厄贝沙坦对局灶脑缺血作用的实验研究

EFFECT OF IRBESARTAN ON FOCAL CEREBRAL ISCHEMIA IN RATS

目的:研究1型血管紧张素Ⅱ受体阻滞剂厄贝沙坦对局灶性脑缺血的神经保护作用及其可能的细胞机制。方法:在激光多谱勒脑血流监测仪对局部脑血流的监测下,应用线栓法建立大鼠大脑中动脉阻塞模型。药物经侧脑室内微泵持续灌注雄性正常血压大鼠,术后行神经功能评分,测定梗死体积,并运用免疫组化染色观察活性Cas-pase-3及其下游多聚ADP-核糖聚合酶(PARP)p85裂解片断的改变,结合TUNEL,比较各组细胞凋亡情况。结果:厄贝沙坦明显改善大鼠的神经功能评分,第7 d的梗死体积较对照组减少了42%,用药后缺血区的TUNEL阳性细胞数,荧光标记的活性Caspase-3以及PARP p85裂解片断表达均明显减少。结论:厄贝沙坦可改善局灶脑缺血的神经功能,抑制细胞凋亡可能是其神经保护机制之一。

Aim： To investigate whether the selective AT1 receptor antagonist irbesartan exerts aneuroprotective effect on focal cerebral ischemia in normotensive rats. Methods： Cerebral ischemia was induced by middle cerebral artery occlusion （MCAO） for 90 min followed by reperfusion, with the monitoring of laser Doppler flowmetry. To avoid the interaction with peripheral AT1 receptors, irbesartan was infused intracerebroventricularly （ICV） at a dose which effectively inhibited brain- but not vascular AT1 receptors. Neurological status was evaluated daily after MCAO. Rats were killed and brain samples were collected for the measurement of infarct size and immunohistochemical evaluation of apoptosis by deoxynucleotidyltransferase-mediated biotinylated UTP nick end labeling （TUNEL） and expression of activated Caspase-3 and the cleavage fragment of poly （ADP-ribose） polymerase （PARP）. Results： Treatment with irbesartan improved significantly the neurobehavioral functions after cerebral ischemia. The infarct size was reduced about 42 % on day 7 after MCAO （P 〈 0.05）. Meanwhile, irbesartan treatment significantly decreased the number of TUNEL-positire cells in the penumbra. The expression of activated Caspase-3 and the downstream cleavage fragment of poly（ADP-ribose） polymerase in the penumbra were also inhibited by irbesartan therapy on day 3 after transient cerebral ischemia. Conclusion： Angiotensin AT1 receptor antagonist exhibits neuroprotection against transient cerebral ischemia in the brain. The neuroprotective effects in ischemic tissue may be associated with its inhibition of apoptotic cell death in the penumbra.