Significant reduction in brain swelling by administration of nonpeptide kinin B-2 receptor antagonist LF 16-0687Ms after controlled cortical impact injury in rats
Jf. Stover et al., Significant reduction in brain swelling by administration of nonpeptide kinin B-2 receptor antagonist LF 16-0687Ms after controlled cortical impact injury in rats, J NEUROSURG, 92(5), 2000, pp. 853-859
Object. Identification of new therapeutic agents aimed at attenuating postt
raumatic brain edema formation remains an unresolved challenge. Among other
s, activation of bradykinin B-2 receptors is known to mediate the formation
of brain edema. The purpose of this study was to investigate the protectiv
e effect of the novel nonpeptide B-2 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) samp
les were collected to determine whether changes in substances associated wi
th edema formation could clarify why LF 16-0687Ms increases water content.
For this, the volume regulator amino acid taurine, the excitatory transmitt
er glutamate, and the adenosine triphosphate degradation products hypoxanth
ine and xanthine were measured. In CSF, the levels of taurine, hypoxanthine
, and xanthine were significantly decreased following a single administrati
on 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 posttraum
atic brain edema, whereas the increased level of glutamate could account fo
r the elevated water content observed in the nontraumatized hemisphere.