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[The effect of neuroleptics on blood proteins during development of toxic cerebral edema-brain swelling].

Simulation of toxic brain edema-swelling allowed one to analyze the dynamics of blood protein alteration in presence of various neuroleptics. Alterations in blood protein fractions correlated with dynamics of nervous tissue impairments. All the drugs studied exhibited similar antiswelling action involving the gamma-globulin sub-system activation. At the same time, the neuroleptics with activating and depriving effects demonstrated an oppositely directed influence on blood albumins.

Animals↗

Influence of granulocytes on brain edema, intracranial pressure, and cerebrospinal fluid concentrations of lactate and protein in experimental meningitis.

Brain water content (brain edema), intracranial pressure, and cerebrospinal fluid (CSF) concentrations of lactate and protein increased significantly during 24 h of experimental meningitis due to Streptococcus pneumoniae, but changes were similar in normal and neutropenic rabbits. In sterile meningitis induced by N-formyl-methionyl-leucyl-phenyl-alanine (fMLP), low and high doses of fMLP were equally effective in inducing CSF pleocytosis, whereas only high doses of fMLP caused brain edema. High doses of fMLP injected intracisternally during pneumococcal meningitis also increased brain water content. The fMLP did not significantly increase intracranial pressure or CSF concentrations of lactate or protein in sterile or pneumococcal meningitis, nor did it cause brain edema in neutropenic animals. Thus, granulocytes may contribute to brain edema during meningitis if adequately stimulated, but intracranial pressure and CSF protein and lactate concentrations appear independent of granulocytes. Stimulation does not appear to occur early in meningitis, when granulocytes were without effect on brain edema.

Animals↗

[Comparison of infectious brain edema models induced by different kinds of pertussis bacilli in rats].

OBJECTIVE: To understand the difference of infectious brain edema models induced by varied kinds of pertussis bacilli in rats and to look for a new infectious brain edema model. METHODS: Sprague-Dawley rats were randomly divided into 3 groups: normal saline group(NS); rude pertussis bacilli(PBR); purified pertussis bacilli(PBP). After infectious brain edema model was induced by rude pertussis bacilli or purified pertussis bacilli, the water content(WC), Evan's blue content(EB), Na+ and K+ content in brain tissues were measured. RESULTS: The WC, EB and Na+ contents in brain tissues in PBR and PBP groups were significantly increased than those in NS group; K+ content was significantly decreased in PBR and PBP groups than that in NS group(P < 0.01). Evan's blue discoloration was demonstrated in all rats of PBR group, but 6 rats of PBP group showed bluish discoloration. EB content in brain tissues was significantly increased in PBR group than that in PBP group. CONCLUSIONS: The infectious brain edema model can be induced by rude pertussis bacilli or purified pertussis bacilli in rats, the former gives priority to mixed brain edema, and the latter mainly avails cytotoxin brain edema.

Animals↗

Noninvasive early detection of brain edema in mice by near-infrared light scattering.

Brain edema accounts for significant morbidity and mortality in many neurologic conditions such as head trauma, stroke, meningitis, and brain tumor. The water channel aquaporin-4 (AQP4) has been found to be an important determinant of brain water accumulation and clearance of excess brain water. We report the development of a noninvasive near-infrared (NIR) light-scattering method to compare the early kinetics of brain swelling in normal and AQP4-deficient mice. Brain tissue was illuminated through the intact skull with NIR light at 850 nm, and steady-state scattered light intensity was monitored at an angle of 90 degrees at a position on the skull approximately 10 mm from the illuminated site. NIR light scattering reversibly increased with brain swelling (DeltaI/Io approximately 25% per 1% increase in brain water content), but was insensitive to changes in cerebral blood flow, blood oxygenation, or blood flow-related changes in intracranial pressure (ICP). DeltaI/Io increased approximately linearly with brain water content as measured by wet-to-dry weight ratios. Acute water intoxication (intraperitoneal water, 20% body weight) produced a gradual increase in DeltaI/Io of 12 +/- 4% in wild-type mice at 5 min, much greater than that of 2 +/- 1% in AQP4-null mice. Correlation of the NIR signal with ICP showed that increased DeltaI/Io preceded measurable increases in ICP, indicating the ability of the NIR method to detect early brain edema before ICP elevation. NIR light scattering provides a simple noninvasive method to monitor brain edema in mice, with potential clinical applications.

Animals↗

Blood-brain barrier disruption and exacerbation of ischemic brain edema after restoration of blood flow in experimental focal cerebral ischemia.

