Relton J K, Beckey V E, Hanson W L, Whalley E T
Cortech Inc., Denver, Colo. 80221, USA.
Stroke. 1997 Jul;28(7):1430-6. doi: 10.1161/01.str.28.7.1430.
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.
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 After 1 hour the filament was retracted and the ischemic tissue reperfused.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.
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.
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.
近期研究表明，基于肽的选择性缓激肽B2受体拮抗剂CP - 0597在大鼠大脑中动脉永久性闭塞（MCAO）后具有显著的神经保护作用。因此，我们评估了该化合物在大鼠可逆性MCAO后的疗效。
雄性Wistar大鼠通过将尼龙单丝插入大脑中动脉起始部进行可逆性MCAO。1小时后抽出单丝，使缺血组织再灌注。MCAO后立即将含有赋形剂或CP - 0597（每分钟300 ng/kg）的预充式微量渗透泵植入皮下空间（每组n = 14）。术后24小时处死动物，固定大脑，从标记为A至E的五个连续组织块中切取4微米切片，并用苏木精和伊红染色。通过神经功能评分和体重变化对大鼠进行临床评估。
CP - 0597治疗显著降低了所有脑切片中缺血半球半球大小的增加百分比（C切片：赋形剂组，40.6±4.3% vs CP - 0597组，20.8±5.3%；P < 0.001）、总梗死体积（赋形剂组，206.5±7.7 mm³ vs CP - 0597组，94.0±19.2 mm³；P <.001）、皮质梗死体积（赋形剂组，145.5±4.5 mm³ vs CP - 0597组，64.0±15.1 mm³；P <.001）、皮质下梗死体积（赋形剂组，55.8±4.1 mm³ vs CP - 0597组，27.5±4.5 mm³；P <.001）以及坏死神经元数量（赋形剂组每视野42.9±3.8个 vs CP - 0597组，23.6±4.7个；P <.01）。神经功能评分（赋形剂组，2.78±0.36 vs CP - 0597组，6.29±0.87；P <.01）和体重变化（赋形剂组， - 28.7±2.0 g vs CP - 0597组， - 18.2±2.8 g；P <.01）也得到显著改善。
目前的数据表明CP - 0597在大鼠可逆性MCAO模型中具有显著的总体疗效，为使用此类缓激肽B2受体拮抗剂治疗中风提供了有力依据。
