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Biomedical subjects

A Baethmann

Publications and source records attributed to A Baethmann.

At least 19 recordsLinked to original sources
PubMed2005

Neuroprotective effects of a postischemic treatment with a bradykinin B2 receptor antagonist in a rat model of temporary focal cerebral ischemia.

Bradykinin, an endogenous nonapeptide produced by activation of the kallikrein-kinin system, promotes neuronal tissue damage as well as disturbances in blood-brain barrier function through activation of B2 receptors. In a rat model of focal cerebral ischemia, blockade of B2 receptors before initiation of ischemia with the B2 receptor antagonist, LF 16-0687 Ms, afforded substantial neuroprotection. In order to assess the potential clinical value of this approach, we evaluated the effect of LF 16-0687 Ms given at reperfusion following focal cerebral ischemia on local cerebral blood flow (LCBF), neurological outcome, and infarct size. Sprague-Dawley rats were subjected to MCA occlusion for 90 min by an intraluminal filament. Animals were assigned to one of four treatment arms (n = 7 each): (1) vehicle, (2) LF 16-0687 Ms (1.0 mg/kg/day), (3) LF 16-0687 Ms (3.0 mg/kg/day), or (4) LF 16-0687 Ms (10.0 mg/kg/day) given at reperfusion and repetitively over 2 days. Neurological recovery was examined daily, and infarct volume was assessed histologically on day 7 after ischemia. Physiological parameters and local CBF were not influenced by the treatment. Significant improvement of neurological outcome was observed on postischemic day 3 in animals receiving 1.0 and 3.0 mg/kg/day of LF 16-0687 Ms (P < 0.05). Inhibition of B2 receptors significantly reduced infarct volume in all treated animals predominantly in the cortex. B2 receptor blockade with LF 16-0687 Ms showed neuroprotective effectiveness even when therapy was initiated upon reperfusion, i.e. 90 min after induction of ischemia. Therefore, blockade of B2 receptors seems to be a promising therapeutic approach after focal cerebral ischemia, which deserves further experimental and clinical evaluation.

Analysis of Variance↗
PubMed2005

Dose finding study of intravenous magnesium sulphate in transient focal cerebral ischemia in rats.

BACKGROUND: During many neurovascular procedures temporary occlusion of cerebral arteries is inevitable. Neuroprotective drugs may reduce the risk of cerebral infarction in this situation. Increasing evidence indicates neuroprotective properties of magnesium in cerebral ischemia. Previous experimental studies on the neuroprotective efficacy of magnesium-treatment in transient focal ischemia provide widely differing results using different magnesium doses and treatment-regimens. The present study was conducted to find the maximum protective dose of intravenous magnesium sulphate in a rat model of transient focal ischemia. METHODS: 45 male Sprague-Dawley rats were subjected to 90 minutes of middle cerebral artery occlusion (MCAO) by an intraluminal thread. Animals were randomly assigned to one of 4 treatment arms: (1) vehicle (2) MgSO(4) 1x0.75 mmol/kg (3) MgSO(4) 2x1 mmol/kg (4) MgSO(4) 1 mmol/kg+0.5 mmol/kg/h. Local cortical blood flow (LCBF) was continuously measured by laser-Doppler flowmetry. Functional deficits were quantified daily, infarct volumes were assessed histologically after 7 days. RESULTS: Magnesium serum levels below 3 mmol/l were well tolerated by the animals. Above 3 mmol/l cardiodepressive effects limited neuroprotection. Total infarct volumes in groups 3 and 4 were significantly reduced by 32% and 42%, respectively, compared to controls. Postoperative neurological recovery was significantly improved in magnesium-treated groups. CONCLUSION: Continuous magnesium-administration with stable serum concentrations between 2 and 3 mmol/l offered the best protection and was well tolerated. Serum concentrations above 3 mmol/l should not be exceeded. An elevation of magnesium serum levels could be useful for brain tissue protection during procedures which are prone to the risk of temporary vessel occlusion.

Animals↗
PubMed2004

Prospective documentation and analysis of the pre- and early clinical management in severe head injury in southern Bavaria at a population based level.

