CP-0597, a selective bradykinin B2 receptor antagonist, inhibits brain injury in a rat model of reversible middle cerebral artery occlusion.

Abstract

BACKGROUND AND PURPOSE:

Recent studies demonstrated a significant neuroprotective action of the selective peptide-based bradykinin B2 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 After 1 hour the filament was retracted and the ischemic tissue reperfused.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-micron 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 < 0.001), total infarct volume (vehicle, 206.5 +/- 7.7 mm3 versus CP-0597, 94.0 +/- 19.2 mm3; P < .001), cortical infarct volume (vehicle, 145.5 +/- 4.5 mm3 versus CP-0597, 64.0 +/- 15.1 mm3; P < .001), subcortical infarct volume (vehicle, 55.8 +/- 4.1 mm3 versus CP-0597, 27.5 +/- 4.5 mm3; 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 bradykinin B2 receptor antagonist in the treatment of stroke.

• Authors: J K Relton, V E Beckey, W L Hanson, E T Whalley
• Journal: Stroke (Stroke) Vol. 28 Issue 7 Pg. 1430-6 (Jul 1997) ISSN: 0039-2499 [Print] United States
• PMID: 9227696 (Publication Type: Journal Article)

Chemical References

• Bradykinin Receptor Antagonists
• CP 0597
• Oligopeptides
• Receptor, Bradykinin B2

Topics

• Animals
• Arterial Occlusive Diseases (drug therapy, metabolism)
• Behavior, Animal (drug effects)
• Body Temperature
• Body Weight
• Bradykinin Receptor Antagonists
• Brain (blood supply)
• Brain Chemistry (physiology)
• Brain Edema (drug therapy, metabolism)
• Brain Ischemia (drug therapy, metabolism)
• Cerebral Arteries
• Cerebrovascular Disorders (drug therapy, metabolism)
• Disease Models, Animal
• Male
• Oligopeptides (pharmacology)
• Rats
• Rats, Wistar
• Receptor, Bradykinin B2
• Reperfusion Injury (drug therapy, metabolism)