anatibant and Brain-Edema

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Cerebral oedema, the accumulation of fluid within the brain, is believed to be an important contributor to the secondary brain damage that occurs following injury. The release of kinins is thought to be an important factor in the development of cerebral vasogenic oedema and the use of beta-2 receptor antagonists, which prevent the release of these kinins, have been proposed as a potential therapeutic intervention.. The objective was to assess the safety and effectiveness of beta-2 receptor antagonists for TBI.. We searched the Cochrane Injuries Group's specialised register, CENTRAL, MEDLINE, EMBASE, National Research Register, LILACs, Zetoc, Web of Knowledge and Current Controlled Trials. We also searched the internet and checked the reference lists of relevant papers to identify any further studies. The searches were conducted in March 2007.. Randomised controlled trials of beta-2 receptor antagonists versus placebo for TBI.. Two authors independently screened search results and assessed the full texts of potentially relevant studies for inclusion. Data were extracted and methodological quality was examined. Relative risks (RR) and 95% confidence intervals (CIs) were calculated and data were pooled using a fixed effect model.. Three studies were included, involving 178 participants. All three studies reported the effects of beta-2 receptor antagonists on mortality. The pooled RR for mortality was 0.63 (95% CI 0.36 to 1.10). Two studies measured disability, the RR of death or severe disability with beta-2 receptor antagonists was 0.81 (95% CI 0.59 to 1.09). Two studies measured the effect on intracranial pressure (ICP), although in only one did this finding reach statistical significance. There was no evidence for the presence of heterogeneity.. There is no reliable evidence that beta-2 receptor antagonists are effective in reducing mortality or disability after TBI. Further well conducted randomised controlled trials are required.

Topics: Acute Disease; Adrenergic beta-2 Receptor Antagonists; Brain Edema; Brain Injuries; Humans; Intracranial Pressure; Peptides; Quinolines; Randomized Controlled Trials as Topic

Brain edema following subarachnoid hemorrhage (SAH) is a result of impairment of cerebral autoregulation and breakdown of the blood-brain barrier. We investigated the role of bradykinin B2 receptors (BrdB2Rs) on brain edema formation after SAH.. In vivo and ex vivo animal study.. University research laboratory.. Male Sprague-Dawley rats.. Rats were subjected to an endovascular perforation of the circle of Willis and were randomly assigned to a) vehicle, b) immediate treatment (30 minutes before and 300 minutes post-SAH) or c) delayed treatment (30 and 300 minutes post-SAH) with the B2 receptor antagonist Anatibant (LF 16-0687 Ms), and d) sham surgery. BrdB2R, kininogen (Kng1), and kallikrein mRNA expression was determined 6 hours after SAH or sham surgery.. SAH resulted in a significant increase in brain water content (vehicle: 80.3% +/- 1.2% vs. sham: 79.1% +/- 0.2%, p < 0.01) after 24 hours. Blockade of BrdB2Rs before SAH significantly prevented brain edema formation (79.0% +/- 0.3%, p < 0.05) and significantly improved neurologic recovery. BrdB2Rs and Kng1 mRNA were significantly increased 6 hours post-SAH (BrdB2R: 216%; Kng1: 2729%; p < 0.02 vs. sham). Delayed treatment regimen failed to reduce brain water content and neurologic impairment.. Our results indicate that BrdB2Rs play a key role in the initial phase after SAH contributing to brain edema formation. Inhibition of B2 receptors in a posttreatment regimen did not influence brain edema formation. Delayed pathophysiologic processes after SAH seem to be independent of B2 receptors.

Topics: Animals; Bradykinin B2 Receptor Antagonists; Brain Edema; Cerebrovascular Circulation; Disease Models, Animal; Drug Administration Schedule; Intracranial Pressure; Laser-Doppler Flowmetry; Male; Quinolines; Rats; Rats, Sprague-Dawley; Recovery of Function; Subarachnoid Hemorrhage

LF 16-0687 Ms previously was reported to improve Neurological Severity Score (NSS) and decrease cerebral edema and prostaglandin E(2) (PGE(2)) release after closed head trauma (CHT) in rats. Here, we examined whether these beneficial effects of LF 16-0687 Ms are altered when CHT is accompanied by acute ethanol administration.. Six groups of rats (n = 8 per group) were examined during combination of the following experimental conditions: CHT versus sham operation, LF 16-0687 Ms 3 mg/kg subcutaneously versus saline, and ethanol 2 g/kg versus saline.. After CHT, brain water content decreased and NSS improved with ethanol + LF 16-0687 Ms as compared with values after saline or ethanol. PGE(2) release decreased with ethanol (147 +/- 59 pg/mg tissue) but not with ethanol + LF 16-0687 Ms (286 +/- 194 pg/mg tissue).. Ethanol does not affect the improvement of NSS and the decrease of cerebral edema seen with LF 16-0687 Ms after CHT, but does reverse the ability of LF 16-0687 Ms to minimize the increase of PGE(2) release. In intoxicated patients, bradykinin antagonist therapy may improve post-CHT outcome without altering PGE(2) release.