Treatment of patients suffering from severe head injury is so far restricted to general procedures, whereas specific pharmacological agents of neuroprotection including hypothermia have not been found to improve the outcome in clinical trials. Albeit effective, symptomatic measures of the preclinical rescue of patients (i.e. stabilization or reestablishment of the circulatory and respiratory system) or of the early clinical care (e.g. prompt diagnosis and treatment of an intracranial space occupying mass, maintenance of a competent circulatory and respiratory system, and others) by and large constitute the current treatment based on considerable organizational and logistical efforts. These and other components of the head injury treatment are certainly worthwhile of a systematic analysis as to their efficacy or remaining deficiencies, respectively. Deficits could be associated with delays of providing preclinical rescue procedures (e.g. until intubation of the patient or administration of fluid). Delays could also be associated in the hospital with the diagnostic establishment of intracranial lesions requiring prompt neurosurgical intervention. By support of the Federal Ministry of Education and Research and under the auspices of the Forschungsverbund Neurotraumatology, University of Munich, a prospective system analysis was carried out on major aspects of the pre- and early clinical management at a population based level in patients with traumatic brain injury. Documentation of pertinent data was made from August 1998 to July 1999 covering a catchment area of Southern Bavaria (5.6 mio inhabitants). Altogether 528 cases identified to suffer from severe head injury (GCS < or = 8 or deteriorating to that level within 48 hrs) were enrolled following admission to the hospital and establishment of the diagnosis. Further, patients dying on the scene or during transport to the hospital were also documented, particularly as to the frequency of severe head injury as underlying cause of mortality. The analysis included also cases with additional peripheral trauma (polytrauma). The efficacy of the logistics and organization of the management was studied by documentation of prognosis-relevant time intervals, as for example until arrival of the rescue squad at the scene of an accident, until intubation and administration of fluid, or upon hospital admission until establishment of the CT-diagnosis and commencement of surgery or transfer to the intensive care unit, respectively. The severity of cases studied in the present analysis is evident from a mortality of far above 40% of cases admitted to the hospital, which was increased by about 20% when including prehospital mortality. The outcome data notwithstanding, the emerging results demonstrate a high efficacy of the pre- and early clinical management, as indicated by a prompt arrival of the rescue squad at the scene, a competent prehospital and early clinical management and care, indicative of a low rate of avoidable complications. It is tentatively concluded on the basis of these findings that the patient prognosis is increasingly determined by the manifestations of primary brain damage vs. the development of secondary complications.

Craniocerebral Trauma↗
PubMed2003

Therapeutical efficacy of a novel non-peptide bradykinin B2 receptor antagonist on brain edema formation and ischemic tissue damage in focal cerebral ischemia.

OBJECTIVE: Bradykinin has been identified as a mediator of secondary brain damage in acute insults. We currently studied neuroprotective properties of a bradykinin B2 receptor antagonist (LF16-0687 Ms) in transitory focal cerebral ischemia to assess infarct formation and the development of brain edema. MATERIAL AND METHODS: 55 Rats were subjected to 90 min of MCA-occlusion. The receptor antagonist was administered at two dose levels, given from 30 min prior to ischemia over two days after ischemia. Ischemic tissue damage was quantified at day 7 after MCA-occlusion together with assessment of brain edema in separate experiments. Neurological recovery was studied daily. RESULTS: Animals receiving treatment (low dose) had a better functional recovery, particularly at days 3 and 4 (P < 0.05). Infarct formation was significantly attenuated in these animals in both total and cortical brain tissue by 50, or 80%, respectively. Postischemic brain swelling was significantly lowered, i.e. by 62%. CONCLUSIONS: Our findings provide further support for a mediator role of bradykinin in ischemic brain damage including edema formation, obviously by ligand binding to the bradykinin B2 receptor. The availability of a receptor antagonist may afford opportunity for translation of this experimental treatment into stroke patients.

Animals↗
PubMed2003

Correlation of lesion volume and brain swelling from a focal brain trauma.

