Pathophysiology of brain edema and cell changes following hyperthermic brain injury.
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Animals↗
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[Prevention of brain edema and dehydrating therapy in acute brain injury].
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Brain↗
Neuroprotective effects of nimodipine and MK-801 on acute infectious brain edema induced by injection of pertussis bacilli to neocortex of rats.
OBJECTIVE: To explore the mechanism and type of acute infectious brain edema induced by injection of pertussis bacilli (PB) in rat neocortex, to study the neuroprotective effect of non-competitive antagonist of N-methl-D-aspartate (NMDA) receptor (MK-801) and antagonist of Ca(2+) channels (nimodipine) on brain edema, and to investigate the relationship between percentage of water content and cytosolic free calcium concentration ([Ca(2+) ](i)) in synaptosomes or content of Evans Blue (EB). METHODS: 95 SD rats were randomly divided into five groups, ie, normal control group, sham-operated control group, PB group, nimodipine treatment group and MK-801 pretreatment group. The acute infectious brain edema was induced by injection of PB into the rats. Quantitative measurements of water content and the concentration of EB were performed. [Ca(2+) ](i) was determined in calcium fluorescent indication Fura-2/AM loaded neuronal synaptosome with a spectrofluorophotometer. To observe the effect of MK-801 and nimodipine, we administered MK-801 48 hours and 24 hours before the injection of PB in MK-801 pretreatment group, and nimodipine after the injection of PB in nimodipine treatment group. The specific binding of NMDA receptor was measured with [(3)H]-MK-801 in the neuronal membrane of cerebral cortex. RESULTS: The levels of water content and EB content of brain tissues, and [Ca(2+) ](i) in the neuronal synaptosomes increased more significantly in the PB-injected cerebral hemisphere in the PB group than those of normal control group and sham-operated control group (P<0.05). The water content and [Ca(2+) ](i) increased with the duration of infectious brain edema. Nimodipine administered after the injection of PB could significantly decrease the water content, EB and [Ca(2+) ](i) (P<0.05). MK-801 could significantly decrease the water content, EB and [Ca(2+) ](i) in 4 h and 24 h groups (P<0.05). The Kd values were 30.5 nmol/L+/-3.0 nmol/L and 42.1 nmol/L+/-4.2 nmol/L in PB group and NS group respectively (P<0.05), and Bmax were 0.606 pmol/mg.pro+/-0.087 pmol/mg.pro and 0.623 pmol/mg.pro+/-0.082 pmol/mg.pro respectively, without statistical significance (P>0.05). CONCLUSIONS: The changes in the permeability of blood-brain barrier (BBB) and Ca(2+)-overload may participate in the pathogenesis of infectious brain edema. Treatment with nimodipine can dramatically reduce the damage of brain edema and demonstrate neuroprotective effect on brain edema by inhibiting the excess of Ca(2+) influx and reducing the permeability of BBB. MK-801 pretreatment may inhibit the delayed Ca(2+) influx into the neurons. The infectious brain edema is not only cytotoxic brain edema (intracellular edema) but also vasogenic brain edema (extracellular edema) followed by earlier BBB breakdown, so infectious brain edema is complicated with brain edema.
Acute Disease↗
Effect of infection brain edema on NMDA receptor binding in rat brain in vivo.
The purpose of this study was to determine the effect of infection brain edema (IBE) in the rat model induced by injecting pertussis bacilli (PB) into the left carotid artery. The specific binding of N-methyl-D-aspartate (NMDA) receptor with [3H] MK-801 was measured in the neuronal membrane of cerebral cortex. The Scatchard plots were performed. The Bmax values were 0.623 +/- 0.082 and 0.606 +/- 0.087 pmol/mg protein in the group that received normal saline (NS) and PB respectively (P < 0.05). The Kd values were 43.1 +/- 4.2 and 30.5 +/- 3.0 nM in the groups NS and PB respectively. The results indicated that the affinity of NMDA receptor was significantly higher in the group PB than group NS, whereas the total number of NMDA receptors had not changed in the IBE model. The increase of affinity of NMDA receptor can be blockaded by MK-801 pretreatment in vivo.
Animals↗
Cerebral blood flow and the development of ammonia-induced brain edema in rats after portacaval anastomosis.
