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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

(1) Cerebral ischemia and reperfusion induce several changes on the endothelial cells at the microcirculatory level. (2) Vasogenic brain edema due to compromised blood-brain barrier, transformation of the endothelial cell surface from an anticoagulant to a procoagulant surface are important factors in the pathogenesis of ischemic stroke. (3) Release of prostaglandins, endothelin-1, complement proteins, and matrix metalloproteinase-9 by microvascular endothelial cells are other components in the complex mechanism of brain ischemia/hypoxia. (4) Ultrastructural studies documented the opened paracellular avenues in the course of vasogenic edema in different experimental models (5) Tight junctions of endothelial cells have been characterized with freeze fracture electron microscopy, and the process of transvesiculation was analyzed using rapid freeze and freeze substitution procedure before electron microscopy studies (6) In endothelial cell-culture experiments, we used rodent and later human brains. (7) Endothelial cells co-cultured with astroglia resulted in an elaborate tight junctional complex. (8) This co-culture technique becomes the basis of in vitro blood-brain barrier studies On endothelial cells of human brain origin, different regulatory factors found to be responsible for the complex mechanism of ischemic stroke.
Cell Mol Neurobiol 2005 Feb
PMID:Human cerebral microvessel endothelial cell culture as a model system to study the blood-brain interface in ischemic/hypoxic conditions. 1596 14

The metabolic crisis of diabetic ketoacidosis (DKA) and its treatment can result in the life-threatening complication of clinical brain edema. However, there is limited information available regarding either the pathophysiology or histology of this acute complication. It has been reported that DKA and its treatment are associated with a systemic inflammatory response involving the activation of the complement cascade with increases of SC5b-9 serum level. We studied the brains of two patients, both of whom died as the result of DKA-related brain edema, for the presence of C5b-9, C1q and the expression of the CD59. Apoptosis was also evaluated by the TUNEL method. All regions of the brain demonstrated varying degrees of C5b-9 deposits on neurons, oligodendrocytes and blood vessels. C5b-9 was co-localized with C1q, suggesting the activation of classical pathway. No expression of CD59 was found on neurons, oligodendrocytes or blood vessels in DKA brain, but this complement inhibitor was present on these cells in the normal brain. Rarely, C5b-9 was co-localized with apoptotic neurons and OLG. Our data demonstrate that the metabolic crisis of DKA results in a loss of CD59 expression and assembly of C5b-9 on neurons and oligodendrocytes, suggesting that complement activation and C5b-9 may play a role in the pathophysiology of the brain edema of DKA.
Exp Mol Pathol 2006 Jun
PMID:Complement activation in diabetic ketoacidosis brains. 1649 64

1. The role of oxidative stress, and accordingly uncontrolled reactive oxygen species generation/action, have been widely documented in a number of different neuronal pathologies. However, the concept of pharmacological interventions in prevention and therapy of oxidative stress-related diseases has not found adequate application in clinical practice. This may be due to the insufficient efficacy of drugs available, their unsuitable pharmacokinetics, side effects, toxicity, etc. 2. Based on stobadine, (--)-cis-2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole, a well-known antioxidant, free radical scavenger, and neuroprotectant, it was attempted to develop new stobadine derivatives with improved pharmacodynamic and toxicity profiles, on applying molecular design, synthesis and adequate tests. Stobadine molecule was modified mostly by electron donating substitution on the benzene ring and by alkoxycarbonyl substitution at N-2 position. A total of >70 derivatives were prepared. 3. In a mice model of head trauma, some of the new stobadine derivatives administered i.v. immediately after the trauma, significantly improved sensomotoric outcome in the animals assessed 1 h later. Accordingly, decrease in brain edema was proved histologically as well as by brain wet weight assessment. 4. Putative neuroprotective action of the compounds was confirmed on rat hippocampal slices exposed to reversible 6 min hypoxia/low glucose by analysis of synaptic transmission in CA1 region neurons. Irreversible impairment of neurotransmission resulting from the hypoxia was significantly reduced by the presence of SMe1EC2, one of the new compounds, in concentration range 0.03-10.0x10(-6) mol l(-1). Both the neuroprotective and antioxidant effect of the compound closely resembled those of stobadine, melatonin, 21-aminosteroids, alpha-phenyl-tert-butylnitrone and others, all well-established antioxidants, except the range of effective concentrations was by 1-2 orders lower in SMe1EC2. 5. A remarkable antioxidant efficacy was observed in the new compounds in rat brain homogenates exposed to iron/ascorbate system by protection of lipids and creatine kinase against the oxidative impairment. A link between the neuroprotective and antioxidant/ scavenger properties in the compounds can be assumed. 6. Acute toxicity of some of the new pyridoindoles was diminished compared to stobadine. That might be due to the virtually full elimination of stobadine's undesired alpha (1)-adrenolytic activity attained by appropriate modifications of its molecule. 7. The new pyridoindoles extend the range of available neuroprotectants interfering with oxidative stress in neuronal tissue.
Cell Mol Neurobiol
PMID:Development of the new group of indole-derived neuroprotective drugs affecting oxidative stress. 1670 80