Brain edema and secondary growth of a traumatic brain tissue necrosis are important manifestations of secondary brain damage and of prognostic significance in severe head injury. Aim of the current study was to analyze the interdependency of the resulting brain swelling from the size of the focal traumatic lesion. Male Sprague-Dawley rats were intubated and mechanically ventilated. A trephination was made over the left parietal cortex for induction of a cold lesion. Different injury severities were achieved by varying the contact time of the cooled copper-cylinder and the exposed cortex. Animals were randomized into 12 experimental groups. Hemispheric brain swelling was measured in groups A1-A6 (n = 4-8) by gravimetry 24 hrs after lesions of six increasing severity levels. Correspondingly, in animals of groups B1-B6 (n = 5-7) the volume of necrosis was planimetrically assessed in histological serial sections of the brain obtained 24 hrs after trauma of different severity. In groups A1-A6. hemispheric brain swelling (increase in weight) was growing with increasing contact duration of the cold probe with the exposed cerebral cortex, i.e. from 7.7 +/- 0.4% (5 s) to a maximum of 9.9 +/- 0.5% (25 s). Longer contact periodes (30 s) were not further effective to increase hemispheric brain swelling. The contact times and extent of swelling were linearly correlated between 5 s and 25 s (r = 0.47; p < 0.01). The volume of necrosis in groups B1-B6 increased from 35.7 +/- 3.7 mm3 (5 s) to 106.3 +/- 10.3 mm3 (30 s). There was again a linear correlation between the duration of contact of the cold probe (i.e. injury severity) with the brain cortex and the volume of necrosis (r = 0.77; p < 0.01). Accordingly. the lesion volume could be increased in a reproducible manner from 35.7 up to 106.3 mm3 by extending the contact times of the cooling device and cerebral cortex. Hemispheric swelling, predominantly due to vasogenic brain edema, was expanding in relationship with the volume of necrosis.

Animals↗
PubMed2003

Neuroprotective efficacy of intra-arterial and intravenous magnesium sulfate in a rat model of transient focal cerebral ischemia.

BACKGROUND: Many neurovascular procedures necessitate temporary occlusion of cerebral arteries. In this situation neuroprotective drugs may increase the safety of the procedures. Magnesium may inhibit ischemic damage by anti-excitotoxic, calcium channel blocking and vasodilatory action. Some evidence suggests that intra-arterial administration might provide a much higher degree of protection than intravenous treatment. In this study the neuroprotective efficacy of intra-arterial and intravenous magnesium administration was examined in a rat model of transient focal ischemia. METHODS: 34 male Sprague-Dawley rats were subjected to 90 minutes of middle cerebral artery occlusion (MCAO) by an intraluminal thread. Before ischemia, animals received an infusion of either (1) vehicle (0.9% NaCl) (2) MgSO4 intra-arterially or (3) MgSO4 intravenously. Local cortical blood flow (LCBF) was continuously measured by laser-Doppler flowmetry. Functional deficits were quantified daily, infarct volumes were assessed histologically after 7 days. FINDINGS: There was no difference between the treatment groups concerning LCBF. Magnesium serum levels increased from approximately 1 mmol/l to approximately 1.8 mmol/l by either route of administration. Both intra-arterial and intravenous treatment improved neurological recovery and equally reduced total infarct volume by approximately 25%. INTERPRETATION: The results indicate that there is no advantage of intra-arterial over intravenous magnesium administration. A comparison with previous studies suggests that even within the normal range of serum magnesium concentrations, low-normal levels may be hazardous and high-normal levels may be protective in transient focal ischemia.

Animals↗
PubMed2003

Secondary growth of a cortical necrosis: effect of NOS inhibition by aminoguanidine post insult.

