Significant reduction in brain swelling by administration of nonpeptide kinin B2 receptor antagonist LF 16-0687Ms after controlled cortical impact injury in rats.

OBJECT 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. METHODS 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). CONCLUSIONS 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.

[1]  A. Artru,et al.  Effect of LF 16-0687MS, a new nonpeptide bradykinin B2 receptor antagonist, in a rat model of closed head trauma. , 1999, Journal of neurotrauma.

[2]  D. Pruneau,et al.  Pharmacological profile of LF 16-0687, a new potent non-peptide bradykinin B2 receptor antagonist. , 1999, Immunopharmacology.

[3]  D. Newell,et al.  Effects of the bradykinin antagonist Bradycor (deltibant, CP-1027) in severe traumatic brain injury: results of a multi-center, randomized, placebo-controlled trial. American Brain Injury Consortium Study Group. , 1999, Journal of neurotrauma.

[4]  U W Thomale,et al.  Effect of cerebral perfusion pressure on contusion volume following impact injury. , 1999, Journal of neurosurgery.

[5]  J F Stover,et al.  Glutamate and taurine are increased in ventricular cerebrospinal fluid of severely brain-injured patients. , 1999, Journal of neurotrauma.

[6]  T. Wieloch,et al.  Novel pharmacologic strategies in the treatment of experimental traumatic brain injury: 1998. , 1998, Journal of neurotrauma.

[7]  A. Rizzi,et al.  Bradykinin receptors and their antagonists. , 1998, European journal of pharmacology.

[8]  J. Bernarding,et al.  Magnetic resonance imaging studies with cluster algorithm for characterization of brain edema after controlled cortical impact injury (CCII). , 1998, Acta neurochirurgica. Supplement.

[9]  P. Narotam,et al.  Traumatic Brain Contusions: A Clinical Role for the Kinin Antagonist CP-0127 , 1998, Acta Neurochirurgica.

[10]  J. Stover,et al.  Cerebrospinal fluid hypoxanthine, xanthine and uric acid levels may reflect glutamate-mediated excitotoxicity in different neurological diseases , 1997, Neuroscience Letters.

[11]  J. Relton,et al.  CP-0597, a selective bradykinin B2 receptor antagonist, inhibits brain injury in a rat model of reversible middle cerebral artery occlusion. , 1997, Stroke.

[12]  R. Dempsey,et al.  The biphasic opening of the blood–brain barrier in the cortex and hippocampus after traumatic brain injury in rats , 1997, Neuroscience Letters.

[13]  J. Urenjak,et al.  Altered glutamatergic transmission in neurological disorders: From high extracellular glutamate to excessive synaptic efficacy , 1997, Progress in Neurobiology.

[14]  A. Unterberg,et al.  Vasomotor and permeability effects of bradykinin in the cerebral microcirculation. , 1996, Immunopharmacology.

[15]  K. Bhoola,et al.  Visualisation of bradykinin B2 receptors on human brain neurons. , 1996, Immunopharmacology.

[16]  S. Jeftinija,et al.  Neuroligand‐Evoked Calcium‐Dependent Release of Excitatory Amino Acids from Cultured Astrocytes , 1996, Journal of neurochemistry.

[17]  T A Gennarelli,et al.  Neuropathological sequelae of traumatic brain injury: relationship to neurochemical and biomechanical mechanisms. , 1996, Laboratory investigation; a journal of technical methods and pathology.

[18]  P. Kochanek,et al.  Severe controlled cortical impact in rats: assessment of cerebral edema, blood flow, and contusion volume. , 1995, Journal of neurotrauma.

[19]  E. Hall,et al.  Therapeutic potential of the lazaroids (21-aminosteroids) in acute central nervous system trauma, ischemia and subarachnoid hemorrhage. , 1994, Advances in pharmacology.

[20]  O. Kempski,et al.  Growth kinetics of a primary brain tissue necrosis from a focal lesion. , 1994, Acta neurochirurgica. Supplementum.