Two mechanisms may account for brain edema in fulminant hepatic failure: the osmotic effects of brain glutamine, a product of ammonia detoxification, and a change of cerebral blood flow (CBF). We have shown brain edema, a marked increase in brain glutamine, and a selective rise in CBF in rats after portacaval anastomosis receiving an ammonia infusion. In this study, we inhibited the activity of glutamine synthetase with methionine-sulfoximine (MSO) and examined ammonia levels, brain water and CBF. Four groups received either a continuous ammonium acetate or control infusion; half of the animals had been pretreated with MSO or vehicle. The ammonia group exhibited brain edema (79.97 +/- 0.04 vs. 81.11 +/- 0. 13% water), an increase in cerebrospinal fluid (CSF) glutamine (1.29 +/- 0.21 vs. 2.84 +/- 0.39 mmol/L) and CBF (63 +/- 11 vs. 266 +/- 45 mL/min/100 g brain). When MSO was added to the ammonia infusion, ammonia levels rose further (928 +/- 51 vs. 1,293 +/- 145 mmol/L, P <.05) but CSF glutamine decreased (2.84 +/- 0.39 vs. 1.61 +/- 0.2 mmol/L, P <.01). Brain edema (80.48 +/- 0.11%) and cerebral hyperemia (140 +/- 25 mL/min/100 g brain) were significantly ameliorated in the ammonia plus MSO group. Brain output of circulating nitric oxide (NO(x)) was increased in the ammonia-infused group but normalized in the ammonia plus MSO group. In this model, the rise of CBF reflects intracranial events that occur after glutamine synthesis. Activation of nitric oxide synthase in the brain could account for these findings.
Ammonia↗
Pathophysiological aspects of brain edema.
Two mayor types of brain edema, related to two different pathomechanisms, can be recognized: 1) cytotoxic type-where the main feature is the swelling of cellular elements of brain parenchyma and 2) vasogenic type-where an increased vascular permeability leading to accumulation of edema fluid in the extracellular spaces plays the principal role. In this type of edema, there is a close interrelationship between extravasation of serum proteins and retention of water in the brain tissue. In the ischemic brain edema both cytotoxic and vasogenic mechanisms are involved. A biphasic opening of the blood-brain barrier, associated with vasogenic edema, is observed following release of major cerebral artery occlusion. The first opening of the barrier is related to a reactive hyperemia which follows promptly recirculation. The second opening, recognizable after a delay, is associated with a severe ischemic brain tissue injury.
Blood Flow Velocity↗
Treatment of cold injury-induced brain edema with a nonspecific matrix metalloproteinase inhibitor MMI270 in rats.
Blood-brain barrier (BBB) disruption is a critical event leading to vasogenic brain edema and secondary brain damage after cold injury-induced brain trauma. Matrix metalloproteinases (MMPs), a family of proteolytic enzymes which degrade the extracellular matrix, are implicated in BBB disruption in this model. The purpose of this study was to examine the effects of MMI270 (N-hydroxy-2(R)-[(4-methoxysulfony) (3-picolyl)-amino]-3-metylbutaneamide hydrochloride monohydrate), a synthetic nonspecific MMP inhibitor, on cold injury-induced brain edema in rats. Cold injury was induced by applying a copper probe cooled with liquid nitrogen on the parietal skull for 30 sec in 38 rats. Treatment with MMI270, a bolus injection at a dose of 30 mg/kg, was started immediately after the induction of cold injury and was continued for 24 h at a dose of 40 mg/kg/day using an intraperitoneal osmotic minipump (n = 7). In the untreated control group (n = 7), rats were administered a vehicle and implanted with a vehicle-containing osmotic pump. Two percent Evans Blue (EB) in saline (1 mL/kg) was administrated intravenously immediately after the cold injury in another group of rats, six of which were untreated and six of which were treated with MMI270 at the above dose. At 24 h after the cold injury, the brain water content and the BBB permeability to EB were determined. To assess the protective effect of MMI270 on secondary brain lesion after the cold injury, the MMI270-treated rats received a bolus injection at a dose of 30 mg/kg, followed by a continuous administration of MMI270 for 7 days at a dose of 40 mg/kg/day using an osmotic minipump (n = 6). In the untreated control group (n = 6), the rats were administered the vehicle and implanted with a vehicle-containing osmotic pump. At 7 days after cold injury, the secondary brain lesion was assessed using hematoxylin and eosin (H-E) staining. Compared with the untreated control group, treatment with MMI270 significantly reduced the brain water content in the ipsilateral core and intermediate areas (p < 0.05 and p < 0.01) and protected the BBB integrity to EB in the ipsilateral core area (p < 0.05) at 24 h after the cold injury. The secondary lesion was significantly smaller in the MMI270-treated animals compared with the untreated animals (p < 0.05) a 7 days after the cold injury. O kur results indicate that treatment with MMI270 in rats exhibits protection in acute brain edema formation and secondary brain damage by attenuating the BBB permeability after cold injury.