BACKGROUND: A cortical tissue necrosis from a focal freezing injury expands to 140% of its initial volume within 24 hrs in rats. Previous studies of our laboratory have shown that administration of the NOS inhibitor aminoguanidine (AG) prior to trauma attenuates this process of secondary brain damage. Objective of the present study was to analyse whether this agent is also protective when treatment commences after the insult. METHOD: A highly standardized freezing lesion was induced in the brain cortex of 30 anaesthetized rats. The animals were divided into three experimental groups. Animals of group I (sham-5 min, n=10) were sacrificed 5 min after trauma for quantitative histomorphometric assessment of the primary cortical lesion. Animals of group II (sham-24 h, n=10) received isotonic saline (16.7 ml/kg b.w., i.p.) at 15 min and 8 hrs after trauma. In the treatment group (group III, AG-24 h, n=10), AG was administered (100 mg/kg b.w.) also at 15 min and 8 hrs after trauma. 24 hrs later--the time point of maximal lesion spread--the animals of group II and III were sacrificed for quantification of the secondary lesion growth. FINDINGS: The focal freezing injury produced a cortical necrosis volume of 6.07+/-1.04 mm(3) immediately after trauma (group I). After sham treatment, the necrosis expanded to 8.39+/-1.57 mm(3) within 24 hrs (group II) corresponding to a lesion growth of 138% compared to the primary necrosis ( p<0.01 vs. group I). In animals treated with AG after the trauma (group III), the volume of necrosis was significantly attenuated at 24 hrs to 6.77+/-0.87 mm(3) representing an expansion of the lesion to only 112% ( p<0.05 vs. group II). Thus, AG was inhibiting the secondary growth of necrosis by no less than 69%. INTERPRETATION: The findings demonstrate that AG retains its neuroprotective potential against secondary brain damage from trauma even when administration begins after trauma.

Animals↗
PubMed2002

Effects of LF 16-0687 Ms, a bradykinin B(2) receptor antagonist, on brain edema formation and tissue damage in a rat model of temporary focal cerebral ischemia.

Bradykinin, an endogenous nonapeptide produced by activation of the kallikrein-kinin system, promotes neuronal tissue damage as well as disturbances in blood-brain barrier function through activation of B(2) receptors. LF 16-0687 Ms, a non-peptide competitive bradykinin B(2) receptor antagonist, was recently found to decrease brain swelling in various models of traumatic brain injury. We have investigated the influence of LF 16-0687 Ms on the edema formation, neurological outcome, and infarct size in temporary focal cerebral ischemia in rats. Sprague-Dawley rats were subjected to MCA occlusion for 90 min by an intraluminal filament. Local CBF was bilaterally recorded by laser Doppler flowmetry. Study I: animals were assigned to one of three treatment arms (n=11 each): (a) vehicle, (b) LF 16-0687 Ms (12.0 mg/kg per day), or (c) LF 16-0687 Ms (36.0 mg/kg per day) given repetitively s.c. over 3 days. The neurological recovery was examined daily. The infarct volume was assessed histologically 7 days after ischemia. Study II: brain swelling and bilateral hemispheric water content were determined at 48 h post ischemia in eight rats, subjected to the low dose regimen as described above, and in eight vehicle-treated control animals. All treated animals showed tendency to exhibit improved neurological recovery throughout the observation period as compared to the vehicle-treated controls, while this improvement was only significant within the low dose group from postischemic days 3 to 4. Low dose LF 16-0687 Ms significantly attenuated the total and cortical infarct volume by 50 and 80%, respectively. Furthermore, postischemic swelling (-62%) and increase in water content of the infarcted brain hemisphere (-60.5%) was significantly inhibited. The present findings provide strong evidence for an involvement of bradykinin-mediated secondary brain damage following from focal cerebral ischemia. Accordingly, specific inhibition of bradykinin B(2) receptors by LF 16-0687 Ms attenuated postischemic brain swelling, improved the functional neurological recovery, and limited ischemic tissue damage, raising its potential for clinical evaluation in patients with acute stroke.

Animals↗
PubMed2002

Anesthetic methods in rats determine outcome after experimental focal cerebral ischemia: mechanical ventilation is required to obtain controlled experimental conditions.

