Significant reduction in brain swelling by administration of nonpeptide kinin B2 receptor antagonist LF 16—0687Ms after controlled cortical impact injury in rats

2000 ◽  
Vol 92 (5) ◽  
pp. 853-859 ◽  
Author(s):  
John F. Stover ◽  
Nils-Kristian Dohse ◽  
Andreas W. Unterberg
Keyword(s):  
Receptor Antagonist ◽  
Water Content ◽  
Brain Edema ◽  
Single Administration ◽  
Brain Swelling ◽  
Edema Formation ◽  
Content Type ◽  
Controlled Cortical Impact Injury ◽  
Impact Injury ◽  
Fine Print

Object. Identification of new therapeutic agents aimed at attenuating posttraumatic brain edema formation remains an unresolved challenge. Among others, activation of bradykinin B2 receptors is known to mediate the formation of brain edema. The purpose of this study was to investigate the protective effect of the novel nonpeptide B2 receptor antagonist, LF 16-0687Ms, in brain-injured rats.Methods. Focal contusion was produced by controlled cortical impact injury. Five minutes after trauma, the rats received a single dose of no, low- (3 mg/kg body weight), or high- (30 mg/kg) dose LF 16-0687Ms. After 24 hours, the amount of brain swelling and hemispheric water content were determined. Low and high doses of LF 16-0687Ms significantly reduced brain swelling by 25% and 27%, respectively (p < 0.03). Hemispheric water content tended to be increased in the nontraumatized hemisphere.In a subsequent series of 10 rats, cisternal cerebrospinal fluid (CSF) samples were collected to determine whether changes in substances associated with edema formation could clarify why LF 16-0687Ms increases water content. For this, the volume regulator amino acid taurine, the excitatory transmitter glutamate, and the adenosine triphosphate degradation products hypoxanthine and xanthine were measured. In CSF, the levels of taurine, hypoxanthine, and xanthine were significantly decreased following a single administration of LF 16-0687Ms (p < 0.005); the level of glutamate, however, was double that found in control animals (p < 0.05).Conclusions. Using the present study design, a single administration of LF 16-0687Ms successfully reduced posttraumatic brain swelling. The decreased levels of taurine, hypoxanthine, and xanthine may reflect reduced posttraumatic brain edema, whereas the increased level of glutamate could account for the elevated water content observed in the nontraumatized hemisphere.

Attenuation of intracerebral hemorrhage and thrombin-induced brain edema by overexpression of interleukin-1 receptor antagonist

2001 ◽  
Vol 95 (4) ◽  
pp. 680-686 ◽  
Author(s):  
Tetsuya Masada ◽  
Ya Hua ◽  
Guohua Xi ◽  
Guo-Yuan Yang ◽  
Julian T. Hoff ◽  
...  
Keyword(s):  
Brain Injury ◽  
Basal Ganglia ◽  
Intracerebral Hemorrhage ◽  
Receptor Antagonist ◽  
Brain Edema ◽  
Inflammatory Reaction ◽  
Interleukin 1 ◽  
Edema Formation ◽  
Content Type ◽  
Fine Print

Object. Adenovirus-mediated overexpression of interleukin-1 receptor antagonist (IL-1ra) attenuates the inflammatory reaction and brain injury that follows focal cerebral ischemia. Recently, an inflammatory reaction after intracerebral hemorrhage (ICH) was identified. In this study the authors examine the hypothesis that overexpression of IL-1ra reduces brain injury (specifically edema formation) after ICH. Methods. Adenoviruses expressing IL-1ra (Ad.RSVIL-1ra) or LacZ, a control protein (Ad.RSVlacZ), or saline were injected into the left lateral cerebral ventricle in rats. On the 5th day after virus injection, 100 µl of autologous blood or 5 U thrombin was infused into the right basal ganglia. Rats with ICH were killed 24 or 72 hours later for measurement of brain water and ion content. Thrombin-treated rats were killed 24 hours later for edema measurements and an assessment of polymorphonuclear leukocyte (PMNL) infiltration by myeloperoxidase (MPO) assay, as well as histological evaluation. Compared with saline-treated and Ad.RSVlacZ—transduced controls, Ad.RSVIL-1ra-transduced rats had significantly attenuated edema in the ipsilateral basal ganglia 3 days after ICH (81.5 ± 0.3% compared with 83.4 ± 0.4% and 83.3 ± 0.5% in control animals). Thrombin-induced brain edema was also reduced in Ad.RSVIL-1ra—treated rats (81.3 ± 0.4% compared with 83.2 ± 0.4% and 82.5 ± 0.4% in control rats). The reduction in thrombin-induced edema was associated with a reduction in PMNL infiltration into the basal ganglia, as assessed by MPO assay (49% reduction) and histological examination. Conclusions. Overexpression of IL-1ra by using an adenovirus vector attenuated brain edema formation and thrombin-induced intracerebral inflammation following ICH. The reduction in ICH-induced edema with IL-1ra may result from reduction of thrombin-induced brain inflammation.

