004Co-Authors: Staffan Holmin, Bo HojebergAbstract:The study was undertaken to analyze intracerebral expression of pro- and anti-inflammatory cytokines after traumatic Brain injury (TBI) in man in order to compare the findings with previous experimental data regarding the pathogenesis of secondary Brain injury. Contused Brain tissue biopsies were obtained from 12 consecutive patients undergoing surgery for Brain Contusions 3 h to 5 days after trauma. Cytokine expression was analyzed by in situ hybridization and immunohistochemistry. In patients undergoing surgery less than 24 h after trauma, strong expression of both the pro-inflammatory cytokines interleukin (IL)-1-beta, IL-6 and interferon (IFN)-gamma and the anti-inflammatory cytokine IL-4 was detected. In patients undergoing surgery between 3 and 5 days after trauma, IL-4 expression was significantly lower (P < 0.05) compared to the patients operated early. IL-1-beta and IFN-gamma expression remained strong in comparison to IL-6 and IL-4 expression (P < 0.05). Immunohistochemistry for IL-1-beta confirmed that the protein was produced with a temporal and regional pattern that corresponded to in situ hybridization results. The study provides in situ data on intracerebral cytokine expression after Contusion in the clinical setting. Strong intracerebral cytokine expression occurs in the perilesional zone both in the early and the delayed phase after traumatic Brain injury in humans. The temporal regulation of pro- and anti-inflammatory cytokines differs which reveals different therapeutic windows for pharmacological intervention.
Marc J. Simard - One of the best experts on this subject based on the ideXlab platform.
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role of sulfonylurea receptor 1 and glibenclamide in traumatic Brain injury a review of the evidence
International Journal of Molecular Sciences, 2020Co-Authors: Ruchira M. Jha, Josh Bell, Giuseppe Citerio, Claude J Hemphill, Taylor W Kimberly, Raj K Narayan, Juan Sahuquillo, Kevin N Sheth, Marc J. SimardAbstract:Cerebral edema and Contusion expansion are major determinants of morbidity and mortality after TBI. Current treatment options are reactive, suboptimal and associated with significant side effects. First discovered in models of focal cerebral ischemia, there is increasing evidence that the sulfonylurea receptor 1 (SUR1)-Transient receptor potential melastatin 4 (TRPM4) channel plays a key role in these critical secondary injury processes after TBI. Targeted SUR1-TRPM4 channel inhibition with glibenclamide has been shown to reduce edema and progression of hemorrhage, particularly in preclinical models of Contusional TBI. Results from small clinical trials evaluating glibenclamide in TBI have been encouraging. A Phase-2 study evaluating the safety and efficacy of intravenous glibenclamide (BIIB093) in Brain Contusion is actively enrolling subjects. In this comprehensive narrative review, we summarize the molecular basis of SUR1-TRPM4 related pathology and discuss TBI-specific expression patterns, biomarker potential, genetic variation, preclinical experiments, and clinical studies evaluating the utility of treatment with glibenclamide in this disease.
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key role of sulfonylurea receptor 1 in progressive secondary hemorrhage after Brain Contusion
Journal of Neurotrauma, 2009Co-Authors: Marc J. Simard, Svetlana Ivanova, Cigdem Tosun, Michael Kilbourne, Orest Tsymbalyuk, John Caridi, Kaspar Keledjian, Grant V Bochicchio, Volodymyr GerzanichAbstract:Abstract An important but poorly understood feature of traumatic Brain injury (TBI) is the clinically serious problem of spatiotemporal progression (“blossoming”) of a hemorrhagic Contusion, a phenomenon we term progressive secondary hemorrhage (PSH). Molecular mechanisms of PSH are unknown and efforts to reduce it by promoting coagulation have met with equivocal results. We hypothesized that PSH might be due to upregulation and activation of sulfonylurea receptor 1 (SUR1)-regulated NCCa-ATP channels in capillary endothelial cells, predisposing to oncotic death of endothelial cells and catastrophic failure of capillary integrity. Anesthetized adult male rats underwent left parietal craniectomy for induction of a focal cortical Contusion. The regulatory subunit of the channel, SUR1, was prominently upregulated in capillaries of penumbral tissues surrounding the Contusion. In untreated rats, PSH was characterized by progressive enlargement of the Contusion deep into the site of cortical impact, including co...