OBJECTIVE: Anesthetic agents, pH, blood gases and blood pressure have all been found to influence the pathophysiology of experimental stroke. In experimental research, rats are predominantly used to investigate the effects of focal cerebral ischemia. Chloral hydrate, applied intraperitoneally (i.p.), and halothane, applied via face-mask in spontaneously breathing animals or via endotracheal tube in mechanically ventilated animals are popular methods of anesthesia. We investigated the potential of these anesthetic methods to maintain physiologic conditions during focal cerebral ischemia and their influence on postischemic mortality and histological outcome. METHODS: Thirty male Sprague-Dawley rats were subjected to 90 min of middle cerebral artery occlusion by insertion of an intraluminal thread and assigned to one of three groups (n=10 each): (A) chloral hydrate i.p./spontaneously breathing; (B) halothane in 70:30 (%) N2O/O2 via face-mask/spontaneously breathing; and (C) halothane in 70:30 (%) N2O/O2 via endotracheal tube/mechanically ventilated. Physiologic parameters were measured before, during, and after ischemia. Infarct volume was histologically assessed after 7 days. RESULTS: All anesthetic techniques except mechanical ventilation via an endotracheal tube resulted in considerably fluctuating blood gases levels, hypercapnia, acidosis and low blood pressure. All spontaneously breathing animals (groups A and B) exhibited a higher postischemic mortality and significantly larger infarct volumes than group C with intubated and ventilated animals. CONCLUSIONS: Intra- and postischemic physiologic parameters such as blood pressure, pH, and blood gases critically determine outcome after focal cerebral ischemia. Although anesthesia by halothane via face-mask allowed better control of depth of anesthesia than chloral hydrate, we have found this method to be unsatisfactory due to insufficient control of ventilation and waste of anesthetic gases. Experiments with rats requiring normal physiologic parameters should be performed under conditions of controlled mechanical ventilation and sufficient analgesia.

Acidosis, Respiratory↗
PubMed2001

Role of bradykinin B2 receptors in the formation of vasogenic brain edema in rats.

Bradykinin is a mediator of brain edema acting through B2 receptors. However, it is not known if bradykinin mediates the formation of cytotoxic or vasogenic brain swelling. To investigate this question we subjected rats to a cryogenic brain lesion over the left parietal cortex, a model well known to produce predominantly vasogenic brain edema. We inhibited bradykinin B2 receptors with the recently characterized nonpeptide B2 receptor antagonist, LF 16-0687. The animals were assigned to three groups (n = 10, each) receiving 10, or 100 microg/kg/min LF 16-0687 or vehicle (0.9% NaCl). Treatment started 15 min before trauma and was continued for 24 h. Another three groups of animals (n = 10, each) received 10 microg/kg/min LF 16-0687 starting 30 or 60 min after trauma or vehicle (0.9% NaCl) for 24 h. Animals were then sacrificed and swelling and water content of the brain were determined. In the vehicle treated group the traumatized hemisphere swelled by 9.3 +/- 1.1% as compared to the untraumatized contralateral side. Pretreatment with 10 microg/kg/min LF 16-0687 decreased brain swelling significantly to 6.4 +/- 1.3% (p < 0.05). Pre-treatment with 100 microg/kg/min was found to be less effective and did not result in a significant reduction of brain swelling (7.4 + 1.3%). Treatment with LF 16-0687 for 24 h (10 microg/kg/min) started 30 or 60 min after trauma did not reduce brain water content or hemispheric swelling. These results demonstrate that brain injury-mediated bradykinin production induces vasogenic brain edema by B2 receptor stimulation. Our findings further clarify the role of bradykinin in the pathophysiology of brain edema formation and confirm the therapeutic potency of bradykinin B2 receptor inhibition.

Algorithms↗
PubMed2001

Role of nitric oxide in the secondary expansion of a cortical brain lesion from cold injury.