Effects of tacrolimus on hemispheric water content and cerebrospinal fluid levels of glutamate, hypoxanthine, interleukin-6, and tumor necrosis factor-α following controlled cortical impact injury in rats

2001 ◽  
Vol 94 (5) ◽  
pp. 782-787 ◽  
Author(s):  
John F. Stover ◽  
Britta Schöning ◽  
Oliver W. Sakowitz ◽  
Christian Woiciechowsky ◽  
Andreas W. Unterberg
Keyword(s):  
Cerebrospinal Fluid ◽  
Tissue Damage ◽  
Tumor Necrosis ◽  
Edema Formation ◽  
Content Type ◽  
Controlled Cortical Impact Injury ◽  
Csf Levels ◽  
Impact Injury ◽  
Necrosis Factor ◽  
Fine Print

Object. Disturbance of calcium homeostasis contributes to evolving tissue damage and energetic impairment following traumatic brain injury (TBI). Calcium-mediated activation of calcineurin results in production of tissue-damaging nitric oxide and free oxygen radicals. Inhibition of calcineurin induced by the immunosuppressant tacrolimus (FK506) has been shown to reduce structural and functional damage after ischemia. The aims of the present study were to investigate time- and dose-dependent short-term antiedematous effects of tacrolimus following TBI. Methods. A left temporoparietal contusion (controlled cortical impact injury [CCII]) was induced in 51 male Sprague—Dawley rats. Tacrolimus (1 or 3 mg/kg body weight) was administered by a single intraperitoneal injection at 5 minutes, 30 minutes, or 4 hours after CCII occurred. Control rats received physiological saline. Water contents of traumatized and nontraumatized hemispheres, as well as cerebrospinal fluid (CSF) levels of mediators reflecting tissue damage (the proinflammatory cytokines interleukin [IL]-6 and tumor necrosis factor [TNF]—α, the excitotoxin glutamate, and the adenosine triphosphate—degradation product hypoxanthine), were determined 24 hours after trauma. Although CSF levels of IL-6 and TNFα were completely suppressed by tacrolimus at all time points and at both concentrations, CSF levels of glutamate and hypoxanthine, as well as edema formation, were only marginally influenced. Significant reduction of cerebral water content was confined to nontraumatized hemispheres. In addition, the higher dose of tacrolimus failed to exert significant antiedematous effects on traumatized hemispheres. Conclusions. Under the present study design, the potency of tacrolimus in reducing edema formation following CCII seems limited. However, its immunosuppressive effects could be of value in influencing the posttraumatic inflammatory response known to aggravate tissue damage.

Contribution of vasogenic and cellular edema to traumatic brain swelling measured by diffusion-weighted imaging

1997 ◽  
Vol 87 (6) ◽  
pp. 900-907 ◽  
Author(s):  
Pál Barzó ◽  
Anthony Marmarou ◽  
Panos Fatouros ◽  
Koji Hayasaki ◽  
Frank Corwin
Keyword(s):  
Water Content ◽  
Diffusion Weighted Imaging ◽  
Vasogenic Edema ◽  
Brain Water Content ◽  
Brain Swelling ◽  
Edema Formation ◽  
Content Type ◽  
Diffusion Weighted ◽  
Brain Water ◽  
Fine Print