Animals↗
Amino acids in extracellular fluid in vasogenic brain edema.
We have investigated if changes in brain dialysate, reflecting alterations in brain extracellular composition, can be detected during the development of vasogenic brain edema. The blood-brain barrier was opened by intracarotid infusion of 5 or 10 mg protamine sulphate. The rats were killed two hours after opening of the BBB when the brains were macroscopically edematous, after 10 mg but not 5 mg protamine sulphate. No significant alterations in the amino acid concentration in the dialysate were observed after the lower dose. 40 min after infusion of 10 mg protamine, the level of glutamate was significantly increased in the dialysate followed by that of aspartate, glycine, phosphoethanolamine and taurine 10 min later and a further delayed increase in GABA. We conclude that the development of vasogenic brain edema is associated with significant increases in extracellular concentration of excitatory amino acids, of taurine, and of phosphoethanolamine and GABA.
Amino Acids↗
[Humoral factors of regulation of water-salt metabolism in experimental traumatic brain edema].
Experiments on albino rats with experimental traumatic brain edema were made to study humoral factors of water-salt metabolism regulation: neuropeptides (vasopressin, angiotensin-II as well as aldosterone in the brain and body tissues using radioimmune analysis. Besides, the effect of natriuretic hormone on brain edema was assessed. It was established in preliminary investigations that the highest water content in the brain was recorded on the third day after the suffering of a craniocerebral injury. During the same time, the injured hemisphere showed an increase of sodium ions. The level of vasopressin in cerebral hemispheres rose whereas in the pituitary and blood plasma, it decreased. The injured hemisphere manifested a dramatic increase of angiotensin content. The craniocerebral injury gave rise to aldosterone secretion enhancement and to its elevation in the plasma and brain. The marked and non-uniform alterations in factors of water-salt metabolism and of the vascular tone regulation are important components in the pathogenesis of brain edema, which determines goal-oriented approaches to the search of agents for the treatment of the pathology under consideration.
Aldosterone↗
[Brain edema].
The most frequent complication of an acute cerebral lesion is brain edema. With increasing size of brain edema an increase in intracranial pressure is observed. This leads to decreased cerebral perfusion and brain death. Cerebral edema can be subdivided into three groups: vasogenic, cytotoxic and interstitial brain edema. This classification is of relative importance because only the extracellular edema can be influenced by drugs. Clinical symptoms of brain edema are related to the increased intracranial pressure, associated with decreased cerebral microperfusion. Symptoms are headache, vomiting, vision disturbances and, with increased intracranial pressure, bradicardy, respiration disturbances and at the end brain death by compression of the cerebrum. Therapy is directed to the underlying disease. Unfortunately, even today specific therapeutical approaches are limited.
Brain↗
The role of the coagulation cascade in brain edema formation after intracerebral hemorrhage.
The coagulation cascade has a potential role in brain edema formation due to intracerebral hemorrhage. In this study blood and other solutions were injected stereotactically into the right basal ganglia in rats. Twenty-four hours following injection, brain water and ion contents were measured to determine the amount of brain edema. Intracerebral blood resulted in an increase in brain water content. The amount of brain edema surrounding the intracerebral hematoma was reduced by a thrombin inhibitor N alpha-(2-Naphthalenesulfonylglycyl)-4-amidino-DL-phenylalaninep iperidide, (alpha-NAPAP) infused into the hematoma after the clot had been allowed to solidify. The inhibitor did not alter the actual size of the clot mass. An artificial clot composed of fibrinogen, thrombin, and styrene microspheres also produced brain edema. A fibrin clot led to edema formation even in the absence of mass effect provided by the microspheres. The single component responsible for production of brain edema in all these models was thrombin. The edema was formed in response to a fibrinogen-independent pathway. These results indicate that the coagulation cascade is involved in brain edema that develops adjacent to an intracerebral hematoma.
Animals↗
Correlates of brain edema in uncontrolled IDDM.
