anatibant and Disease-Models--Animal

Phospholipase A

Topics: Acetophenones; Adult; Aged; Animals; Animals, Newborn; Astrocytes; Benzopyrans; Bradykinin; Bradykinin B2 Receptor Antagonists; Brain; Brain Injuries, Traumatic; Disease Models, Animal; Enzyme Inhibitors; Epilepsy; Female; Humans; Inflammation; Male; Middle Aged; Phospholipases A2, Cytosolic; Quinolines; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B2; Up-Regulation; Young Adult

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

Kinin B1 and B2 receptor (R) gene expression (mRNA) is increased in the sensory system after peripheral nerve injury. This study measured the densities of B1R and B2R binding sites in the spinal cord and dorsal root ganglia (DRG) by quantitative autoradiography, and evaluated the effects of two selective non-peptide antagonists at B1R (LF22-0542) and B2R (LF16-0687) on pain behavior after partial ligation of the left sciatic nerve. Increases of B1R binding sites were seen in superficial laminae of the ipsi- and contralateral spinal cord at 2 and 14 days while B2R binding sites were increased on the ipsilateral side at 2 days and on both sides at 14 days. In DRG, B1R and B2R binding sites were significantly increased at 2 days (ipsilateral) and 14 days on both sides. Whereas tactile allodynia started to develop progressively from 2 to 25 days post-ligation, the occurrence of cold allodynia and thermal hyperalgesia became significant from day 8 and day 14 post-ligation, respectively. At day 21 after sciatic nerve ligation, thermal hyperalgesia was blocked by LF22-0542 (10 mg/kg, s.c.) and LF16-0687 (3 mg/kg, s.c.), yet both antagonists had no effect on tactile and cold allodynia. Data highlight the implication of both kinin receptors in thermal hyperalgesia but not in tactile and cold allodynia associated with peripheral nerve injury. Hence LF22-0542 and LF16-0687 present therapeutic potential for the treatment of some aspects of neuropathic pain.

Topics: Acrylamides; Animals; Binding Sites; Disease Models, Animal; Fumarates; Hyperalgesia; Male; Quinolines; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B1; Receptor, Bradykinin B2

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.

Topics: Analysis of Variance; Animals; Brain Ischemia; Cerebral Infarction; Cerebrovascular Circulation; Disease Models, Animal; Dose-Response Relationship, Drug; Laser-Doppler Flowmetry; Male; Neuroprotective Agents; Quinolines; Rats; Rats, Sprague-Dawley; Recovery of Function; Time Factors; Treatment Outcome

Bradykinin (B) contributes to secondary brain injury. This injury is mediated in part by prostaglandin (PG). Antagonism of B(2) receptors improves neurological status after brain injury, but the effect of B(2) antagonism on brain tissue PG is unknown. This study examined the effect of LF 16-0687 Ms, a new B(2) receptor antagonist, on brain tissue PGE(2) after closed head trauma (CHT).. Rats were anesthetized and received sham+saline, sham+LF 16-0687 Ms, CHT+saline, or CHT+LF 16-0687 Ms. Brain tissue samples were obtained at 24 h for determination of PGE(2) (after 2 h of ex vivo incubation) and water content. Neurological severity score (NSS) was assessed at 1 and 24 h.. In the group receiving CHT+LF 16-0687 Ms, brain tissue PGE(2) (77.7+/-65.9 pg/mg tissue, mean+/-SD) was less than in the group receiving CHT+saline (368.1+/-186.2 pg/mg tissue) and not different than sham+saline (78.7+/-30.7 pg/mg tissue). LF 16-0687 Ms also improved NSS and decreased brain water content by 51%.. We conclude that the beneficial effect of LF 16-0687 Ms on outcome after CHT is accompanied by blockade of PGE(2) increase in injured brain tissue.

Topics: Animals; Bradykinin Receptor Antagonists; Brain; Culture Techniques; Dinoprostone; Disease Models, Animal; Head Injuries, Closed; Intracranial Pressure; Male; Multivariate Analysis; Probability; Quinolines; Random Allocation; Rats; Rats, Sprague-Dawley; Reference Values; Statistics, Nonparametric

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

Inhibition of the bradykinin B2 receptor type (B2R) has been shown to improve neurological outcome in models of focal traumatic brain injury. However, the involvement of B2R in trauma-induced diffuse injury has not yet been explored. This is an important point, since in humans a pattern of diffuse injury is commonly found in severely injured patients and has been associated with a poor neurological outcome and prognosis. Using the non-peptide B2R antagonist LF 16-0687 Ms and B2R null (B2R-/-) mice, we investigated the role of B2R in a model of closed head trauma (CHT). LF 16-0687 Ms given 30 min after injury reduced the neurological deficit by 26% and the cerebral edema by 22% when evaluated 4 h after CHT. Neurological function after CHT was improved in B2R-/- mice compared to B2R+/+ mice, although there was no difference in the development of brain edema. Treatment with LF 16-0687 Ms and B(2)R gene deletion decreased the accumulation of neutrophils at 24 h after CHT (50% and 36%, respectively). In addition, the inducible NO synthase (iNOS) mRNA level increased markedly, and this was reduced by LF 16-0687 Ms. Taken together, these data support a detrimental role of B2R in the development of the neurological deficit and of the inflammatory secondary damage resulting from diffuse traumatic brain injury. Therefore, blockade of bradykinin B2 receptors might represent an attractive therapeutic approach in the pharmacological treatment of traumatic brain injury.

Topics: Animals; Bradykinin B2 Receptor Antagonists; Brain Injuries; Disease Models, Animal; Gene Deletion; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Quinolines; Receptor, Bradykinin B2

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