The mechanism of exacerbation of ischemic brain edema after blood flow restoration was studied in 20 cats under ketamine and alpha-chloralose anesthesia. Regional cerebral blood flow was measured by the hydrogen clearance method, and the left middle cerebral artery (MCA) was occluded for 6 h in group A, and for 3 h with subsequent 3 h recirculation in group B. Severity of brain edema was assessed by specific gravity measurement of tissue samples taken from coronal brain sections at the MCA area, while severity of blood-brain barrier (BBB) disruption was determined by measuring the amount of extravasated serum albumin by using [125I]albumin and tissue-uptake method in the same samples as those used for gravimetry. Structural and ultrastructural change was correlated with the severity of ischemic brain edema and BBB disruption. The results obtained showed that: (i) ischemic brain edema observed in group A was not associated with BBB opening to serum proteins; (ii) ischemic edema in group B was exacerbated significantly after recirculation in correlation with serum protein extravasation in most of the post-ischemic area; (iii) in the severely edematous area, serum protein extravasation reached a plateau and morphological examination at this type of area revealed cell membrane disruption especially of astrocytes, with leakage of intracellular substances. Our study indicated that the increase of extracellular osmotic pressure due to leakage of serum proteins via the disrupted BBB and of intracellular substances via the ischemically injured cell membrane into the extracellular space is the mechanism responsible for edema fluid accumulation in exacerbated ischemic brain edema.

Animals↗

Mild hypothermia induced before cardiac arrest reduces brain edema formation in rats.

OBJECTIVES: The mechanisms by which hypothermia improves cardiac arrest (CA)-induced brain damage are unclear. The authors hypothesized that mild hypothermia induced before CA attenuates brain edema formation by preventing neutrophil-mediated dysfunction of the endothelial cell junction proteins. METHODS: Eighteen rats were randomized to normal control surgery (group 1, n = 6), normothermic (37.5 degrees C) CA (group 2, n = 6), or hypothermic (34 degrees C) CA (group 3, n = 6). Hypothermia was induced with external cooling before CA in group 3. Cardiac arrest was induced by 8 minutes of asphyxiation. Brain edema was determined by wet-to-dry weight ratio and cerebral spinal fluid pressure (CSFP). Brain neutrophil content was determined by myeloperoxidase (MPO) activity, and occludin degradation was assessed by western blotting. RESULTS: Normothermic CA significantly increased brain wet-to-dry weight ratio from 4.52 +/- 0.04 in group 1 to 4.80 +/- 0.04 in group 2 (p = 0.0003) and CSFP from 3.6 +/- 0.9 in group 1 to 8.9 +/- 0.9 mm Hg in group 2 (p = 0.004). Mild hypothermia before CA in group 3 significantly reduced brain wet-to-dry weight ratio (4.68 +/- 0.03, p = 0.008 vs. group 2) and CSFP (3.8 +/- 0.5 mm Hg, p = 0.004 vs. group 2). Cardiac arrest increased brain MPO from 0.07 +/- 0.025 in group 1 to 0.16 +/- 0.02 units/gram brain weight in group 2 (p = 0.006) that was not decreased by hypothermia before CA (0.12 +/- 0.02 in group 3 (p = 0.07 vs. group 2). There was no occludin proteolysis in any group. CONCLUSIONS: Mild hypothermia before CA decreases CA-induced brain edema. The hypothermia-elicited reduction in brain edema does not appear to be neutrophil-dependent and the early brain edema formation may not involve the proteolysis of occludin.

Analysis of Variance↗

The effects of blood or plasma clot on brain edema in the rat with intracerebral hemorrhage.

The causes and characteristics of the brain edema which forms adjacent to an acute intracerebral hemorrhage (ICH) have not been explored thoroughly. This study was designed to examine the edema process in rat brain provoked by two different blood clot components. An intracerebral clot was produced by stereotactic injection of 100 microl of either blood (bICH) or cryoprecipitate/thrombin (pICH) into the right caudate nucleus. Water, Na+, K+, and Cl- contents were measured at 0, 4.24, 48, and 72 h after instillation of the clot. During the first 24 h, the water content of the ipsilateral caudate nucleus and cortex gradually increased in both groups. By 48 h brain edema was more severe in the bICH compared to that with pICH in the ipsilateral basal ganglia and cortex. The edema formation was accompanied by significant increase in sodium and chloride, as well as a decrease in potassium content by 48 h and sustained to 72 h. These results suggest that both blood and plasma clots can cause brain edema, but a plasma clot is less damaging than a blood clot in the immediate vicinity of the mass.