✓ The contribution of brain edema to brain swelling in cases of traumatic brain injury remains a critical problem. The authors believe that cellular edema, the result of complex neurotoxic events, is the major contributor to brain swelling and that vasogenic edema, secondary to blood-brain barrier compromise, may be overemphasized. The objective of this study, therefore, was to quantify temporal water content changes and document the type of edema that forms during the acute and late stages of edema development following closed head injury (CHI). The measurement of brain water content was based on magnetic resonance imaging—determined values of tissue longitudinal relaxation time (T1-weighted imaging) and their subsequent conversion to percentage of water, whereas the differentiation of edema formation (cellular vs. vasogenic) was based on the measurement of the apparent diffusion coefficient (ADC) by diffusion-weighted imaging. A new impact-acceleration model was used to induce CHI. Thirty-six adult Sprague—Dawley rats were separated into two groups: Group I, control (six animals); and Group II, trauma (30 animals). Fast ADC measurements (localized, single-voxel) were obtained sequentially (every minute) up to 1 hour postinjury. The T1-weighted images, used for water content determination, and the diffusion-weighted images (ADC measurement with conventional diffusion-weighted imaging) were obtained at the end of the 1st hour postinjury and on Days 1, 3, 7, 14, 28, and 42 in animals from the trauma and control groups. In the animals subjected to trauma, the authors found a significant increase in ADC (10 ± 5%) and brain water content (1.3 ± 0.9%) during the first 60 minutes postinjury. This is consistent with an increase in the volume of extracellular fluid and vasogenic edema formation as a result of blood-brain barrier compromise. This transient increase, however, was followed by a continuing decrease in ADC that began 40 to 60 minutes postinjury and reached a minimum value on Days 7 to 14 (10 ± 3% reduction). Because the water content of the brain continued to increase during the first 24 hours postinjury (1.9 ± 0.9%), it is suggested that the decreased ADC indicated cellular edema formation, which started to develop soon after injury and became dominant between 1 and 2 weeks postinjury. The study provides supportive evidence that cellular edema is the major contributor to posttraumatic swelling in diffuse CHI and defines the onset and duration of the increase in cellular volume.

Complement activation in the brain after experimental intracerebral hemorrhage

2000 ◽  
Vol 92 (6) ◽  
pp. 1016-1022 ◽  
Author(s):  
Ya Hua ◽  
Guohua Xi ◽  
Richard F. Keep ◽  
Julian T. Hoff
Keyword(s):  
Brain Edema ◽  
Complement Activation ◽  
Autologous Blood ◽  
Complement Cascade ◽  
Edema Formation ◽  
Content Type ◽  
Erythrocyte Lysis ◽  
The Brain ◽  
Brain Edema Formation ◽  
Fine Print

Object. Brain edema formation following intracerebral hemorrhage (ICH) appears to be partly related to erythrocyte lysis and hemoglobin release. Erythrocyte lysis may be mediated by the complement cascade, which then triggers parenchymal injury. In this study the authors examine whether the complement cascade is activated after ICH and whether inhibition of complement attenuates brain edema around the hematoma.Methods. This study was divided into three parts. In the first part, 100 µl of autologous blood was infused into the rats' right basal ganglia, and the animals were killed at 24 and 72 hours after intracerebral infusion. Their brains were tested for complement factors C9, C3d, and clusterin (a naturally occurring complement inhibitor) by using immunohistochemical analysis. In the second part of the study, the rats were killed at 24 or 72 hours after injection of 100 µl of blood. The C9 and clusterin proteins were quantitated using Western blot analysis. In the third part, the rats received either 100 µl of blood or 100 µl of blood plus 10 µg of N-acetylheparin (a complement activation inhibitor). Then they were killed 24 or 72 hours later for measurement of brain water and ion contents. It was demonstrated on Western blot analysis that there had been a sixfold increase in C9 around the hematoma 24 hours after the infusion of 100 µl of autologous blood. Marked perihematomal C9 immunoreactivity was detected at 72 hours. Clusterin also increased after ICH and was expressed in neurons 72 hours later. The addition of N-acetylheparin significantly reduced brain edema formation in the ipsilateral basal ganglia at 24 hours (78.5 ± 0.5% compared with 81.6 ± 0.8% in control animals, p < 0.001) and at 72 hours (80.9 ± 2.2% compared with 83.6 ± 0.9% in control animals, p < 0.05) after ICH.Conclusions. It was found that ICH causes complement activation in the brain. Activation of complement and the formation of membrane attack complex contributes to brain edema formation after ICH. Blocking the complement cascade could be an important step in the therapy for ICH.