1. Stroke is the neurological evidence of a critical reduction of cerebral blood flow in a circumscribed part of the brain, resulting from the sudden or gradually progressing obstruction of a large brain artery. Treatment of stroke requires the solid understanding of stroke pathophysiology and involves a broad range of hemodynamic and molecular interventions. This review summarizes research that has been carried out in many laboratories over a long period of time, but the main focus will be on own experimental research. 2. The first chapter deals with the hemodynamics of focal ischemia with particular emphasis on the collateral circulation of the brain, the regulation of blood flow and the microcirculation. In the second chapter the penumbra concept of ischemia is discussed, providing a detailed list of the physiological, biochemical and structural viability thresholds of ischemia and examples of how these thresholds can be applied for imaging the penumbra. The third chapter summarizes the pathophysiology of infarct progression, focusing on the role of peri-infarct depolarisation, the multitude of putative molecular injury pathways, brain edema and inflammation. Finally, the fourth chapter provides an overview of currently discussed therapeutic approaches, notably the effect of mechanical or thrombolytic reperfusion, arteriogenesis, pharmacological neuroprotection, ischemic preconditioning and regeneration. 3. The main emphasis of the review is placed on the balanced differentiation between hemodynamic and molecular factors contributing to the manifestation of ischemic injury in order to provide a rational basis for future therapeutic interventions.
Cell Mol Neurobiol
PMID:Pathophysiology and therapy of experimental stroke. 1671 Jul 59

CEP-7055, a fully synthetic, orally active N,N-dimethylglycine ester of CEP-5214, a C3-(isopropylmethoxy)-fused pyrrolocarbazole with potent pan-vascular endothelial growth factor receptor (VEGFR) kinase inhibitory activity, has recently completed phase I clinical trials in cancer patients. These studies evaluated the antitumor efficacy of CEP-7055 using orthotopic models of glioblastoma and colon carcinoma in combination with temozolomide, and irinotecan and oxaliplatin, respectively, for their effects on primary and metastatic tumor burden and median survival. Chronic administration of CEP-7055 (23.8 mg/kg/dose) and temozolomide resulted in improvement of median survival of nude mice bearing orthotopic human glioblastoma xenografts compared with temozolomide alone (261 versus 192 days, respectively; P < or = 0.02). Reductions in neurologic dysfunction, brain edema, hemorrhage, and intratumoral microvessel density (CD34 staining) were observed in glioma-bearing mice receiving CEP-7055 alone, temozolomide alone, and the combination of CEP-7055 and temozolomide relative to vehicle and to temozolomide monotherapy. The administration of CEP-7055 in combination with irinotecan (20 mg/kg/dose i.p. x 5 days), and to a lesser degree with oxaliplatin (10 mg/kg/dose i.v.), showed reductions on primary colon carcinoma and hepatic metastatic burden in the CT-26 tumor model relative to that achieved by irinotecan and oxaliplatin monotherapy. These data show the significant efficacy and tolerability of optimal efficacious doses of CEP-7055 when given in combination with temozolomide and irinotecan relative to monotherapy with these cytotoxic agents in preclinical orthotopic glioma and colon carcinoma models and lend support for the use of these treatment regimens in a clinical setting in patients with glioblastoma and colon carcinoma.
Mol Cancer Ther 2006 Jul
PMID:The effects of the oral, pan-VEGF-R kinase inhibitor CEP-7055 and chemotherapy in orthotopic models of glioblastoma and colon carcinoma in mice. 1689 60

