endothelin-1 and Brain-Edema

Vascular damage caused by cerebral ischemia leads to edema, hemorrhage formation, and worsened outcomes in ischemic stroke patients. Therapeutic interventions need to be developed to provide vascular protection. The purpose of this review is to identify the pathophysiologic processes involved in vascular damage after ischemia, which may lead to strategies to provide vascular protection in ischemic stroke patients.. The pathologic processes caused by vascular injury after an occlusion of a cerebral artery can be separated into acute (hours), subacute (hours to days), and chronic (days to months). Targets for intervention can be identified for all 3 stages. Acutely, superoxide is the predominant mediator, followed by inflammatory mediators and proteases subacutely. In the chronic phase, proapoptotic gene products have been implicated.. Pharmacological agents designed to target specific pathologic and protective processes affecting the vasculature should be used in clinical trials of vascular protection after acute ischemic stroke.

Topics: Acute Disease; Angiopoietins; Angiotensin II; Antioxidants; Apoptosis; Blood-Brain Barrier; Brain Edema; Brain Ischemia; Cerebral Arteries; Cerebral Hemorrhage; Chronic Disease; Endothelin-1; Endothelium, Vascular; Humans; Inflammation Mediators; Matrix Metalloproteinases; Neuroprotective Agents; Neutrophils; Oxidative Stress; Reactive Oxygen Species; Vascular Endothelial Growth Factor A; Vasculitis

Serum biomarkers are associated with hemorrhagic transformation and brain edema after cerebral infarction. However, whether serum biomarkers predict hemorrhagic transformation in large vessel occlusion stroke even after mechanical thrombectomy, which has become widely used, remains uncertain. In this prospective study, we enrolled patients with large vessel occlusion stroke in the anterior circulation. We analyzed 91 patients with serum samples obtained on admission. The levels of matrix metalloproteinase-9 (MMP-9), amyloid precursor protein (APP) 770, endothelin-1, S100B, and claudin-5 were measured. We examined the association between serum biomarkers and hemorrhagic transformation within one week. Fifty-four patients underwent mechanical thrombectomy, and 17 patients developed relevant hemorrhagic transformation (rHT, defined as hemorrhagic changes ≥ hemorrhagic infarction type 2). Neither MMP-9 (no rHT: 46 ± 48 vs. rHT: 15 ± 4 ng/mL, P = 0.30), APP770 (80 ± 31 vs. 85 ± 8 ng/mL, P = 0.53), endothelin-1 (7.0 ± 25.7 vs. 2.0 ± 2.1 pg/mL, P = 0.42), S100B (13 ± 42 vs. 12 ± 15 pg/mL, P = 0.97), nor claudin-5 (1.7 ± 2.3 vs. 1.9 ± 1.5 ng/mL, P = 0.68) levels on admission were associated with subsequent rHT. When limited to patients who underwent mechanical thrombectomy, the level of claudin-5 was higher in patients with rHT than in those without (1.2 ± 1.0 vs. 2.1 ± 1.7 ng/mL, P = 0.0181). APP770 levels were marginally higher in patients with a midline shift ≥ 5 mm than in those without (79 ± 29 vs. 97 ± 41 ng/mL, P = 0.084). The predictive role of serum biomarkers has to be reexamined in the mechanical thrombectomy era because some previously reported serum biomarkers may not predict hemorrhagic transformation, whereas the level of APP770 may be useful for predicting brain edema.

Topics: Aged; Aged, 80 and over; Amyloid beta-Protein Precursor; Biomarkers; Brain Edema; Cerebral Infarction; Cerebrovascular Disorders; Claudin-5; Endothelin-1; Female; Gene Expression; Humans; Male; Matrix Metalloproteinase 9; Predictive Value of Tests; Prospective Studies; S100 Calcium Binding Protein beta Subunit; Stroke; Thrombectomy

The therapeutic effects of atorvastatin on early brain injury (EBI), cerebral edema and its association with aquaporin 4 (AQP4) were studied in rabbits after subarachnoid hemorrhage (SAH) using western blot analysis and the dry-wet method. Seventy-two healthy male New Zealand rabbits weighing between 2.5 and 3.2 kg were randomly divided into three groups: the SAH group (n=24), sham-operated group (n=24) and the SAH + atorvastatin group (n=24). A double SAH model was employed. The sham-operated group were injected with the same dose of saline solution, the SAH + atorvastatin group received atorvastatin 20 mg/kg/day after SAH. All rabbit brain samples were taken at 72 h after the SAH model was established successfully. Brain edema was detected using the dry-wet method after experimental SAH was induced; AQP4 and caspase-3 expression was measured by western blot analysis, and neuronal apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) staining at 72 h after SAH. The results indicated that brain edema and injury appeared soon after SAH, while brain edema and EBI were ameliorated and increased behavior scores were noted after prophylactic use of atorvastatin. Compared with the SAH group, the level of AQP4 and the cerebral content of water was significantly decreased (P<0.01) by atorvastatin, and TUNEL staining and studying the expression of caspase-3 showed that the apoptosis of neurons was reduced markedly both in the hippocampus and brain cortex by atorvastatin. The results suggest that atorvastatin ameliorated brain edema and EBI after SAH, which was related to its inhibition of AQP4 expression. Our findings provide evidence that atorvastatin is an effective and well-tolerated approach for treating SAH in various clinical settings.