Topics: Alcoholic Intoxication; Animals; Bradykinin Receptor Antagonists; Brain; Brain Diseases; Brain Edema; Dinoprostone; Disease Models, Animal; Ethanol; Head Injuries, Closed; Neuropsychological Tests; Quinolines; Rats; Rats, Sprague-Dawley; Severity of Illness Index

1. Bradykinin promotes neuronal damage and brain edema through the activation of the B(2) receptor. The neuroprotective effect of LF 16-0687 Ms, a B(2) receptor antagonist, has been described when given prior to induction of transient focal cerebral ischemia in rat, but there are no data regarding the consequence of a treatment when given after injury. Therefore, in a murine model of transient middle cerebral artery occlusion (MCAO), we evaluated the effect of LF 16-0687 Ms given prior to and/or after the onset of ischemia on neurological deficit, infarct volume and inflammatory responses including cerebral edema, blood-brain barrier (BBB) disruption and neutrophil accumulation. 2. LF 16-0687 Ms (1, 2 and 4 mg kg(-1)) administered 0.5 h before and, 1.25 and 6 h after MCAO, decreased the infarct volume by a maximum of 33% and significantly improved the neurological recovery. 3. When given at 0.25 and 6.25 h after MCAO, LF 16-0687 Ms (1.5, 3 and 6 mg kg(-1)) decreased the infarct volume by a maximum of 25% and improved the neurological score. 4. Post-treatment with LF 16-0687 Ms (1.5 mg kg(-1)) significantly decreased brain edema (-28%), BBB disruption (-60%) and neutrophil accumulation (-65%) induced by ischemia. Physiological parameters were not modified by LF 16-0687 Ms. 5. These data emphasize the role of bradykinin B(2) receptor in the development of infarct lesion, neurological deficit and inflammatory responses resulting from transient focal cerebral ischemia. Therefore, B(2) receptor antagonist might represent a new therapeutic approach in the pharmacological treatment of stroke.

Topics: Animals; Blood Pressure; Blood-Brain Barrier; Bradykinin B2 Receptor Antagonists; Brain; Brain Edema; Brain Infarction; Brain Ischemia; Disease Models, Animal; Male; Mice; Neutrophil Infiltration; Quinolines

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.. 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.. 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%.. 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.

Topics: Animals; Bradykinin B2 Receptor Antagonists; Brain; Brain Edema; Brain Ischemia; Cerebral Infarction; Male; Nervous System; Organ Size; Quinolines; Rats; Rats, Sprague-Dawley

Bradykinin is an endogenous inflammatory agent that enhances vascular permeability and produces tissue edema. We investigated whether LF 16-0687 Ms, a potent nonpeptide antagonist of bradykinin type-2 (B(2)) receptor, was able to reduce brain swelling and to improve the recovery of neurological function following closed head trauma (CHT) in rats. In dose-effect studies, LF 16-0687 Ms doses of 0.75-4.5 mg/kg given 1 h after trauma significantly reduced the development of edema in the injured hemisphere by a maximum of 70%. It had no effect on the brain water content of sham-operated rats. LF 16-0687 Ms also significantly improved neurological recovery evaluated by a Neurological Severity Score (NSS) based on motor, reflex, and behavioral tests. In time-window studies LF 16-0687 Ms (2.25 mg/kg) was given 1, 2, 4, and 10 h after CHT. The extent of edema was significantly reduced when LF 16-0687 Ms was given 1 h (-45%), 2 h (-52%), and 4 h (-63%) but not 10 h (-24%) after CHT. Given at any time-point, LF 16-0687 Ms significantly improved the recovery of the NSS at 24 h. In duration of treatment studies, rats tended to recover normal neurological function over 14 days after CHT. However, time to recovery was longer in severely than in moderately injured animals, unless they were treated with LF 16-0687 Ms. This study provides further evidence that blockade of bradykinin B(2) receptors represents a potential effective approach to the treatment of focal cerebral contusions.

Topics: Animals; Bradykinin Receptor Antagonists; Brain Edema; Brain Injuries; Dose-Response Relationship, Drug; Head Injuries, Closed; Neuroprotective Agents; Quinolines; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B2; Recovery of Function; Time Factors; Trauma Severity Indices

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.

Topics: Animals; Bradykinin Receptor Antagonists; Brain; Brain Edema; Brain Ischemia; Disease Models, Animal; Male; Quinolines; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B2; Receptors, Bradykinin

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.