Blood glucose, plasma sodium, bicarbonate (HCO3-), vasopressin, and hematocrit were monitored before and during treatment in patients with uncontrolled insulin-dependent diabetes mellitus (IDDM). These parameters were correlated with simultaneous serial cranial computed tomography readings of brain edema. Six of seven patients had positive computed tomography readings for brain edema on admission. Initial brain edema correlated directly with blood glucose (r = 0.79, P = 0.033) and inversely with HCO3- (r = -0.76, P = 0.047). At 6 h, brain edema still correlated with acidosis (HCO3-; r = -0.79, P = 0.033) but no longer with blood glucose. At that time, however, brain edema correlated with the rate of change in blood glucose (r = 0.915, P = 0.005). Results of interactive stepwise regression analysis suggest that the change in the calculated effective plasma osmolality plays a predominant role in the progression of brain edema during therapy (r = 0.995, P less than 0.001). Thus, although hyperglycemia and acidosis probably predispose to diabetic brain edema, osmotic factors may be major predictors of its evolution. No relationships were detected between brain edema and initiation of insulin therapy, plasma vasopressin, or changes in hematocrit. The factors responsible for initial brain edema and its progression, statistically identified in this study, require reassessment of common theories that attribute brain edema exclusively to therapy.
Adolescent↗
Modifications of synaptosomal Na+ -K+ -ATPase activity during vasogenic brain edema in the rabbit.
This study investigates the functioning of synaptosomal ouabain-sensitive Na+ -K+ -ATPase in cold-induced edema. During vasogenic brain edema development, the enzyme affinities for Na+ and K+ are progressively decreased paralleling the increase in the tissue water content, whereas maximal velocity of the reaction is not changed. On the basis of these data, it is likely that Na+ -K+ -ATPase impairment accounts for the intracellular uptake of water in this model of edema.
Animals↗
Brain edema after experimental intracerebral hemorrhage: role of hemoglobin degradation products.
OBJECT: The mechanisms involved in brain edema formation following intracerebral hemorrhage (ICH) have not been fully elucidated. The authors have found that red blood cell lysis plays an important role in edema development after ICH. In the present study, they sought to determine whether degradation products of hemoglobin cause brain edema. METHODS: Hemoglobin, hemin, bilirubin, or FeCl2 were infused with stereotactic guidance into the right basal ganglia of Sprague-Dawley rats. The animals were killed 24 hours later to determine brain water and ion contents. Western blot analysis and immunohistochemistry were applied for heme oxygenase-1 (HO-1) measurement. The effects of an HO inhibitor, tin-protoporphyrin (SnPP), and the iron chelator deferoxamine, on hemoglobin-induced brain edema were also examined. Intracerebral infusion of hemoglobin, hemin, bilirubin, or FeCl2 caused an increase in brain water content at 24 hours. The HO-1 was upregulated after hemoglobin infusion and HO inhibition by SnPP-attenuated hemoglobin-induced edema. Brain edema induced by hemoglobin was also attenuated by the intraperitoneal injection of 500 mg/kg deferoxamine. CONCLUSIONS: Hemoglobin causes brain edema, at least in part, through its degradation products. Limiting hemoglobin degradation coupled with the use of iron chelators may be a novel therapeutic approach to limit brain edema after ICH.
Animals↗
Ischemic brain edema and the osmotic gradient between blood and brain.
The relationship of the osmotic pressure gradient between blood and brain, and the development of ischemic brain edema was studied. Focal cerebral ischemia was produced by left middle cerebral artery occlusion in rats. Brain osmolality was determined with a vapor pressure osmometer, brain water content by wet-dry weight, and tissue sodium and potassium contents by flame photometry. Permeability of the BBB was tested by Evans blue. Measurements were made from the ischemic cortex within 14 days of occlusion. Brain osmolality increased from 311 +/- 2 to 329 +/- 2 mOsm/kg by 6 h after occlusion. Serum osmolality did not change significantly. The osmotic gradient between blood and brain peaked at approximately 26 mOsm/kg. Brain osmolality then decreased to 310 +/- 2 mOsm/kg by 12 h after occlusion and remained at about that same level. Water content increased progressively within 1 day of occlusion, then gradually decreased by 14 days. Brain tissue sodium plus potassium content did not increase within 6 h of occlusion, and Evans blue extravasation was not seen within that time. These findings indicate that an osmotic pressure gradient contributes to the formation of edema only during the early stage of cerebral ischemia. Furthermore, the increase in brain osmolality is not related to tissue electrolyte change or BBB disruption to protein.
Animals↗
The role of hydrostatic pressure in ischemic brain edema.