Topics: Animals; Apoptosis; Aquaporin 4; Atorvastatin; Brain; Brain Edema; Brain Injuries; Caspase 3; Endothelin-1; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Neuroprotective Agents; Rabbits; Subarachnoid Hemorrhage; Water

To determine the effects of minimally invasive surgery (MIS) at various stages after intracerebral hemorrhage (ICH) on perihematomal endothelin (ET)-1 levels and neurological functioning.. Sixty rabbits were randomly distributed into a model control group (MC group, 30 rabbits) or a MIS group (MI group, 30 rabbits). An ICH model was established in all animals. In the MI group, ICH was evacuated by MIS at 6, 12, 18, 24, and 48 hours (six rabbits at each time point) after the ICH was established. The animals in the MC group underwent the same procedures for ICH evacuation, but with a sham operation without hematoma aspiration. All the animals were sacrificed 7 days after the ICH was established. Neurological deficit scores were determined, and the perihematomal brain tissue was removed to determine the ET-1 levels, blood-brain barrier (BBB) permeability, and brain water content (BWC).. The neurological deficit scores, perihematomal ET-1 levels, BBB permeability, and BWC all decreased significantly in the MI group compared to the MC group. Performing the MIS for evacuating the ICH at 6 hours resulted in the most remarkable decreases in these indices, followed by a significant difference observed at 12 hours within the MI subgroups.. Performing MIS at 6-12 hours after ICH resulted in the most significant decreases in neurological deficit scores, ET-1 levels, BBB permeability, and brain edema. The optimal time window for performing MIS for ICH evacuation might be within 6-12 hours after hemorrhage.

Topics: Animals; Blood-Brain Barrier; Brain; Brain Edema; Cerebral Hemorrhage; Disease Models, Animal; Endothelin-1; Hematoma; Male; Minimally Invasive Surgical Procedures; Neurosurgical Procedures; Permeability; Rabbits; Recovery of Function; RNA, Messenger

The pathophysiological role of influenza infection is poorly understood. In this study, one non-neurovirulent virus (IAV/Aichi/2/68/H3N2) strain was used to infect intra-nasally mice at different age to investigate the mechanism of cerebral edema formation and lower activities of mitochondria enzymes after influenza A virus (IAV) infection. Mice suffered 46.4% mortality in newborn compared with 96.0% in weanling, 100% in adult on day 7, respectively. IAV-RNA was easily detected in the brain of newborn mice. Significant production of endothelin-1 and inducible nitric oxide syntheses were increased on the 3rd and 5th day after IAV infection, associated with increasing blood-brain barrier permeability, brain edema formation and the higher mortality of animals. Production of tumor necrosis factor-α was related to inhibition of mitochondrial enzyme activities, suggesting that over expression of inflammatory cytokines and lower enzyme activities in mitochondria after IAV infection.

Topics: Animals; Blood-Brain Barrier; Brain Edema; Capillary Permeability; Disease Models, Animal; Endothelin-1; Host-Pathogen Interactions; Inflammation Mediators; Influenza A virus; Lipid Metabolism; Mice, Inbred C57BL; Mitochondria; Nitric Oxide Synthase Type II; Orthomyxoviridae Infections; RNA, Viral; Time Factors; Tumor Necrosis Factor-alpha; Viral Load

Endothelin-1 (ET-1) is synthesized by endothelial cells and astrocytes in stroke and in brains of Alzheimer's disease patients. Our transgenic mice with ET-1 overexpression in the endothelial cells (TET-1) showed more severe blood-brain barrier (BBB) breakdown, neuronal apoptosis, and glial reactivity after 2-hour transient middle cerebral artery occlusion (tMCAO) with 22-hour reperfusion and more severe cognitive deficits after 30 minutes tMCAO with 5 months reperfusion. However, the role of astrocytic ET-1 in contributing to poststroke cognitive deficits after tMCAO is largely unknown. Therefore, GET-1 mice were challenged with tMCAO to determine its effect on neurologic and cognitive deficit. The GET-1 mice transiently displayed a sensorimotor deficit after reperfusion that recovered shortly, then more severe deficit in spatial learning and memory was observed at 3 months after ischemia compared with that of the controls. Upregulation of TNF-α, cleaved caspase-3, and Thioflavin-S-positive aggregates was observed in the ipsilateral hemispheres of the GET-1 brains as early as 3 days after ischemia. In an in vitro study, ET-1 overexpressing astrocytic cells showed amyloid secretion after hypoxia/ischemia insult, which activated endothelin A (ETA) and endothelin B (ETB) receptors in a PI3K/AKT-dependent manner, suggesting role of astrocytic ET-1 in dementia associated with stroke by astrocyte-derived amyloid production.