Contribution of edema and cerebral blood volume to traumatic brain swelling in head-injured patients

2000 ◽  
Vol 93 (2) ◽  
pp. 183-193 ◽  
Author(s):  
Anthony Marmarou ◽  
Panos P. Fatouros ◽  
Pal Barzó ◽  
Gennarina Portella ◽  
Masaaki Yoshihara ◽  
...  
Keyword(s):  
Brain Edema ◽  
Brain Tissue ◽  
Blood Volume ◽  
Cerebral Blood Volume ◽  
Brain Swelling ◽  
Tissue Water ◽  
Content Type ◽  
Head Injured ◽  
Injured Patients ◽  
Fine Print

Object. The pathogenesis of traumatic brain swelling remains unclear. The generally held view is that brain swelling is caused primarily by vascular engorgement and that edema plays a relatively minor role in the swelling process. The goal of this study was to examine the roles of cerebral blood volume (CBV) and edema in traumatic brain swelling.Methods. Both brain-tissue water and CBV were measured in 76 head-injured patients, and the relative contribution of edema and blood to total brain swelling was determined. Comparable measures of brain-tissue water were obtained in 30 healthy volunteers and CBV in seven volunteers. Brain edema was measured using magnetic resonance imaging, implementing a new technique for accurate measurement of total tissue water. Measurements of CBV in a subgroup of 31 head-injured patients were based on consecutive measures of cerebral blood flow (CBF) obtained using stable xenon and calculation of mean transit time by dynamic computerized tomography scanning after a rapid bolus injection of iodinated contrast material. The mean (± standard deviation) percentage of swelling due to water was 9.37 ± 8.7%, whereas that due to blood was −0.8 ± 1.32%.Conclusions. The results of this study showed that brain edema is the major fluid component contributing to traumatic brain swelling. Moreover, CBV is reduced in proportion to CBF reduction following severe brain injury.

Focal brain edema associated with acute arterial hypertension

1986 ◽  
Vol 64 (4) ◽  
pp. 643-649 ◽  
Author(s):  
Shizuo Hatashita ◽  
Julian T. Hoff ◽  
Shozo Ishii
Keyword(s):  
Blood Pressure ◽  
Arterial Hypertension ◽  
Water Content ◽  
Brain Edema ◽  
Evans Blue ◽  
Blue Dye ◽  
Boundary Zone ◽  
Tissue Pressure ◽  
Content Type ◽  
Fine Print

✓ Acute arterial hypertension was studied in normal cats to determine its role in the formation of brain edema. Arterial hypertension was induced for 30 minutes by inflation of a balloon catheter situated in the descending aorta. Cerebral edema was evaluated by gross and microscopic observations, tissue water content by wet/dry weights, and blood-brain barrier (BBB) permeability by extravasation of horseradish peroxidase (HRP) and Evans blue dye. For 1 hour after the hypertensive insult, tissue pressure and regional cerebral blood flow (rCBF) were measured from the arterial boundary zone and from a non-boundary region, and intracranial pressure was recorded from the lateral ventricle as ventricular fluid pressure. Focal lesions with increased BBB permeability to Evans blue dye or HRP were usually located symmetrically in the cortex, corresponding to the occipitoparietal parts of the arterial boundary zones. The increase in water content was found only in areas of increased permeability. Tissue pressure increased simultaneously with the abrupt rise in blood pressure, and an increase in rCBF paralleled the elevation of blood pressure. Tissue pressure and rCBF returned to a steady state when blood pressure returned to normal. There were no differences in tissue pressure or rCBF between the arterial boundary zone and the non-boundary zone, even during arterial hypertension. In cerebral hemispheres examined 48 hours after the hypertensive challenge, brain edema had not continued to develop. The data indicate that acute arterial hypertension may produce focal brain edema with increased permeability of the BBB in the cortex of normal brain, particularly in the arterial boundary zones. The authors postulate that increased cerebral blood volume, high intraluminal pressure, and breakthrough of autoregulation play an important role in the formation of hypertensive brain edema.