We have investigated the role of nitric oxide (NO) as mediator of the secondary growth of a traumatic cortical necrosis. For this purpose, a highly standardized focal lesion of the brain was induced in 46 Sprague-Dawley rats by cold injury. Twenty-four hours later--the timepoint of maximal lesion spread--the animals were sacrificed and brains were removed for histomorphometry of the maximal necrosis area and volume. The animals were divided into five experimental groups. Group I received the NO donor L-arginine as i.v. bolus 10 min prior to trauma (300 mg/kg body weight; n = 10) and a second bolus of the same dosage intraperitoneally 1 h after trauma. Group II (n = 10)--serving as control of group I--was infused with an i.v. bolus of 1 mL/kg isotonic saline 10 min prior to and a subsequent bolus i.p. 1 h after trauma. Group III (n = 8) received 100 mg/kg b.w. of the inducible NOS (iNOS) inhibitor aminoguanidine (AG) 1 h before and 8 h after trauma by intraperitoneal route. Group IV was administered with the nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine (L-NNA; 100 mg/kg b.w., i.p.; n = 8); group V--the controls of group III and IV--was administered with isotonic saline (1 mL/kg b.w. i.p.; n = 10) 1 h before and 8 h after trauma. In the control group with i.v./i.p. sham treatment (II), the focal lesion led to a cortical necrosis with a maximum area of 3.1 +/- 0.3 mm2 and a lesion volume of 5.7 +/- 0.5 mm3 at 24 h after trauma. In animals with administration of L-arginine, the focal lesion had a maximum area of 3.1 +/- 0.3 mm2 and a volume of 5.3 +/- 0.5 mm3. Hence, the NO donor did not affect the secondary growth of necrosis. Animals with i.p. sham treatment (group V) had a maximal lesion area of 3.6 +/- 0.2 mm2 and lesion volume of 6.2 +/- 0.4 mm3. Administration of aminoguanidine afforded significant attenuation of the lesion growth. Accordingly, the maximal area of necrosis spread only to 2.8 +/- 0.2 mm2 with a volume of 4.5 +/- 0.5 mm3, respectively, at 24 h after trauma (p < 0.01 vs group V). On the other hand, administration of L-NNA did not influence the maximal lesion area (3.7 +/- 0.2 mm2) or lesion volume (6.5 +/- 0.5 mm3) evolving at 24 h after trauma. Thus, neither the enhancement of the formation of NO by L-arginine nor gross inhibition of the synthesis of NO by L-NNA did affect the secondary spread of the necrosis from a focal trauma. The marked attenuation of the posttraumatic necrosis growth by the iNOS inhibitor aminoguanidine strongly indicates an important role of iNOS product in this phenomenon. These findings, thus, demonstrate that the expansion of a primary necrotic focal lesion is a secondary process which can be therapeutically inhibited. Thereby, the growth of a focal tissue necrosis from trauma is clearly identified as a manifestation of secondary brain damage. This information is deemed important for the better understanding of the pathophysiology of traumatic brain injury and for the targeted development of specific treatment modalities.

Animals↗
PubMed2000

Neurological impairment in rats after transient middle cerebral artery occlusion: a comparative study under various treatment paradigms.

The assessment of the functional outcome - in addition to the conventional endpoints as histomorphometry of the ischemic brain damage - for the evaluation of cerebroprotective therapies is increasingly recommended, although there is little consensus on appropriate procedures. We evaluated a battery of sensorimotor tasks in rats after transient middle cerebral artery occlusion (MCAO) to select those with the highest potential to discriminate between various degrees of neuronal damage. A total of 40 Sprague-Dawley rats were subjected to 90 min of MCAO and assigned to one of four treatment arms: (1) sham-operated controls, (2) vehicle-treated controls, (3) moderately effective neuroprotection by 2x100 mg/kg alpha-phenyl-N-tert-butyl nitrone (PBN), (4) highly effective neuroprotection by mild hypothermia (33 degrees C). Functional deficits were daily quantified using the beam balance task (1.5 cm, 2.5 cm diameter rectangular and 2.5 cm diameter cylindrical beam), the prehensile traction task, the rotarod, and a six-point neuro-score. Infarction of cerebral cortex and basal ganglia was assessed one week after ischemia. Treatment with PBN significantly reduced cortical infarction (-31%), while treatment with hypothermia resulted in a significantly smaller infarct volume of cortex (-94%) and basal ganglia (-27%). Beam balance, prehensile traction and rotarod failed to demonstrate any difference in motor performance. The six-point neuro-score showed a significant correlation with cortical infarction from day 2 and with total infarct volume from day 3. The smaller the reduction of infarct volume, the later the corresponding difference in neuro-score became apparent. Functional outcome after MCAO in rats can be assessed by a relatively simple measurement of neurological deficit. The slope of functional recovery is closely related with the degree of the morphological, particularly cortical damage. If expected treatment effects are small, an observation period of at least 3 days should be planned for the study design. The functional impairment from focal brain ischemia and its subsequent recovery could provide valuable information for future studies evaluating the neuroprotective potential of novel agents and procedures.

Animals↗
PubMed2000

Mechanisms of arachidonic acid induced glial swelling.