Topics: Amyloidogenic Proteins; Animals; Astrocytes; Brain Edema; Brain Ischemia; Cognition; Dementia; Endothelin-1; Hippocampus; Humans; Hypoxia, Brain; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Male; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Nervous System Diseases

Aging is a major risk factor for cerebrovascular disease. Growth hormone (GH) and its anabolic mediator, insulin-like growth factor (IGF)-1, decrease with advancing age and this decline has been shown to promote vascular dysfunction. In addition, lower GH/IGF-1 levels are associated with higher stroke mortality in humans. These results suggest that decreased GH/IGF-1 level is an important factor in increased risk of cerebrovascular diseases. This study was designed to assess whether GH/IGF-1-deficiency influences the outcome of cerebral ischemia. We found that endothelin-1-induced middle cerebral artery occlusion resulted in a modest but nonsignificant decrease in cerebral infarct size in GH/IGF-1 deficient dw/dw rats compared with control heterozygous littermates and dw/dw rats with early-life GH treatment. Expression of endothelin receptors and endothelin-1-induced constriction of the middle cerebral arteries were similar in the three experimental groups. Interestingly, dw/dw rats exhibited reduced brain edema and less astrocytic infiltration compared with their heterozygous littermates and this effect was reversed by GH-treatment. Because reactive astrocytes are critical for the regulation of poststroke inflammatory processes, maintenance of the blood-brain barrier and neural repair, further studies are warranted to determine the long-term functional consequences of decreased astrocytic activation in GH/IGF-1 deficient animals after cerebral ischemia.

Topics: Aging; Animals; Astrocytes; Brain Edema; Brain Ischemia; Cerebral Infarction; Disease Models, Animal; Dwarfism; Endothelin-1; Female; Growth Hormone; Insulin-Like Growth Factor I; Male; Rats; Rats, Inbred Lew; Rats, Mutant Strains

Cerebral edema is a potentially life-threatening illness, but knowledge of its underlying mechanisms is limited. Here we report that hypobaric hypoxia induces rat cerebral edema and neuronal apoptosis and increases the expression of corticotrophin releasing factor (CRF), CRF receptor type 1 (CRFR1), aquaporin-4 (AQP4), and endothelin-1 (ET-1) in the cortex. These effects, except for the increased expression of CRF itself, could all be blocked by pretreatment with an antagonist of the CRF receptor CRFR1. We also show that, in cultured primary astrocytes: (i) both CRFR1 and AQP4 are expressed; (ii) exogenous CRF, acting through CRFR1, triggers signaling of cAMP/PKA, intracellular Ca(2+), and PKCε; and (iii) the up-regulated cAMP/PKA signaling contributes to the phosphorylation and expression of AQP4 to enhance water influx into astrocytes and produces an up-regulation of ET-1 expression. Finally, using CHO cells transfected with CRFR1(+) and AQP4(+), we show that transfected CRFR1(+) contributes to edema via transfected AQP4(+). In conclusion, hypoxia triggers cortical release of CRF, which acts on CRFR1 to trigger signaling of cAMP/PKA in cortical astrocytes, leading to activation of AQP4 and cerebral edema.

Topics: Animals; Apoptosis; Aquaporin 4; Astrocytes; Brain Edema; CHO Cells; Corticotropin-Releasing Hormone; Cricetinae; Cricetulus; Endothelin-1; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Neurons; Phosphorylation; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone; Signal Transduction; Transfection; Up-Regulation

Blood-brain-barrier (BBB) disruption, inflammation and thrombosis are important steps in the pathophysiology of acute ischemic stroke but are still inaccessible to therapeutic interventions. Rolipram specifically inhibits the enzyme phosphodiesterase (PDE) 4 thereby preventing the inactivation of the intracellular second messenger cyclic adenosine monophosphate (cAMP). Rolipram has been shown to relief inflammation and BBB damage in a variety of neurological disorders. We investigated the therapeutic potential of rolipram in a model of brain ischemia/reperfusion injury in mice. Treatment with 10mg/kg rolipram, but not 2 mg/kg rolipram, 2 h after 60 min of transient middle cerebral artery occlusion (tMCAO) reduced infarct volumes by 50% and significantly improved clinical scores on day 1 compared with vehicle-treated controls. Rolipram maintained BBB function upon stroke as indicated by preserved expression of the tight junction proteins occludin and claudin-5. Accordingly, the formation of vascular brain edema was strongly attenuated in mice receiving rolipram. Moreover, rolipram reduced the invasion of neutrophils as well as the expression of the proinflammatory cytokines IL-1β and TNFα but increased the levels of TGFβ-1. Finally, rolipram exerted antithrombotic effects upon stroke and fewer neurons in the rolipram group underwent apoptosis. Rolipram is a multifaceted antiinflammatory and antithrombotic compound that protects from ischemic neurodegeneration in clinically meaningful settings.