The neuropathogenesis of influenza-associated encephalopathy in children and Reye's syndrome remains unclear. A surveillance effort conducted during 2000-2003 in South-West Japan reveals that almost all fatal and handicapped influenza-associated encephalopathy patients exhibit a disorder of mitochondrial beta-oxidation with elevated serum acylcarnitine ratios (C(16:0)+C(18:1))/C(2). Here we show invasion by a non-neurotropic epidemic influenza A H3N2 virus in cerebral capillaries with progressive brain edema after intranasal infection of mice having impaired mitochondrial beta-oxidation congenitally or posteriorly in the newborn/ suckling periods. Mice genetically lacking of carnitine transporter OCTN2, resulting in carnitine deficiency and impaired beta-oxidation, exhibited significant higher virus-genome numbers in the brain, accumulation of virus antigen exclusively in the cerebral capillaries and increased brain vascular permeability compared to in wild type mice. Mini-plasmin, which proteolytically potentiates influenza virus multiplication in vivo and destroys the blood-brain barrier, accumulated with virus antigen in the brain capillaries of OCTN2-deficient mice but only a little in wild-type mice. These results suggest that the impaired mitochondrial beta-oxidation changes the susceptibility to a non-neurotropic influenza A virus as to multiplication in the brain capillaries and to cause brain edema. These pathological findings in the brain of mice having impaired mitochondrial beta-oxidation after influenza virus infection may have implications for human influenza-associated encephalopathy.
Mol Cell Biochem 2007 May
PMID:Impaired long-chain fatty acid metabolism in mitochondria causes brain vascular invasion by a non-neurotropic epidemic influenza A virus in the newborn/suckling period: implications for influenza-associated encephalopathy. 1689 40

A systemic inflammatory response (SIR) occurs prior to and during the treatment of severe diabetic ketoacidosis (DKA). IL-1beta, TNF-alpha and C5b-9 are components of SIR and have been speculated to be involved in the clinical brain edema (BE) of DKA. We studied IL-1beta, TNF-alpha, C5b-9, inducible nitric oxide (iNOS), ICAM-1, IL-10 and Hsp70 expression in the brains of two patients who died as the result of clinical BE during the treatment of DKA. IL-1beta was strongly expressed in the choroid plexus epithelium (CPE) and ependyma, and to a lesser extent in the hippocampus, caudate, white matter radiation of the pons, molecular layer of the cerebellum and neurons of the cortical gray matter. TNF-alpha was expressed to a lesser extent than IL-1beta, and only in the CP. C5b-9, previously shown to be deposited on neurons and oligodendrocytes, was found on CPE and ependymal cells. iNOS and ICAM-1 had increased expression in the CPE and ependyma. Hsp70 and IL-10 were also expressed in the CPE of the case with the shorter duration of treatment. Our data demonstrate the presence of a multifaceted neuroinflammatory cytotoxic insult of the CPE, which may play a role in the pathophysiology of the fatal brain edema of DKA.
Exp Mol Pathol 2007 Aug
PMID:Neuroinflammatory response of the choroid plexus epithelium in fatal diabetic ketoacidosis. 1733 2