Animals↗

Blocking of interleukin-1 activity is a beneficial approach to ischemia brain edema formation.

We examined the therapeutic value of an interleukin-1 inhibitor on brain edema formation using a transient focal ischemia model in rats. Rats were given an interleukin-1 blocker, or interleukin-1 release inhibitor immediately after reperfusion. In rats treated with interleukin-1 inhibitor, ischemic brain edema 1 day after reperfusion was significantly decreased compared to that of saline-treated control rats. The simultaneous application of an IL-1 release inhibitor and a lipoxygenase inhibitor showed an additive beneficial effect on brain edema formation. These findings suggest that blocking IL-1 activity ameliorates brain edema and attenuates the neuronal damage induced by focal transient ischemia in rats.

Animals↗

[Effect of heat shock protein 70 on nuclear factor-KappaB/inhibitor protein-alpha of nuclear factor-KappaB in brain edema induced by infection in rat].

OBJECTIVE: To study the effect of heat shock protein 70 (HSP70) on activation of nuclear factor-KappaB (NF-KappaB) and degradation of inhibitor KappaB-alpha protein (I-Kappa B alpha) in brain edema induced by Pertussis bacilli infection in rats. METHODS: Brain edema was induced by injection of Pertussis bacilli suspension via the left internal carotid artery. Seventy-two Sprague-Dawley rats were divided randomly into brain edema group, pretreatment with heat shock group, and normal saline control group. The rats were sacrificed 4, 8 and 24 hours after injection of Pertussis bacilli and normal saline, respectively. HSP70 expression and the degradation of I-Kappa B alpha were assayed in all animals with Western blot analysis. Electrophoretic mobility shift assay (EMSA) was performed to assess NF-KappaB activation of nuclear extract of neurones. RESULTS: The results showed that HSP70 expression was significantly increased in heat shock group compared with control group and brain edema group. The activity of NF-KappaB started to increase at 2 hours in brain edema group and peaked at 24 hours. The expression of I-Kappa B alpha began to decrease at 2 hours and reached the lowest level at 24 hours. In heat shock group the activity of NF-KappaB complexes was lower than that in brain edema group, and the expression of I-Kappa B alpha higher than that in brain edema group at corresponding time points. CONCLUSION: HSP70 shows a protective effect on development of brain edema as its expression increases. The mechanism might be associated with its inhibitory effect on degradation of I-Kappa B alpha and activation of NF-KappaB.

Animals↗

Effect of body temperature on brain edema and encephalopathy in the rat after hepatic devascularization.

Brain edema is a fatal complication of fulminant hepatic failure and its pathogenesis remains unclear. To determine its presence in a model of ischemic hepatic failure, rats were subjected to a portacaval anastomosis followed by hepatic artery ligation. Brain water was measured using the sensitive gravimetric method. Preliminary studies revealed marked hypothermia in devascularized animals kept at room temperature (26.9 degrees +/- 2.8 degrees C). An additional group of devascularized rats was kept in an incubator. As expected for hypothermia, such animals had a lower arterial pressure and heart rate; the duration of encephalopathy was markedly prolonged. Water content of the cortical gray matter was only increased in normothermic devascularized rats: 80.14% +/- 0.31%, normal; 80.06% +/- 0.22%, portacaval shunt only; 80.42% +/- 0.26%, devascularized at room temperature; 81.29% +/- 0.38%, devascularized at controlled temperature (p less than 0.001). Such differences could not be detected using the dry-weight technique in whole cerebral hemispheres. Astrocyte changes in the cortical gray matter were noted in both edematous and nonedematous devascularized groups, coupled with the presence of vesicles containing horseradish peroxidase in the endothelial capillary cell. This suggests that in this model, brain edema may be due to both a cytotoxic mechanism and changes in the permeability of the blood-brain barrier. Future studies with this widely used model will require strict control of temperature to allow interpretation of experimental results. A therapeutic role for hypothermia in the management of brain edema deserves further attention.

Animals↗

Brain edema.

Current concepts on the development of brain edema are briefly reviewed. The common classification into vasogenic and cytotoxic edema is a simplification and does not cover all types of edema. Alternative routes of edema resolution are discussed. More basic data on the mechanisms of development and regression of brain edema are needed before more successful treatments are likely to be found.

Animals↗

Amelioration of brain edema by topical application of glial cell line-derived neurotrophic factor in reperfused rat brain.