Topics: Animals; Blood-Brain Barrier; Brain Edema; Brain Injuries; Cytokines; Disease Models, Animal; Encephalitis; Endothelin-1; Hemodynamics; Infarction, Middle Cerebral Artery; Laser-Doppler Flowmetry; Male; Mice; Mice, Inbred C57BL; Nerve Tissue Proteins; Occludin; Phosphodiesterase 4 Inhibitors; Rolipram; Stroke; Thrombosis

Status epilepticus (SE) induces vasogenic edema in the piriform cortex with disruptions of the blood-brain barrier (BBB). However, the mechanisms of vasogenic edema formation following SE are still unknown. Here we investigated the endothelin B (ETB) receptor-mediated pathway of SE-induced vasogenic edema. Following SE, the release of tumor necrosis factor-α (TNF-α) stimulated endothelin-1 (ET-1) release and expression in neurons and endothelial cells. In addition, TNF-α-induced ET-1 increased BBB permeability via ETB receptor-mediated endothelial nitric oxide synthase (eNOS) activation in endothelial cells. ETB receptor activation also increased intracellular reactive oxygen species by NADPH oxidase production in astrocytes. These findings suggest that SE results in BBB dysfunctions via endothelial-astroglial interactions through the TNF-α-ET-1-eNOS/NADPH oxidase pathway, and that these ETB receptor-mediated interactions may be an effective therapeutic strategy for vasogenic edema in various neurological diseases.

Topics: Animals; Astrocytes; Blood-Brain Barrier; Brain Edema; Cerebral Cortex; Disease Models, Animal; Endothelial Cells; Endothelin-1; Gene Expression Regulation; Male; Microdialysis; NADPH Oxidases; Neurons; Nitric Oxide Synthase Type III; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptor, Endothelin A; Signal Transduction; Status Epilepticus; Stereotaxic Techniques; Tumor Necrosis Factor-alpha

Endothelin-1 (ET-1) is involved on the development of cerebral edema in acute ischemic stroke. As edema is a therapeutic target in cerebral ischemia, our aim was to study the effect of antagonists for ET-1 receptors (Clazosentan® and BQ-788, specific antagonists for receptors A and B, respectively) on the development of edema, infarct volume and sensorial-motor deficits in rats subjected to ischemia by occlusion of the middle cerebral artery (MCAO). We used Wistar rats (280-320 g) submitted to ischemia by intraluminal transient (90 min) MCAO. After ischemia, rats were randomized into 4 groups (n = 6) treated with; 1) control group (saline), 2) Clazosentan® group (10 mg/kg iv), 3) BQ-788 group (3 mg/kg iv), and 4) combined treatment (Clazosentan® 10 mg/kg plus BQ-788 3 mg/kg iv). We observed that rats treated with Clazosentan® showed a reduction of edema, measured by MRI, at 72 h (hours) and at day 7 (both p < 0.0001), and a decrease in the serum levels of ET-1 at 72 h (p < 0.0001) and at day 7 (p = 0.009). The combined treatment also induced a reduction of edema at 24 h (p = 0.004), 72 h (p < 0.0001) and at day 7 (p < 0.0001), a reduction on infarct volume, measured by MRI, at 24 and 72 h, and at day 7 (all p < 0.01), and a better sensorimotor recovery at 24 and 72 h, and at day 7 (all p < 0.01). Moreover, Clazosentan® induced a decrease in AQP4 expression, while BQ-788 induced an increase in AQP9 expression. These results suggest that antagonists for ET-1 receptors may be a good therapeutic target for cerebral ischemia.

Topics: Animals; Aquaporins; Blotting, Western; Brain Edema; Brain Ischemia; Dioxanes; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Evoked Potentials, Somatosensory; Image Processing, Computer-Assisted; Infarction, Middle Cerebral Artery; Magnetic Resonance Imaging; Male; Nervous System Diseases; Neuroprotective Agents; Oligopeptides; Piperidines; Pyridines; Pyrimidines; Rats; Rats, Wistar; Stroke; Sulfonamides; Tetrazoles

Endothelin-1 (ET-1) is one of potential factors to induce vasogenic edema formation, since exogenous ET-1 treatment decreases aquaporin 4 (AQP4) expression and increases chemokines induction. To identify the role of endogenous ET-1 in vasogenic edema formation, we examined the correlation between endogenous ET-1 expression and vasogenic edema formation in the pirifom cortex following status epilepticus (SE). In the present study, SMI-71 (a brain-blood barrier marker) immunoreactivity was significantly reduced in blood vessels at 1 day after SE when vasogenic edema and neuronal damage were observed. ET-1 expression was up-regulated in endothelial cells prior to reduction in SMI-71 immunoreactivity. Furthermore, ET-1 expressing endothelial cells showed the absence of SMI-71 immunoreactivity. Increase in ET-1 expression was followed by reduced AQP4 immunoreactivity prior to vasogenic edema formation. Only a few microglia showed monocyte chemotactic protein-1 (a chemokine induced by ET-1) outside vasogenic edema lesion. Taken together, our findings suggest that endothelial ET-1 expression may contribute to SE-induced vasogenic edema formation via brain-blood barrier disruption at AQP4/MCP-1 independent manners.

