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.