Glial cell line-derived neurotrophic factor (GDNF) was applied topically on the brain surface of reperfused rat brain after 90 min of transient middle cerebral artery occlusion. In contrast to the cases treated with vehicle, a formation of brain edema was greatly reduced at 2 days by the treatment with GDNF. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL) staining was also markedly reduced in the cases with GDNF treatment both at 1 and 2 days of reperfusion. However, amelioration of the induction of immunoreactive 70 kDa heat shock protein was only a minimum by the GDNF treatment. The present results suggest that the treatment with GDNF has a significant effect on ameliorating brain edema formation after transient focal brain ischemia, and the effect is greatly associated with the reduction of TUNEL staining, but minimally with that of stress response of cells.

Animals↗

Cortical tissue pressure gradients in early ischemic brain edema.

We examined the role of ischemic brain edema, tissue pressure gradients, and regional CBF (rCBF) in adjacent regions of cerebral cortex in cats with middle cerebral artery (MCA) occlusion (MCAO). Tissue pressure, rCBF, and water content were measured from gray matter in the central core and the peripheral margin of the MCA territory over 6 h after MCAO. Ventricular fluid pressure and CSF pressure were recorded. Tissue pressure in the ischemic core, with a flow of approximately 5 ml/100 g/min, increased more than that in the periphery where flow was approximately 19 ml/100 g/min. Tissue pressure rose progressively to 14.8 +/- 1.0 mm Hg in the core over 6 h after MCAO, establishing a significant pressure gradient between that tissue and the lateral ventricle nearby or the subarachnoid space in the middle fossa within the first 3 h. The increase in tissue pressure was linearly related to the amount of edema fluid that developed until the edema reached a severe degree. This study shows that a hydrostatic tissue pressure gradient within ischemic cortex is associated with ischemic brain edema. The magnitude of the gradient that develops is related to the severity of ischemic edema in that tissue.

Animals↗

Proposed toxic oxidant inhibitors fail to reduce brain edema.

Toxic oxidants (oxygen free radicals) have been implicated in the formation of brain edema from ischemia-reperfusion injury or tumor growth. We investigated the ability of an iron chelator, a calcium channel blocker, and a xanthine oxidase inhibitor to reduce formation of brain edema following a cold lesion in cats. The agents were given independently of each other in an attempt to inhibit the Haber-Weiss reaction, prevent Ca++ modulated uncoupling of oxidative phosphorylation, and inhibit the generation of toxic oxidants via xanthine oxidase, respectively. Pentastarch-deferoxamine conjugate at a dose of 50 mg/kg was given 15 minutes before and 60 minutes after the cold lesion. Nimodipine was given at a dose of 1 mg/kg 1 hour before and 2 hours after the cold lesion. Allopurinol was given at a dose of 50 mg/kg 24 hours before, at the time of the lesion and, 24 and 48 hours after the lesion. Gravimetric measurements of multiple brain areas were performed at 24 hours post-lesion in the pentastarch-deferoxamine and nimodipine groups and at 72 hours post-lesion in the allopurinol group. None of these agents led to significant reduction in brain edema formation as measured with a gravimetric column of kerosene and bromobenzene. Pentastarch-deferoxamine conjugate was utilized to avoid the confounding effects of arterial hypotension which is seen with intravenous deferoxamine. There was even a suggestion of increased edema in the periventricular white matter in animals treated with nimodipine. Taken together, independent inhibition of the Haber-Weiss reaction, of calcium channels, or of xanthine oxidase does not reduce formation of brain edema in the cold lesion model.

Allopurinol↗

Multiphasic helical computed tomography predicts subsequent development of severe brain edema in acute ischemic stroke.

OBJECTIVE: To evaluate the use of multiphasic helical computed tomography (CT) in predicting subsequent development of severe brain edema in patients with acute middle cerebral artery (MCA) stroke. DESIGN: Case-control study. SETTING: Tertiary referral hospital. PATIENTS: We studied 31 patients with acute MCA stroke who had a baseline National Institutes of Health Stroke Scale score of 15 or higher within 6 hours of symptom onset. Sequential 4-phasic enhanced helical CT scans were performed after taking precontrast CT scans. The severity of perfusion deficit was graded as "severe" or "moderate" depending on collateral blood flow. MAIN OUTCOME MEASURES: Patients were classified as having severe brain edema if they showed signs of uncal herniation or deterioration with mass effect leading to hemicraniectomy. RESULTS: Severe brain edema developed in 10 patients (32%). Severe perfusion deficit greater than 50% of the presumed MCA territory on multiphasic helical CT was more often found in patients with severe brain edema than in those without (8 of 10 vs 4 of 21, P =.002). In contrast, parenchymal hypodensity greater than 50% on precontrast CT was observed only in 5 patients with severe brain edema (5 of 10 vs 4 of 21, P =.10). Additional involvement of the anterior or posterior cerebral artery territory was found on multiphasic CT (6 of 10 vs 0 of 21, P <.001) and on precontrast CT (4 of 10 vs 0 of 21, P =.007) only in patients with severe brain edema. CONCLUSION: Multiphasic helical CT is more useful than precontrast CT for predicting subsequent severe brain edema in acute MCA stroke based on the findings of severe perfusion deficit greater than 50% of the MCA territory and additional involvement of the anterior or posterior cerebral artery territory.