Topics: Animals; Aquaporin 4; Blood-Brain Barrier; Brain Edema; Cerebral Cortex; Chemokine CCL2; Endothelin-1; Endothelium, Vascular; Male; Neurons; Rats; Rats, Sprague-Dawley; Status Epilepticus; Up-Regulation

Brain edema is detrimental in ischemic stroke and its treatment options are limited. Kinins are proinflammatory peptides that are released during tissue injury. The effects of kinins are mediated by 2 different receptors (B1 and B2 receptor [B1R and B2R]) and comprise induction of edema formation and release of proinflammatory mediators.. Focal cerebral ischemia was induced in B1R knockout, B2R knockout, and wild-type mice by transient middle cerebral artery occlusion. Infarct volumes were measured by planimetry. Evan's blue tracer was applied to determine the extent of brain edema. Postischemic inflammation was assessed by real-time reverse-transcriptase polymerase chain reaction and immunohistochemistry. To analyze the effect of a pharmacological kinin receptor blockade, B1R and B2R inhibitors were injected.. B1R knockout mice developed significantly smaller brain infarctions and less neurological deficits compared to wild-type controls (16.8+/-4.7 mm(3) vs 50.1+/-9.1 mm(3), respectively; P<0.0001). This was accompanied by a dramatic reduction of brain edema and endothelin-1 expression, as well as less postischemic inflammation. Pharmacological blockade of B1R likewise salvaged ischemic tissue (15.0+/-9.5 mm(3) vs 50.1+/-9.1 mm(3), respectively; P<0.01) in a dose-dependent manner, even when B1R inhibitor was applied 1 hour after transient middle cerebral artery occlusion. In contrast, B2R deficiency did not confer neuroprotection and had no effect on the development of tissue edema.. These data demonstrate that blocking of B1R can diminish brain infarction and edema formation in mice and may open new avenues for acute stroke treatment in humans.

Topics: Animals; Bradykinin; Bradykinin B1 Receptor Antagonists; Bradykinin B2 Receptor Antagonists; Brain Edema; Cerebral Arteries; Cerebral Infarction; Cerebrovascular Circulation; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Encephalitis; Endothelin-1; Gene Expression; Infarction, Middle Cerebral Artery; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptor, Bradykinin B1; Receptor, Bradykinin B2; RNA, Messenger

Transgenic mice overexpressing endothelin-1 (ET-1) in astrocytes (GET-1) displayed more severe brain edema and neurologic dysfunction after experimental ischemic stroke. However, it was not clear whether astrocytic ET-1 contributed to cytotoxic or vasogenic edema associated with stroke. In this study, the role of astrocytic ET-1 in cytotoxic edema and brain injury was investigated. Upon acute water intoxication, the GET-1 mice had a lower survival rate and more severe neurologic deficits. Such an exacerbated condition in the GET-1 mice may be a result of a significant increase in cerebral water content and increased expression of the water channel protein, aquaporin 4 (AQP-4). The GET-1 mice treated with OPC-31260, a nonpeptide arginine vasopressin V(2) receptor antagonist, were alleviated from the cerebral water accumulation and neurologic deficit during the early time period after water intoxication. In addition, a significant reduction of AQP-4 expression was observed in astrocytic end-feet AQP-4 in the hippocampus of the GET-1 mice treated with OPC-31260. Therefore, ET-1-induced AQP-4 expression and cerebral water accumulation are the key factors in brain edema associated with acute water intoxication. The V(2) receptor antagonist, OPC-31260, may be one of the effective drugs for the early treatment of ET-1-induced cytotoxic edema and brain injury.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Aquaporin 4; Astrocytes; Benzazepines; Brain; Brain Edema; Endothelin-1; Glial Fibrillary Acidic Protein; Mice; Mice, Transgenic; Up-Regulation; Water; Water Intoxication