Topics: Algorithms; Animals; Blood Pressure; Body Water; Bradykinin Receptor Antagonists; Brain Edema; Cerebrovascular Circulation; Functional Laterality; Male; Organ Size; Quinolines; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B2; Receptors, Bradykinin

Giving LF 16-0687 Ms (a bradykinin B2 receptor antagonist) 1 hour after closed head trauma (CHT) previously was reported to decrease brain edema at 24 hours and improve neurologic severity score (NSS) at 7 days. It is not certain whether a greater benefit could be achieved by treatment sooner after CHT.. To examine the latter possibility we studied a surrogate condition for the earliest possible administration of LF 16-0687 Ms after CHT, e.g., we examined brain edema and NSS when LF 16-0687 Ms was given 15 min before CHT in rats.. LF 16-0687 Ms decreased brain water content (80.0 +/- 1.4%, mean +/- SD) at 24 hours and improved NSS (2 +/- 3, median +/- range) at 7 days after CHT in comparison to that with CHT + saline (82.9 +/- 1.3% and 8 +/- 4).. Similarity of the present results to those previously reported indicates that the benefit of giving LF 16-0687 Ms 1 hour after CHT appears to represent the maximal benefit afforded by this drug.

Topics: Analysis of Variance; Animals; Blood Pressure; Bradykinin Receptor Antagonists; Brain Edema; Head Injuries, Closed; Quinolines; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B2; Statistics, Nonparametric; Time Factors

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.. 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).. 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.

Topics: Analysis of Variance; Animals; Body Water; Bradykinin Receptor Antagonists; Brain Chemistry; Brain Edema; Brain Injuries; Glutamic Acid; Hypoxanthine; Injections, Subcutaneous; Kinins; Male; Neuroprotective Agents; Quinolines; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B2; Taurine; Xanthine

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

Topics: Animals; Blood-Brain Barrier; Bradykinin Receptor Antagonists; Brain Damage, Chronic; Brain Edema; Cerebral Cortex; Dose-Response Relationship, Drug; Male; Quinolines; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B2

Activation of the kallikrein-kinin system contributes to traumatic brain edema formation. Inhibition of bradykinin 2 (B2) receptors has been shown to successfully reduce brain edema formation. 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. Contusion was produced in forty rats by controlled cortical impact injury. Five minutes after trauma rats received a single dose of 0, 3, or 30 mg/kg of LF 16-0687Ms. After 24 hours brain swelling and hemispheric water content were determined. Brain swelling was significantly decreased by 25% in the low and 27% in the high dose group compared to controls (p < 0.03). Water content of the traumatized hemisphere tended to be decreased (80.2 +/- 0.1 vs. 80.4 +/- 0.1%) while water content of the non-traumatized hemispheres tended to be increased after administering LF 16.0687Ms (79.3 +/- 0.1 vs. 79.0 +/- 0.1%). Single administration of the novel nonpeptide B2 receptor antagonist LF 16-0687Ms significantly reduces brain swelling. The missing significant reduction in water content of the traumatized hemisphere, however, could be related to an unspecific increase in water content due to LF 16.0687Ms as suggested by increased water content in the non-traumatized hemisphere.

Topics: Animals; Blood Pressure; Bradykinin Receptor Antagonists; Brain Concussion; Brain Edema; Cerebral Cortex; Dose-Response Relationship, Drug; Male; Neuroprotective Agents; Quinolines; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B2

Bradykinin is an endogenous nonapeptide which potently dilates the cerebral vasculature and markedly increases vascular permeability. These effects are mediated by B2 receptors located on the vascular endothelium. Previous experimental studies have shown that blockade of the kallikreinkinin system, which mediates the formation of bradykinin, afforded a reduction of the brain edema that developed following a cryogenic cortical lesion. In the present study, we investigated the effect of LF 16-0687MS, a novel nonpeptide B2 receptor antagonist, on cerebral edema and neurological severity score (NSS) after closed head injury to rats. LF 16-0687MS or its vehicle (NaCl 0.9%) was continuously infused at 10, 30, and 100 microg/kg/min over 23 h starting 1 h after a focal trauma to the left hemisphere was induced using a weight-drop device. The extent of edema formation was evaluated 24 h after trauma from left and right hemispheres samples by measurement of specific gravity and water content. In a separate study, a neurological severity score based on scoring of behavioural and motor functions was evaluated 1 h and over 1 week after trauma. LF 16-0687MS at 100 microg/kg/min markedly reduced the development of brain edema as indicated by a 68% increase in specific gravity (p<0.05) and a 64% decrease of water content (p<0.05) in the left hemisphere. In addition the recovery of neurological function was significantly improved by 100 microg/kg/min LF 16-0687MS from day 3 to day 7 after CHT. In a separate experiment, we also showed that LF 16-0687MS at 100 microg/kg/min given either 1 h before or 30 min after CHT did not affect mean arterial blood pressure. These results show that blockade of bradykinin B2 receptors is an effective approach to reduce cerebral edema and to improve neurological outcome after a focal contusion to the cranium.

Topics: Animals; Blood Pressure; Bradykinin Receptor Antagonists; Brain Edema; Head Injuries, Closed; Quinolines; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B2