Accumulation of arachidonic acid (AA) in the brain during ischaemia may contribute to development of brain oedema. In this study we investigated the effect of selected drugs on AA-induced cytotoxic brain oedema in C6 glioma cells. Suspended C6 glioma cells were preincubated with drugs and AA (0.1 mM) was added. When no drug was administered cell volume increased immediately after the addition of AA with a maximum cell swelling of 13.1+/-1.9% at 15 min (mean +/- S.E. M.). Preincubation of cells with BW 755C, a dual inhibitor of cyclo- and lipoxygenases, showed no reduction in cell swelling from AA, whereas superoxide dismutase, amiloride and the protein kinase inhibitor H-9370 led to a significant attenuation of volume increase (p<0.05). The role of Na(+) ions during cell swelling from AA was evaluated after pretreatment of C6 glioma cells with ouabain. This resulted in a reversal of cell swelling (p<0.01). We conclude that there is potential involvement of free radicals, signal transduction systems and intracellular accumulation of Na(+) ions in glial cell swelling from AA.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed2000

Effect of hypothermia on the volume of rat glial cells.

1. The cell volume of suspended C6 glioma cells and primary cultured rat astrocytes was measured at normothermia (37 degrees C), and at mild (32 degrees C) and moderate (27 degrees C) hypothermia by flow cytometry with electrical cell sizing. 2. Under control conditions (37 degrees C), C6 glioma cells had a volume of 809 +/- 29 microm3. Moderate hypothermia (27 degrees C) led to rapid cell swelling, with a maximum volume of 113.1 +/- 1.3 % of control being achieved after 50 min. After rewarming to 37 degrees C, cell volume recovered very slowly and incompletely (to 107.2 +/- 0.4 % of control). Less severe hypothermia (32 degrees C) led to a smaller increase in cell volume (108.7 +/- 0.5 % of control). 3. The maximal cell swelling response and the kinetics of swelling were similar in C6 glioma cells and primary cultured astrocytes. 4. Hypothermia-induced cell swelling was dependent on the presence of extracellular Na+ and was reduced by the Na+-H+ antiporter inhibitor EIPA. 5. The underlying mechanisms of hypothermia-induced cell swelling are an intracellular accumulation of Na+ by (1) differential effects of hypothermia on the membrane permeabilities of Na+ and K+ and (2) activation of the Na+-H+ antiporter by a shift of its activation curve to a more alkaline value.

Animals↗
PubMed2000

Intracranial hypertension influences the resolution of vasogenic brain edema following intracerebral hemorrhage.

Aim of the current study was to investigate the influence of intracranial hypertension on the resolution of vasogenic brain edema following intracerebral hemorrhage. An intracerebral hematoma was induced by 500 microliters of blood injected into the left frontal lobe of rabbits (n = 25). Na(+)-fluorescein (MW376) and Texas-Red-albumin (MW67.000) were administered intravenously as edema markers. By using a closed cranial window for superfusion of the brain surface and a ventriculo-cisternal perfusion the clearance of both fluorescence markers was measured in the CSF-effluates up to 8 hours using spectrophotometry. ICP was adjusted between 2-6 mmHg (low pressure, n = 10), 8-12 mmHg (moderate pressure, n = 10) or 14-20 mmHg (high pressure, n = 5). In all groups Na(+)-fluorescein started to accumulate at 60 min after induction of the hematoma in the subarachnoid space, while at 90 min in the ventricular system. In the low intracranial pressure group Na(+)-fluorescein (mean +/- SEM) in the ventricular system amounted to 1.47 +/- 0.42 nmol as compared to 1.34 +/- 0.41 nmol in the moderate, or 0.38 +/- 0.11 nmol in the high intracranial pressure group. In the subarachnoid space the marker reached 1.96 +/- 0.57 nmol, 4.15 +/- 1.28 nmol, or 0.96 +/- 0.32 nmol, respectively. In conclusion, the data demonstrate that vasogenic edema induced by an intracerebral hematoma is cleared into both CSF compartments, albeit with delay into the ventricular system. Edema resorption occurred earlier and to a higher extent into the subarachnoid space as compared to the ventricular system. Further, edema resorption is influenced by the actual intracranial pressure, with marked inhibition by a high intracranial pressure.