Severe cerebral edema is associated with poor outcome in patients with acute stroke. Experimental studies suggest that astrocytic endothelin-1 (ET-1) has deleterious effects on water homeostasis, cerebral edema, and blood brain barrier (BBB) integrity, which contribute to more severe ischemic brain injury. In this study we analyze the association between high serum levels of ET-1 and the development of severe cerebral edema in patients treated with t-PA.. One hundred thirty-four patients treated with t-PA according SITS-MOST (Safe Implementation of Thrombolysis in Stroke Monitoring Study) criteria were prospectively studied. Serum levels of ET-1, matrix metalloproteinase-9 (MMP-9), and cellular fibronectin (c-Fn) were determined by ELISA in serum samples obtained on admission, before t-PA bolus. Severe brain edema was diagnosed if extensive swelling caused any shifting of the structures of the midline was detected on the cranial CT performed at 24 to 36 hours. Stroke severity was evaluated before t-PA administration and at 24 hours by NIHSS. Functional outcome at 3 months was evaluated by the modified Rankin Scale (mRS).. Nineteen patients (14.2%) developed severe brain edema. Median ET-1 (8.4 [6.7, 9.6] versus 1.9 [1.6, 3.2] fmol/mL, P<0.0001) and c-Fn (6.0 [4.1, 6.7] versus 3.2 [2.1, 4.6] mg/L, P<0.0001) serum levels were significantly higher in patients with severe cerebral edema. The best cut-off values for ET-1 and c-Fn serum levels for the prediction of severe brain edema were 5.5 fmol/mL (sensitivity 95% and specificity 94%) and 4.5 mg/L (sensitivity 73% and specificity 77%) respectively. ET-1 serum levels >5.5 fmol/mL before t-PA treatment were independently associated with development of severe brain edema (OR, 139.7; CI95%, 19.3 to 1012.2; P<0.0001), after adjustment for baseline stroke severity, early CT signs of infarction, serum levels of cFn >4.5 mg/L, and cardioembolic stroke subtype.. ET-1 serum levels >5.5 fmol/mL are associated with severe brain edema in acute stroke patients treated with t-PA. These results suggest that ET-1 may be a new diagnostic marker for development of severe brain edema in patients with acute ischemic stroke treated with t-PA.

Topics: Aged; Brain Edema; Brain Ischemia; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Fibronectins; Humans; Male; Matrix Metalloproteinase 9; Middle Aged; Odds Ratio; Stroke; Thrombolytic Therapy; Tissue Plasminogen Activator

It has been established that hyperbaric oxygen (HBO) treatment reduces brain edema, decreases infarct volume, contributes to neurological functional recovery and suppresses apoptosis in suture-induced focal cerebral ischemic animal models. In the present study, we evaluated the therapeutic effect of HBO in an endothelin-1-induced focal cerebral ischemia in rats and explored the associated mechanisms of HBO-induced brain protection. One hundred twenty male Sprague-Dawley rats (280 to 320 g) were randomly assigned to sham, focal cerebral ischemia and focal cerebral ischemia treated with HBO groups. Brain water content, neurological function, morphology and molecular biological markers were assessed. HBO (100% O2, 2.5 atmosphere absolute for 2 h) was initiated at 1 h after focal cerebral ischemia. Rats were killed at 24 h to harvest tissues for Western blot or for histology. In HBO-treated animals, an enhanced ratio of Bcl-2 and Bax and a reduced expression of hypoxia-inducible factor-1alpha (HIF-1alpha) in the hippocampus after focal cerebral ischemia were observed. These results indicate that HBO provides brain protection that is probably associated with the inhibition of HIF-1alpha and the elevation of Bcl-2.

Topics: Analysis of Variance; Animals; bcl-2-Associated X Protein; Brain Edema; Brain Infarction; Brain Ischemia; Disease Models, Animal; Endothelin-1; Gene Expression Regulation; Hyperbaric Oxygenation; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley

Stroke patients have increased levels of endothelin-1 (ET-1), a strong vasoconstrictor, in their plasma or cerebrospinal fluid. Previously, we showed high level of ET-1 mRNA expression in astrocytes after hypoxia/ischemia. It is unclear whether the contribution of ET-1 induction in astrocytes is protective or destructive in cerebral ischemia. Here, we generated a transgenic mouse model that overexpress ET-1 in astrocytes (GET-1) using the glial fibrillary acidic protein promoter to examine the role of astrocytic ET-1 in ischemic stroke by challenging these mice with transient middle cerebral artery occlusion (MCAO). Under normal condition, GET-1 mice showed no abnormality in brain morphology, cerebrovasculature, absolute cerebral blood flow, blood-brain barrier (BBB) integrity, and mean arterial blood pressure. Yet, GET-1 mice subjected to transient MCAO showed more severe neurologic deficits and increased infarct, which were partially normalized by administration of ABT-627 (ET(A) antagonist) 5 mins after MCAO. In addition, GET-1 brains exhibited more Evans blue extravasation and showed decreased endothelial occludin expression after MCAO, correlating with higher brain water content and increased cerebral edema. Aquaporin 4 expression was also more pronounced in astrocytic end-feet on blood vessels in GET-1 ipsilateral brains. Our current data suggest that astrocytic ET-1 has deleterious effects on water homeostasis, cerebral edema and BBB integrity, which contribute to more severe ischemic brain injury.