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key role of sulfonylurea receptor 1 in progressive secondary hemorrhage after Brain Contusion
Journal of Neurotrauma, 2009Co-Authors: Marc J. Simard, Svetlana Ivanova, Cigdem Tosun, Michael Kilbourne, Orest Tsymbalyuk, John Caridi, Kaspar Keledjian, Grant V Bochicchio, Volodymyr GerzanichAbstract:An important but poorly understood feature of traumatic Brain injury (TBI) is the clinically serious problem of spatiotemporal progression ("blossoming") of a hemorrhagic Contusion, a phenomenon we term progressive secondary hemorrhage (PSH). Molecular mechanisms of PSH are unknown and efforts to reduce it by promoting coagulation have met with equivocal results. We hypothesized that PSH might be due to upregulation and activation of sulfonylurea receptor 1 (SUR1)-regulated NC(Ca-ATP) channels in capillary endothelial cells, predisposing to oncotic death of endothelial cells and catastrophic failure of capillary integrity. Anesthetized adult male rats underwent left parietal craniectomy for induction of a focal cortical Contusion. The regulatory subunit of the channel, SUR1, was prominently upregulated in capillaries of penumbral tissues surrounding the Contusion. In untreated rats, PSH was characterized by progressive enlargement of the Contusion deep into the site of cortical impact, including corpus callosum, hippocampus, and thalamus, by progressive accumulation of extravasated blood, with a doubling of the volume during the first 12 h after injury, and by capillary fragmentation in penumbral tissues. Block of SUR1 using low-dose (non-hypoglycemogenic) glibenclamide largely eliminated PSH and capillary fragmentation, and was associated with a significant reduction in the size of the necrotic lesion and in preservation of neurobehavioral function. Antisense oligodeoxynucleotide against SUR1, administered after injury, reduced both SUR1 expression and PSH, consistent with a requirement for transcriptional upregulation of SUR1. Our findings provide novel insights into molecular mechanisms responsible for PSH associated with hemorrhagic Contusions, and point to SUR1 as a potential therapeutic target in TBI.
Volodymyr Gerzanich - One of the best experts on this subject based on the ideXlab platform.
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key role of sulfonylurea receptor 1 in progressive secondary hemorrhage after Brain Contusion
Journal of Neurotrauma, 2009Co-Authors: Marc J. Simard, Svetlana Ivanova, Cigdem Tosun, Michael Kilbourne, Orest Tsymbalyuk, John Caridi, Kaspar Keledjian, Grant V Bochicchio, Volodymyr GerzanichAbstract:Abstract An important but poorly understood feature of traumatic Brain injury (TBI) is the clinically serious problem of spatiotemporal progression (“blossoming”) of a hemorrhagic Contusion, a phenomenon we term progressive secondary hemorrhage (PSH). Molecular mechanisms of PSH are unknown and efforts to reduce it by promoting coagulation have met with equivocal results. We hypothesized that PSH might be due to upregulation and activation of sulfonylurea receptor 1 (SUR1)-regulated NCCa-ATP channels in capillary endothelial cells, predisposing to oncotic death of endothelial cells and catastrophic failure of capillary integrity. Anesthetized adult male rats underwent left parietal craniectomy for induction of a focal cortical Contusion. The regulatory subunit of the channel, SUR1, was prominently upregulated in capillaries of penumbral tissues surrounding the Contusion. In untreated rats, PSH was characterized by progressive enlargement of the Contusion deep into the site of cortical impact, including co...
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key role of sulfonylurea receptor 1 in progressive secondary hemorrhage after Brain Contusion
Journal of Neurotrauma, 2009Co-Authors: Marc J. Simard, Svetlana Ivanova, Cigdem Tosun, Michael Kilbourne, Orest Tsymbalyuk, John Caridi, Kaspar Keledjian, Grant V Bochicchio, Volodymyr GerzanichAbstract:An important but poorly understood feature of traumatic Brain injury (TBI) is the clinically serious problem of spatiotemporal progression ("blossoming") of a hemorrhagic Contusion, a phenomenon we term progressive secondary hemorrhage (PSH). Molecular mechanisms of PSH are unknown and efforts to reduce it by promoting coagulation have met with equivocal results. We hypothesized that PSH might be due to upregulation and activation of sulfonylurea receptor 1 (SUR1)-regulated NC(Ca-ATP) channels in capillary endothelial cells, predisposing to oncotic death of endothelial cells and catastrophic failure of capillary integrity. Anesthetized adult male rats underwent left parietal craniectomy for induction of a focal cortical Contusion. The regulatory subunit of the channel, SUR1, was prominently upregulated in capillaries of penumbral tissues surrounding the Contusion. In untreated rats, PSH was characterized by progressive enlargement of the Contusion deep into the site of cortical impact, including corpus callosum, hippocampus, and thalamus, by progressive accumulation of extravasated blood, with a doubling of the volume during the first 12 h after injury, and by capillary fragmentation in penumbral tissues. Block of SUR1 using low-dose (non-hypoglycemogenic) glibenclamide largely eliminated PSH and capillary fragmentation, and was associated with a significant reduction in the size of the necrotic lesion and in preservation of neurobehavioral function. Antisense oligodeoxynucleotide against SUR1, administered after injury, reduced both SUR1 expression and PSH, consistent with a requirement for transcriptional upregulation of SUR1. Our findings provide novel insights into molecular mechanisms responsible for PSH associated with hemorrhagic Contusions, and point to SUR1 as a potential therapeutic target in TBI.
Mattias K Skold - One of the best experts on this subject based on the ideXlab platform.
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vegf and vegf receptor expression after experimental Brain Contusion in rat
Journal of Neurotrauma, 2005Co-Authors: Mattias K Skold, Tiit Mathiesen, Christina Von Gertten, Annchristin Sandbergnordqvist, Staffan HolminAbstract: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.