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目的:探讨大黄苷元联合不同时间窗溶栓治疗对脑缺血大鼠神经细胞凋亡的阻抑作用及其对相关调控基因蛋白表达的影响。方法:大鼠随机分为假手术组、模型组、尿激酶溶栓组(简称溶栓组)、大黄苷元组和联合组(大黄苷元+尿激酶组)。大鼠自体血栓结合线栓阻塞大脑中动脉制备血栓栓塞性脑缺血动物模型。大鼠分别于缺血后3,6,9 h经导管由颈内动脉用尿激酶进行溶栓。动脉给尿激酶后24 h,观察大鼠脑组织病理改变;免疫组织化学法检测神经细胞凋亡和凋亡相关基因蛋白Bax,caspase-3和Bcl-2表达。结果:各模型组大鼠病理改变明显,TUNEL细胞增多、Bax和caspase-3表达增强、Bcl-2表达下调;各用药组较模型组TUNEL细胞减少,6 h和9 h组Bax和caspase-3表达减弱、6 h组Bcl-2表达上调;各组9 h分别较其3h的TUNE细胞数增加、Bax增强、Bcl-2减弱;联合组分别较单一用药各时间组TUNEL细胞数减少、6 h和9 h组Bax及caspase-3表达减弱、Bcl-2表达上调。结论:脑缺血可使促凋亡基因Bax表达上调和抑凋亡基因Bcl-2下调,引起神经细胞凋亡,且随缺血时间延长而明显。大黄苷元及尿激酶溶栓可下调Bax,caspase-3,上调Bcl-2表达,对脑缺血神经细胞凋亡有阻抑作用,以二者联合用药的效果尤为理想。
Objective: To investigate the inhibitory effect of rhubarb aglycone combined with different time window thrombolytic therapy on neuronal apoptosis in rats with cerebral ischemia and its effect on the expression of related regulatory gene proteins. METHODS: Rats were randomly divided into sham operation group, model group, urokinase thrombolysis group (abbreviated as thrombolysis group), rhubarb aglycone group, and combination group (rhinosin glycoside + urokinase group). Rat thromboembolic cerebral ischemia model was established by blocking the middle cerebral artery with a thrombus-combined suture in rats. Rats were thrombolysed from the internal carotid artery with urokinase via a catheter at 3, 6, and 9 h after ischemia. 24 hours after arterial administration of urokinase, pathological changes of rat brain were observed. The expression of apoptosis-related gene proteins Bax, caspase-3 and Bcl-2 was detected by immunohistochemistry. RESULTS: The pathological changes of rats in each model group were obvious, TUNEL cells increased, Bax and caspase-3 expressions increased, and Bcl-2 expression was down-regulated. Each drug group had less TUNEL cells than the model group, and Bax and caspase-3 at 6 and 9 hours. The expression of Bcl-2 was down-regulated after 6 h, and the number of TUNE cells increased, Bax increased, and Bcl-2 decreased in each group at 9 h, respectively. The number of TUNEL cells in the combined group was lower than that of the single administration group, 6 h. The expression of Bax and caspase-3 was down-regulated and Bcl-2 was up-regulated after 9 h. Conclusion: Cerebral ischemia can up-regulate the expression of pro-apoptosis gene Bax and down-regulate anti-apoptosis gene Bcl-2, which induces apoptosis of neurons and is evident with the prolongation of ischemic time. Rhubarb aglycone and urokinase thrombolysis can down-regulate Bax, caspase-3 and up-regulate the expression of Bcl-2, which can inhibit the apoptosis of neurons in cerebral ischemia. The combination of rhubarb aglycone and urokinase is particularly effective.