Topics: Animals; Aquaporin 4; Aquaporins; Astrocytes; Blood Pressure; Blood-Brain Barrier; Blotting, Western; Brain; Brain Edema; Coloring Agents; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Evans Blue; Glial Fibrillary Acidic Protein; In Situ Hybridization; Infarction, Middle Cerebral Artery; Mice; Mice, Transgenic; Nervous System Diseases; Reperfusion Injury; Reverse Transcriptase Polymerase Chain Reaction; Water

To determine the protective effect of ONO-1078, a leukotriene receptor antagonist, on focal cerebral ischemia induced by endothelin-1 in rats.. Slow microinjection of endothelin-1 (120 pmol in 6 microL, for > 6 min) into the region near the middle cerebral artery was used to induce focal cerebral ischemia. ONO-1078 (0.1 mg.kg-1) was i.p. injected 1 h before endothelin-1 injection. Neurological symptoms, brain edema, brain infarction size, and the survival neurons in cortex and striatum were observed 24 h after ischemia.. Intracerebral microinjection of endothelin-1 induced remarkable neurological symptoms, brain infarction, brain edema, and decrease of survival neurons in the cortex and striatum. In rats pretreated with ONO-1078, endothelin-1-induced brain edema and brain infarction size were decreased. The numbers of survival neurons in striatum and cortex were increased significantly. The neurological symptoms were improved but not significantly.. ONO-1078 possesses neuroprotective effect against cerebral ischemic injury induced by endothelin-1, therefore, leukotrienes may play a role in the injury of cerebral ischemia.

Topics: Animals; Behavior, Animal; Brain Edema; Brain Ischemia; Cerebral Cortex; Cerebral Infarction; Chromones; Corpus Striatum; Endothelin-1; Leukotriene Antagonists; Male; Neurons; Neuroprotective Agents; Rats; Rats, Sprague-Dawley

Recent evidence strongly suggests that endothelins (ETs) play an important role in the regulation of blood-brain barrier (BBB) functions. The aim of the present study was to evaluate the role of ETs on edema formation and BBB permeability change after cerebral ischemia/reperfusion.. We examined the brain tissue ET-1 content and evaluated the time and dose response of the therapeutic effects of the specific ET type A receptor (ET(A)) antagonist, S-0139, on brain edema formation, development of infarction, and disruption of BBB after 1 hour of middle cerebral artery occlusion (MCAO) in rats.. After 1-hour MCAO and reperfusion, the brain ET-1 content did not change during the first 3 hours, increased at 6 hours, and rose almost continuously over 48 hours in the ischemic region as well as in the ischemic rim. Rats infused with S-0139 (0.03 to 1.0 mg/kg per hour) during reperfusion showed dose-dependent and significant attenuation of the increase in brain water content 24 hours after reperfusion. When the infusion of S-0139 was begun after 10 minutes and 1 hour of reperfusion, the brain edema formation and infarct size were significantly attenuated. Furthermore, posttreatment with S-0139 significantly attenuated the increased Evans blue dye-quantified albumin extravasation and improved the mortality of animals after cerebral ischemia/reperfusion.. Our data demonstrate that infusion with S-0139, an ET(A) antagonist, results in significant reduction of brain injury and plasma extravasation after transient MCAO. Thus, ETs may contribute to cerebral ischemia/reperfusion injury at least partly by increasing the BBB permeability via ET(A)s.

Topics: Animals; Blood-Brain Barrier; Brain; Brain Chemistry; Brain Edema; Caffeic Acids; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Infarction, Middle Cerebral Artery; Ischemic Attack, Transient; Male; Neuroprotective Agents; Oleanolic Acid; Peroxidase; Rats; Rats, Wistar; Receptor, Endothelin A; Reperfusion Injury; Survival Rate; Time Factors; Water

Endothelium plays a central role in regulating the vascular tone, blood flow and blood brain barrier (BBB) permeability. The experiments presented here examine the mechanisms by which nitric oxide (NO) and endothelin-1 (ET-1) may be involved in these processes. The findings indicate that ET-1-stimulated [Ca2+]i accumulation occurs through activation of ETA receptor. The capacity of NO to affect this response was indicated by results showing: 1) a two-fold increase in ET-1-stimulated [Ca2+]i by L-NAME, the inhibitor of nitric oxide synthase, and 2) a dose-dependent decrease in [Ca2+]i accumulation by pretreatment with Nor-1 (NO donor). Abrogation of this Nor-1 effect by ODQ (an inhibitor of guanylyl cyclase) or Rp-8-pCPT-cGMPS (an inhibitor of protein kinase G) and inhibition of ET-1 stimulated intracellular Ca2+ accumulation by 8-bromo-cGMP (a permeable, analog of cGMP) substantiate the involvement of interplay between ET-1 and NO in [Ca2+]i accumulation in HBMEC. ET-1 treatment also increased thickness of F-actin cytoskeletal filaments in HBMEC. This effect was attenuated by pretreatment with NO; NO also rarefied F-actin filaments in control cultures. The findings support a linkage between NO and ET-1 in regulating microvascular tone, microcirculation and BBB permeability and indicate a role for cGMP/cGMP protein kinase system and cytoskeletal changes in responses of HBMEC.