Intracerebral infusion of thrombin as a cause of brain edema

1995 ◽  
Vol 83 (6) ◽  
pp. 1045-1050 ◽  
Author(s):  
Kevin R. Lee ◽  
A. Lorris Betz ◽  
Richard F. Keep ◽  
Thomas L. Chenevert ◽  
Seoung Kim ◽  
...  
Keyword(s):  
Brain Edema ◽  
Brain Parenchyma ◽  
Thrombin Inhibitor ◽  
Neurosurgical Procedures ◽  
Edema Formation ◽  
Content Type ◽  
The Right ◽  
The Brain ◽  
Brain Water ◽  
Fine Print

✓ Purified thrombin from an exogenous source is a hemostatic agent commonly used in neurosurgical procedures. The toxicity of thrombin in the brain, however, has not been examined. This study was performed to assess the effect of thrombin on brain parenchyma, using the formation of brain edema as an indicator of injury. Ten µl of test solution was infused stereotactically into the right basal ganglia of rats. The animals were sacrificed 24 hours later, and the extent of brain edema and ion content were measured. Concentrations of human thrombin as low as 1 U/µl resulted in a significant increase in brain water content. Rats receiving 10 U/µl had a mortality rate of 33% compared to no mortality in the groups receiving smaller doses. Thrombin-induced brain edema was inhibited by a specific and potent thrombin inhibitor, hirudin. A medical grade of bovine thrombin commonly used in surgery also caused brain edema when injected at a concentration of 2 U/µl. Edema formation was prevented by another highly specific thrombin inhibitor, Nα-(2-Naphthalenesulfonylglycyl)-4-dl-phenylalaninepiperidide (α-NAPAP). Thrombininduced brain edema was accompanied by increases in brain sodium and chloride contents and a decrease in brain potassium content. Changes in brain ions were inhibited by both hirudin and α-NAPAP, corresponding to the inhibition of brain water accumulation. This study shows that thrombin causes brain edema when infused into the brain at concentrations as low as 1 U/µl, an amount within the range of concentrations used for topical hemostasis in neurosurgery.

Comparison of waterjet dissection and ultrasonic aspiration: an in vivo study in the rabbit brain

2004 ◽  
Vol 100 (3) ◽  
pp. 498-504 ◽  
Author(s):  
Joachim Oertel ◽  
Michael Robert Gaab ◽  
Dirk-Thomas Pillich ◽  
Henry W. S. Schroeder ◽  
Rolf Warzok ◽  
...  
Keyword(s):  
Brain Edema ◽  
Rabbit Model ◽  
Rabbit Brain ◽  
Surgical Trauma ◽  
Edema Formation ◽  
Content Type ◽  
Vessel Preservation ◽  
Waterjet Dissection ◽  
Fine Print

Object. The waterjet method of dissection has been shown to enable the precise dissection of the parenchyma vessels while preserving blood in cadaveric pig brains. The waterjet device has also been applied clinically to treat various diseases and disorders without complications. Evidence still remains to be gathered as to how the instrument performs in reducing surgical trauma, intraoperative blood loss, and postsurgical brain edema. In the present study the authors investigate these parameters in a comparison between waterjet dissection and ultrasonic aspiration in the rabbit brain in vivo. Methods. Thirty-one rabbits received identical bilateral frontal corticotomies, which were created using the waterjet device or an ultrasonic aspirator. The animals were killed 1, 3, or 7 days, or 6 weeks after surgery and their brains were processed for immunohistological analysis. Blood vessel preservation, intraoperative hemorrhage, postsurgical brain edema, and posttraumatic microglial and astoglial reactions were evaluated. Only in animals subjected to waterjet dissection were preserved vessels observed within the corticotomies. In addition, less intraoperative bleeding occurred in animals in which the waterjet was used. The microglial reaction was significantly reduced by waterjet dissection compared with ultrasonic aspiration; however, no difference in edema formation or astrocytic reactivity was observed. Conclusions. These results demonstrate that waterjet dissection appears to be less traumatic than ultrasonic aspiration with respect to intraoperative hemorrhage and postoperative microglial reactivity in the rabbit model. Nevertheless, no difference in edema formation could be demonstrated. It remains to be proven that the observed differences are of clinical relevance.