Animals↗
PubMed2000

Influence of hypothermia on cell volume and cytotoxic swelling of glial cells in vitro.

In view of the increasing significance of mild hypothermia (32 degrees C) as an efficient procedure of neuroprotection, the present study was performed to examine the influence of this level of hypothermia on the volume of glial cells under physiological as well as under pathological conditions. The influence of mild (32 degrees C) and moderate (27 degrees C) hypothermia on cell volume and cell viability of C6 glioma cells was studied for 60 minutes in vitro. Cells were suspended in an incubation chamber under continuous control of temperature, pH and pO2. Cell volume was measured by an advanced Coulter system. Hypothermia itself was causing significant cell swelling in a dose-dependent manner, which could be prevented by omission of Na(+)-ions from the suspension medium, while the replacement of Cl(-)-ions failed to prevent cell swelling from hypothermia. Inhibition of the Na+/H(+)-antiporter with EIPA (5N-ethyl-n-isopropyl-amiloride, 50 microM) was significantly reducing the hypothermia induced cell swelling, indicating activation of the Na+/H(+)-antiporter. Conversely, mild or moderate hypothermia failed to prevent cell swelling from lactic acid, arachidonic acid or glutamate, i.e. agents which are mediating the development of cytotoxic brain edema in vivo in cerebral trauma, ischemia and other acute insults. The findings indicate that cerebral protection by hypothermia in vivo is most likely not attributable to an inhibition of cytotoxic brain edema. Further investigations, however, are required in vivo and in vitro to elucidate the hypothermia-induced swelling of glial cells in more detail, e.g. as to the role of the Na+/H(+)-antiporter.

Brain Neoplasms↗
PubMed2000

LF16-0687 a novel non-peptide bradykinin B2 receptor antagonist reduces vasogenic brain edema from a focal lesion in rats.

Head injury world wide is still the most frequent cause of morbidity and mortality among the population under 45 years. Approximately 50% of patients dying from severe head injury have a therapy refractory intracranial pressure rise (Baethmann 1998). Traumatic brain edema, e.g. resulting from disruption of the blood-brain barrier is viewed as an important factor of the increased intracranial pressure. Bradykinin, an active peptide of the kallikrein-kinin system is considered to enhance brain edema formation which is attributed to its permeabilizing effect on the blood-brain barrier and on dilation of arterial blood vessels in the brain mediated by B2-receptors facilitating extravasation. Currently, LF16-0687, a novel non-peptide bradykinin B2 receptor antagonist was experimentally tested as to its therapeutical potential on vasogenic brain edema from a cortical focal lesion. Following trephination of the skull in anaesthesia, male Sprague-Dawley rats were subjected to a focal cold injury of the left parietal cortex. Animals of two experimental groups were receiving either LF16-0687 as high or low dose, whereas one group of untreated animals with trauma was treated with 0.9% NaCl as continuous infusion beginning 10 min before until 24 h after lesion. 24 h after trauma the brain was removed from the skull, and the cerebral hemispheres were separated in the median plane for gravimetric assessment of hemispheric swelling. No significant reduction of hemispheric brain swelling (+7.4 +/- 2.9%) was found in animals receiving high-dose LF16-0687 as compared to the untreated controls. Brain swelling, however was significantly attenuated by the low-dose treatment, i.e. to +6.4 +/- 1.3%; vs. +9.3 +/- 1.1% found in the controls, (p < 0.05). The current data confirm that blocking of bradykinin B2-receptors by LF16-0687 is significantly attenuating vasogenic brain edema from a focal cold lesion. The therapeutical properties of the antagonist on brain edema formation cannot be attributed to a lowering of the blood pressure. Rather, specific blocking effects of B2-receptors in the brain appear to be involved. In conclusion, the understanding of secondary brain damage including brain edema in head injury has been markedly enhanced by the discovery of pathophysiologically active mediator compounds playing a role in its various manifestations. The current data confirm a pathophysiological function of bradykinin in vasogenic brain edema mediated by activation of B2-receptors. Currently it is studied whether LF16-0687 also reduces brain swelling when given after an insult.

Animals↗