Topics: Actins; Blood-Brain Barrier; Brain; Brain Edema; Calcium; Capillary Permeability; Cells, Cultured; Endothelin-1; Endothelium, Vascular; Humans; Microcirculation; Nitric Oxide; Signal Transduction

These studies were performed in an attempt to clarify some of the pathophysiologic mechanisms which occur during and after global ischemia. Both nitric oxide and endothelin were demonstrated in gerbils to participate in responses to ischemia. It was shown that endogenous nitric oxide influences early postischemic reperfusion, systemic blood pressure and postischemic dopamine metabolism. Furthermore, the results indicated that nitric oxide played a role in dopamine release and that preischemic intracerebral nitric oxide formation significantly decreased ischemic dopamine release. In addition, ischemic release of endothelin-1 was detected; participation of nitric oxide in this release was observed. Further indication of functional interactions between nitric oxide and endothelin-1 in postischemic reperfusion were indicated by observations that endothelin-1 antagonists inhibited early hypoperfusion caused by Nitro-L-arginin and late hypoperfusion caused by endogenous endothelin-1. Nitric oxide was shown to decrease edema formation during the early postischemic period but contribute to edema formation during the late postischemic period. The findings indicate the importance of nitric oxide in stroke and ischemia.

Topics: Animals; Blood Pressure; Brain; Brain Edema; Cerebral Infarction; Cerebrovascular Circulation; Dopamine; Endothelin-1; Gerbillinae; Nitric Oxide; Reperfusion Injury

Recently, the authors showed that thrombin contributes to the formation of brain edema following intracerebral hemorrhage. The current study examines whether the action of thrombin is due to an effect on cerebral blood flow (CBF), vasoreactivity, blood-brain barrier (BBB) function, or cell viability. In vivo solutions of thrombin were infused stereotactically into the right basal ganglia of rats. The animals were sacrificed 24 hours later; CBF and BBB permeability were measured. The actions of thrombin on vasoreactivity were examined in vitro by superfusing thrombin on cortical brain slices while monitoring microvessel diameter with videomicroscopy. In separate experiments C6 glioma cells were exposed to various concentrations of thrombin, and lactate dehydrogenase release, a marker of cell death, was measured. The results indicate that thrombin induces BBB disruption as well as death of parenchymal cells, whereas CBF and vasoreactivity are not altered. The authors conclude that cell toxicity and BBB disruption by thrombin are triggering mechanisms for the edema formation that follows intracerebral hemorrhage.

Topics: Animals; Blood-Brain Barrier; Brain Edema; Cell Death; Cell Membrane Permeability; Cells, Cultured; Cerebral Hemorrhage; Cerebrovascular Circulation; Endothelin-1; In Vitro Techniques; L-Lactate Dehydrogenase; Male; Rats; Rats, Sprague-Dawley; Thrombin; Vasoconstriction

Brain swelling is a serious complication associated with focal ischemia in stroke and severe head injury. Experimentally, reperfusion following focal cerebral ischemia exacerbates the level of brain swelling. In this study, the permeability of the blood-brain barrier has been investigated as a possible cause of reperfusion-related acute brain swelling. Blood-brain barrier disruption was investigated using Evans Blue dye and [14C]aminoisobutyric acid autoradiography in a rodent model of reversible middle cerebral artery (MCA) occlusion. Acute brain swelling and cerebral blood flow (CBF) during ischemia and reperfusion were analyzed from double-label CBF autoradiograms after application of the potent vasoconstrictor peptide endothelin-1 to the MCA. Ischemia was apparent within ipsilateral MCA territory, 5 min after endothelin-1 application to the exposed artery. Reperfusion, examined at 30 min and 1, 2, and 4 h, was gradual but incomplete within this time frame in the core of middle cerebral artery territory and associated with significant brain swelling. Ipsilateral hemispheric swelling increased over time to a maximum (>5%) at 1-2 h after endothelin-1 but was not associated with a significant increase in the ipsilateral transfer constant for [14C]aminoisobutyric acid over this time frame. These results indicate that endothelin-1 induced focal cerebral ischemia is associated with an acute but reversible hemispheric swelling during the early phase of reperfusion which is not associated with a disruption of the blood-brain barrier.

Topics: Aminoisobutyric Acids; Animals; Blood-Brain Barrier; Brain Edema; Cerebrovascular Circulation; Dominance, Cerebral; Endothelin-1; Ion Transport; Ischemic Attack, Transient; Male; Permeability; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Time Factors; Tissue Distribution