Aquaporin 4 (AQP4) is a key molecule for maintaining water balance in the central nervous system, and its dysfunction might cause brain edema. However, little is known about the regulation of AQP4 expression. Because thrombin has been implicated in brain edema formation, the purpose of this study is to determine whether thrombin affects expression of AQP4 in astrocytes. Here, the effect of thrombin on AQP4 expression in vitro was evaluated using Western blot analysis and RT-PCR. Meanwhile, we investigated whether the effect of thrombin on AQP4 expression was due to protease-activated receptor 1 (PAR-1). In addition, we examined the role of protein kinase C (PKC) in the effect of thrombin on AQP4 expression using Western blot analysis. We found that thrombin did not affect cell viability at concentrations of 0.05, 0.5, 5, or 50 nM but killed astrocytes at concentrations of 500 nM, with approx 72% of astrocytes surviving at 500 nM thrombin. Our data showed that AQP4 protein expression achieved only 28% of controls in 500 nM thrombin treatment, even if astrocytes survived approx 72% of controls at 500 nM thrombin. Thrombin significantly inhibited AQP4 in a time- and dose dependent manner in vitro (p<0.05). Cathepsin-G, a thrombin PAR-1 inhibitor, reversed significantly (p<0.05) the effect of thrombin on AQP4 mRNA and protein expression in astrocytes. We also observed that PKC inhibitor H-7 or prolonged pretreatment with TPA can rapidly increase AQP4 expression (p<0.05). Thrombin might inhibit AQP4 expression in rat astrocytes, and this effect is possibly mediated by the PKC pathway.
J Mol Neurosci 2007
PMID:Thrombin inhibits aquaporin 4 expression through protein kinase C-dependent pathway in cultured astrocytes. 1741 72

Edema formation has been linked to thrombin toxicity induced by blood clot at the acute stage of intracerebral hemorrhage. Thrombin induces cell toxicity in neuron, microglia and astrocyte. Aquaporin (AQP) 4 and 9 are proteins expressed on astrocyte in rat brain and involved in the brain water accumulation in brain edema. Recombinant hirudin (r-Hirudin) is a direct inhibitor of thrombin that can block the toxicitic effect of thrombin. In this study, we demonstrated that autologous whole blood infusion in caudate nucleus up-regulates the expression of AQP4 and AQP9 mRNAs and proteins. AQP4 and AQP9 mRNAs expression peaked at about 6 h after blood infusion. The AQP4 protein peaked at about 48 h while AQP9 at about 24 h after blood infusion. Thrombin induced up-regulation of AQP4 and AQP9 were inhibited by r-Hirudin administration and significantly decreased the expression of both AQPs. We further investigated the relationship between edema formation and expression of AQP4 and AQP9. The data presented here may be helpful in optimizing r-Hirudin as an anti-thrombin drug in the treatment of edema at the acute stage of ICH.
Mol Biol Rep 2009 May
PMID:Recombinant hirudin treatment modulates aquaporin-4 and aquaporin-9 expression after intracerebral hemorrhage in vivo. 1857 11

Brain microvessels possess barrier structures comprising tight junctions which are critical for the maintenance of central nervous system homeostasis. Brain vascular diseases, such as ischemic stroke damage to blood-brain barrier, increase the vascular permeability, and then lead to vasogenic brain edema. Herein, we examined whether angiopoietin-1 (Ang-1) could regulate zonula occludens-2 (ZO-2) expression and counteract vascular endothelial growth factor (VEGF)-induced vascular permeability. When we treated brain microvascular endothelial cells with Ang-1, Ang-1 caused a time- and dose-dependent increase of ZO-2 and down-regulation in endothelial permeability. VEGF, one of the key regulators of ischemia-induced vascular permeability, increased endothelial cell permeability in vitro, whereas, Ang-1 reversed this VEGF effect by up-regulating ZO-2 expression. Additionally, the recovery effect of Ang-1 on permeability was strongly blocked by siRNA against ZO-2. Collectively, our results suggest that Ang-1 shows anti-permeability activity through up-regulation of ZO-2.
Int J Mol Med 2009 Feb
PMID:Angiopoietin-1 reduces vascular endothelial growth factor-induced brain endothelial permeability via upregulation of ZO-2. 1914 54


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