[21]  Y. Katayama,et al.  The Role of Bradykinin in Mediating Ischemic Brain Edema in Rats , 1993, Stroke.

[22]  L. Hösli,et al.  Autoradiographic localization of binding sites for neuropeptide Y and bradykinin on astrocytes. , 1993, Neuroreport.

[23]  R. M. Hays,et al.  ADH-induced depolymerization of F-actin in the toad bladder granular cell: a confocal microscope study. , 1992, The American journal of physiology.

[24]  K. Bhoola,et al.  Bioregulation of kinins: kallikreins, kininogens, and kininases. , 1992, Pharmacological reviews.

[25]  R. Vannucci,et al.  Cerebral energy metabolism during hypoxia-ischemia and early recovery in immature rats. , 1992, The American journal of physiology.

[26]  G. Schneider,et al.  Mechanisms of glial swelling induced by glutamate. , 1992, Canadian journal of physiology and pharmacology.

[27]  S. Oja,et al.  Excitatory amino acids evoke taurine release from cerebral cortex slices from adult and developing mice , 1991, Neuroscience.

[28]  S. Harik,et al.  Bradykinin Receptors of Cerebral Microvessels Stimulate Phosphoinositide Turnover , 1991, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[29]  D. Hovda,et al.  Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury. , 1990, Journal of neurosurgery.

[30]  U. Ungerstedt,et al.  Changes in Cortical Extracellular Levels of Energy-Related Metabolites and Amino Acids following Concussive Brain Injury in Rats , 1990, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[31]  A. Schousboe,et al.  Volume‐sensitive release of taurine from cultured astrocytes: Properties and mechanism , 1990, Glia.

[32]  E. Ellis,et al.  Brain kininogen following experimental brain injury: evidence for a secondary event. , 1989, Journal of neurosurgery.

[33]  K. Maier-Hauff,et al.  Release of glutamate and of free fatty acids in vasogenic brain edema. , 1989, Journal of neurosurgery.

[34]  A. Unterberg,et al.  Mediators of Blood-Brain Barrier Dysfunction and Formation of Vasogenic Brain Edema , 1988, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[35]  R. Harkness.  Hypoxanthine, xanthine and uridine in body fluids, indicators of ATP depletion. , 1988, Journal of chromatography.

[36]  J. Kornhuber,et al.  Positive correlation between contamination by blood and amino acid levels in cerebrospinal fluid of the rat , 1986, Neuroscience Letters.

[37]  A. Unterberg,et al.  The kallikrein-kinin system as mediator in vasogenic brain edema. Part 3: Inhibition of the kallikrein-kinin system in traumatic brain swelling. , 1986, Journal of neurosurgery.

[38]  E. Ellis,et al.  Evidence for a possible role of the brain kallikrein-kinin system in the modulation of the cerebral circulation. , 1985, Circulation research.

[39]  A. Unterberg,et al.  Effects of Bradykinin on Permeability and Diameter of Pial Vessels In vivo , 1984, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[40]  A. Unterberg,et al.  The kallikrein-kinin system as mediator in vasogenic brain edema. Part 1: Cerebral exposure to bradykinin and plasma. , 1984, Journal of neurosurgery.

[41]  R. Spector,et al.  Nucleoside and Oxypurine Homeostasis in Adult Rabbit Cerebrospinal Fluid and Plasma , 1984, Journal of neurochemistry.

[42]  L. Edvinsson,et al.  Effects of Bradykinin on Pial Arteries and Arterioles in vitro and in situ , 1983, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[43]  Y. Tsuda,et al.  The disappearance rate of intraventricular bradykinin in the brain of the conscious rat. , 1982, Biochemical and biophysical research communications.

[44]  M. Schachter.  Kallikreins (kininogenases)--a group of serine proteases with bioregulatory actions. , 1979, Pharmacological reviews.

[45]  F. Graeff,et al.  Behavioural and somatic effects of bradykinin injected into the cerebral ventricles of unanaesthetized rabbits , 1969, British journal of pharmacology.