CP-0597, a selective bradykinin B-2 receptor antagonist, inhibits brain injury in a rat model of reversible middle cerebral artery occlusion

Background and Purpose Recent studies demonstrated a significant neuroprotective action of the selective peptide-based bradykinin B-2 receptor antagonist CP-0597 after permanent middle cerebral artery (MCA) occlusion (MCAO) in the rat. We therefore evaluated the efficacy of this compound after reversible MCAO in the rat. Methods Male Wistar rats underwent reversible MCAO by insertion of a nylon monofilament to the origin of the MCA. After 1 hour the filament was retracted and the ischemic tissue reperfused. Immediately after MCAO, primed miniosmotic pumps containing either vehicle or CP-0597 (300 ng/kg per minute) were implanted into the subcutaneous space (n=14 per group). Twenty-four hours after surgery, animals were killed and brains fixed, and 4-mu m sections were taken from five sequential tissue blocks labeled A through E and stained with hematoxylin and eosin. Clinical evaluation of rats was performed by neurological scoring and change in body weight. Results Treatment with CP-0597 significantly reduced percent increase in hemisphere size of the ischemic hemisphere in all brain sections (C section: vehicle, 40.6+/-4.3% versus CP-0597, 20.8+/-5.3%; P<.001), total infarct volume (vehicle, 206.5+/-7.7 mm(3) versus CP-0597, 94.0+/-19.2 mm(3); P<.001), cortical infarct volume (vehicle, 145.5+/-4.5 mm(3) versus CP-0597, 64.0+/-15.1 mm(3); P<.001), subcortical infarct volume (vehicle, 55.8+/-4.1 mm(3) versus CP-0597, 27.5+/-4.5 mm(3); P<.001), and the number of necrotic neurons (vehicle, 42.9+/-3.8 versus CP-0597, 23.6+/-4.7 per field; P<.01). Neurological score (vehicle, 2.78+/-0.36 versus CP-0597, 6.29+/-0.87; P<.01) and change in body weight (vehicle, -28.7+/-2.0 g versus CP-0597, -18.2+/-2.8 g; P<.01) were also significantly improved. Conclusions The present data demonstrate the significant overall efficacy profile of CP-0597 in a rat model of reversible MCAO and provide strong rationale for the use of such abradykinin B-2 receptor antagonist in the treatment of stroke.