The mechanisms responsible for early prenecrotic ischemic brain edema were investigated in rats by comparing brain metabolism, tissue water (HOH) content, and sodium and potassium ion concentration in brain during ischemia induced by decapitation, by the Pulsinelli-Brierley technique, and by carotid embolization. Although brain metabolic functions were similarly disturbed in all three groups, an increase in brain HOH occurred only in the embolism model, which allowed collateral perfusion. Early ischemic brain edema is therefore dependent upon (1) impaired energy-dependent ion pumps and (2) a hydrostatic pressure gradient from patient vascular lumens. Elevated perfusion pressure increases the extent of this early edema. Induced hypertension causes impairment of blood-brain barrier function, as evidenced by extravasation of Evans blue dye 5 minutes after embolic ischemia, and strikingly increases the extent of macromolecular extravasation 4 hours after ictus. This increased protein leakage is accompanied by elevated HOH content and sodium concentration, as compared to findings in normotensive animals. It is concluded that the use of induced hypertension as a therapeutic modality in patients with acute stroke may be harmful.
Animals↗
Chronic hyponatremia exacerbates ammonia-induced brain edema in rats after portacaval anastomosis.
BACKGROUND/AIM: Abnormalities in brain organic osmolytes are associated with hepatic encephalopathy and with chronic hyponatremia. In spite of the high frequency of hyponatremia in acute and chronic hepatic failure, its role in the development of neurological complications in liver disease is poorly understood. We aimed to study the effect of prior hyponatremia on the development of ammonia-induced brain edema in rats after portacaval anastomosis. In this model, brain swelling is mediated in part through an increase in brain glutamine, an organic osmolyte. METHODS: Hyponatremia was induced in rats with 1-desamino-8-D-arginine vasopressin (DDAVP) administered through an osmotic minipump for 1 week. This was followed by performance of a portacaval anastomosis and ammonia infusion. At the end of the infusion, brain water (density gradient) and key brain organic osmolytes (HPLC) were measured. RESULTS: Rats with hyponatremia showed a decrease in all three brain organic osmolytes measured: glutamine, myo-inositol and taurine. Hyperammonemia resulted in the expected rise in glutamine, with a reduction of myo-inositol and taurine. In the combined group (hyponatremia plus hyperammonemia), the rise in brain glutamine induced by ammonia infusion was attenuated (10.6+/-0.9 mM/kg vs. 15.5+/-0.8 mM/kg hyperammonemia alone; p<0.05). In spite of this limited rise in brain glutamine, ammonia infusion to hyponatremic rats exacerbated brain swelling (82.3+/-0.3% vs. 80.6+/-0.1%; p<0.05). CONCLUSIONS: Hyponatremia worsens brain swelling in a model of ammonia-induced brain edema. The decrease in the concentration of brain organic osmolytes induced by hyponatremia does not protect the brain from the development of ammonia-induced brain edema.
Ammonia↗
Ammonia and related amino acids in the pathogenesis of brain edema in acute ischemic liver failure in rats.
The pathogenesis of brain edema in acute liver failure is poorly understood. We have previously shown that rats with ischemic acute liver failure (portacaval anastomosis followed by hepatic artery ligation) exhibit brain edema and intracranial hypertension, with swelling of cortical astrocytes as the most prominent neuropathological abnormality. Because ammonia has been shown to induce swelling of astrocytes in vivo and in vitro, we examined the relationship between brain ammonia, amino acids generated from ammonia metabolism and brain water content in this model. Four groups of animals were studied: rats subjected to two sham operations, rats subjected to portacaval anastomosis and a sham operation, rats subjected to a sham operation and hepatic artery ligation and rats subjected to portacaval anastomosis and hepatic artery ligation. The last group of animals was studied at three progressive stages of encephalopathy. Cortical gray matter water increased from 80.26% +/- 0.22% (sham + sham) to 82.46% +/- 0.06% (last stage of devascularization). In cerebral cortex, brain ammonia increased to a maximum of 5.4 mmol/L. Glutamine, generated in glial cells from ammonia and glutamate, increased sixfold to 24 mmol/L and remained at this level throughout all stages of encephalopathy. Alanine, which may be generated from the transamination of glutamine, increased in parallel to the increase in water (r = 0.80, n = 15). In this model of fulminant liver failure and associated brain edema, brain ammonia increases to levels associated with in vitro swelling of brain slices and glial cells. The accumulation of osmogenic aminoacids such as glutamine and alanine may contribute to the selective astrocyte swelling seen in this condition.(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acids↗