Significant reduction in brain swelling by administration of nonpeptide kinin B2 receptor antagonist LF 16-0687Ms after controlled cortical impact injury in rats.
OBJECTIVE
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.
Stover
J F
JF
Department of Neurosurgery, Charité--Virchow Medical Center, Berlin, Germany. john.stover@charite.de
Dohse
N K
NK
Unterberg
A W
AW
D000704:Analysis of Variance; D000818:Animals; D001834:Body Water / Q000737:chemistry; D065168:Bradykinin Receptor Antagonists; D001923:Brain Chemistry; D001929:Brain Edema / Q000134:cerebrospinal fluid / Q000378:metabolism / Q000517:prevention & control*; D001930:Brain Injuries / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000378:metabolism; D018698:Glutamic Acid / Q000134:cerebrospinal fluid / Q000187:drug effects; D019271:Hypoxanthine / Q000134:cerebrospinal fluid; D007279:Injections, Subcutaneous; D007705:Kinins; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D011804:Quinolines / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043782:Receptor, Bradykinin B2; D013654:Taurine / Q000134:cerebrospinal fluid / Q000187:drug effects; D019820:Xanthine / Q000134:cerebrospinal fluid
D065168:Bradykinin Receptor Antagonists; D007705:Kinins; C403051:LF 16-0687; D018696:Neuroprotective Agents; D011804:Quinolines; D043782:Receptor, Bradykinin B2; D019820:Xanthine; D013654:Taurine; D019271:Hypoxanthine; D018698:Glutamic Acid