Academic Medical Centers↗

Proton nuclear magnetic resonance studies on brain edema.

The water in normal and edematous brain tissues of rats was studied by the pulse nuclear magnetic resonance (NMR) technique, measuring the longitudinal relaxation time (T1) and the transverse relaxation time (T2). In the normal brain, T1 and T2 were single components, both shorter than in pure water. Prolongation and separation of T2 into two components, one fast and one slow, were the characteristic findings in brain edema induced by both cold injury and triethyl tin (TET), although some differences between the two types of edema existed in the content of the lesion and in the degree of changes in T1 and T2 values. Quantitative analysis of T1 and T2 values in their time course relating to water content demonstrated that prolongation of T1 referred to the volume of increased water in tissues examined, and that two phases of T2 reflected the distribution and the content of the edema fluid. From the analysis of the slow component of T2 versus water content during edema formation, it was demonstrated that the increase in edema fluid was steady, and its content was constant during formation of TET-induced edema. On the contrary, during the formation of cold-injury edema, water-rich edema fluid increased during the initial few hours, and protein-rich edema fluid increased thereafter. It was concluded that proton NMR relaxation time measurements may provide new understanding in the field of brain edema research.

Animals↗

Pial arterial pressure contribution to early ischemic brain edema.

The effect of pial arterial pressure (PAP) on brain edema was examined in cats with middle cerebral artery (MCA) occlusion. Measurements of PAP and regional CBF (rCBF) were collected in the central core and the peripheral margin of the MCA territory over 180 min post MCA occlusion. Brain water content in each region was determined at the end of the experiment. MCA occlusion resulted in decreased PAP and rCBF in both the core (PAP = 13 mm Hg, rCBF = 9 ml/100 g/min) and the peripheral region (PAP = 15 mm Hg, rCBF = 18 ml/100 g/min). Brain edema developed in both the core and the peripheral region. Brain water content was correlated inversely with PAP in the core region and positively in the peripheral region. The results indicate that decreased blood flow contributes to cytotoxic edema in the core, and a hydrostatic pressure gradient preferentially enhances edema formation in the peripheral region. Maintenance of high perfusion pressure early after ischemia onset may suppress brain edema in the core region.

Animals↗

Matrix metalloproteinase-9 is associated with blood-brain barrier opening and brain edema formation after cortical contusion in rats.

Matrix metalloproteinases (MMPs) are associated with blood-brain opening and may be involved in the pathophysiology of acute brain injury. Previous research demonstrated that knockout mice deficient in MMP-9 subjected to transient focal cerebral ischemia had reduced blood-brain barrier (BBB) disruption and attenuated cerebral infarction. In this study, we examined MMP-9 up-regulation, BBB disruption, and brain edema formation after cortical impact injury in rats. Cortical contusion was induced by controlled cortical impact. Animals were sacrificed at intervals after injury. MMP up-regulation was assessed by gelatin zymography, and BBB integrity was evaluated using Evans blue dye with a spectrophotometric assay. Brain water content was measured by comparing wet and dry weights of each hemisphere as an indicator of brain edema. Zymograms showed elevated MMP-9 as early as at 3 hours after injury, reaching a maximum at 18 hours. Peak levels of BBB disruption occurred 6 hours after injury. Brain edema became progressively more severe, peaking 24 hours after injury. Compared to control group, treatment with MMP-inhibitor GM6001 significantly reduced BBB disruption 6 hours and brain water content (85.9 +/- 0.5% vs. 82.6 +/- 0.3%; p < 0.05) 24 hours after injury. These findings suggest that MMP-9 may contribute to BBB disturbance and subsequent brain edema after traumatic brain injury.

Animals↗