Erythrocytes and delayed brain edema formation following intracerebral hemorrhage in rats

1998 ◽  
Vol 89 (6) ◽  
pp. 991-996 ◽  
Author(s):  
Guohua Xi ◽  
Richard F. Keep ◽  
Julian T. Hoff
Keyword(s):  
Intracerebral Hemorrhage ◽  
Brain Edema ◽  
Sprague Dawley ◽  
Edema Formation ◽  
Content Type ◽  
Packed Red Blood Cells ◽  
Brain Water ◽  
Packed Rbcs ◽  
Brain Edema Formation ◽  
Fine Print

Object. The mechanisms of brain edema formation following spontaneous intracerebral hemorrhage (ICH) are not well understood. In previous studies, no significant edema formation has been found 24 hours after infusion of packed red blood cells (RBCs) into the brain of a rat or pig; however, there is evidence that hemoglobin can be neurotoxic. In this study, the authors reexamined the role of RBCs and hemoglobin in edema formation after ICH. Methods. The experiments involved infusion of whole blood, packed RBCs, lysed RBCs, rat hemoglobin, or thrombin into the right basal ganglia of Sprague—Dawley rats. The animals were killed at different time points and brain water and ion contents were measured. The results showed that lysed autologous erythrocytes, but not packed erythrocytes, produced marked brain edema 24 hours after infusion and that this edema formation could be mimicked by hemoglobin infusion. Although infusion of packed RBCs did not produce dramatic brain edema during the first 2 days, it did induce a marked increase in brain water content 3 days postinfusion. Edema formation following thrombin infusion peaked at 24 to 48 hours. This is earlier than the peak in edema formation that follows ICH, suggesting that there is a delayed, nonthrombin-mediated, edemogenic component of ICH. Conclusions. These results demonstrate that RBCs play a potentially important role in delayed edema development after ICH and that RBC lysis and hemoglobin toxicity may be useful targets for therapeutic intervention.

Effect of magnesium given 1 hour after head trauma on brain edema and neurological outcome

1996 ◽  
Vol 85 (1) ◽  
pp. 131-137 ◽  
Author(s):  
Zeev Feldman ◽  
Boris Gurevitch ◽  
Alan A. Artru ◽  
Arieh Oppenheim ◽  
Esther Shohami ◽  
...  
Keyword(s):  
Brain Edema ◽  
Brain Tissue ◽  
Head Trauma ◽  
Neurological Outcome ◽  
Edema Formation ◽  
Content Type ◽  
Standard Curve ◽  
Baseline Values ◽  
Brain Edema Formation ◽  
Fine Print

✓ Excitatory amino acids (EAA), mainly glutamate and aspartate, are released in excessive amounts from terminals of ischemic or traumatically injured neurons. These excessive levels of EAAs initiate a cascade of events believed to lead to secondary delayed damage to the surrounding brain. The N-methyl-d-aspartate receptor antagonists MK-801 and ketamine are reported to suppress excessive EAA release and to attenuate the development of focal brain edema following neuronal injury. Magnesium is also reported to work at the postsynaptic receptor to reduce the neurotoxic effect of glutamate. The present study was undertaken to examine the effect of postinjury treatment with Mg++ on brain edema and neurological outcome after traumatic brain injury. Sixty-nine rats that survived halothane anesthesia and closed head trauma (CHT) were randomly assigned to one of seven experimental groups: sham, CHT, and CHT with administration of Mg++ 1 hour postinjury. At 48 hours, brain tissue Mg++ concentration (calculated from optical density using a standard curve) was significantly increased compared to baseline levels (10.06 ± 2.44 mg/g vs. 6.83 ± 0.81 mg/g, p < 0.01 calculated by one-way analysis of variance). Also at 48 hours postinjury, brain tissue specific gravity in the contused hemisphere of Mg++-treated rats was significantly greater than that in the contused hemisphere of untreated rats, indicating attenuation of brain edema formation by Mg++. The neurological severity score (NSS) of rats treated with Mg++ improved significantly at both 18 and 48 hours, compared to baseline values obtained 1 hour after CHT but prior to administration of Mg++ (11.2 ± 2.5 vs. 15.2 ± 4.1, p = 0.03; and 12.3 ± 6.1 vs. 17.3 ± 3.6, p = 0.004, respectively). In the untreated groups, the NSS at 18 and 48 hours was not significantly different from baseline values (that is, no neurological improvement). The present study indicates that postinjury treatment with Mg++ attenuates brain edema formation and improves neurological outcome after experimental CHT.

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