目的 探讨同仁牛黄清心丸对血管性认知障碍模型大鼠脑组织保护作用及对核苷酸结合寡聚化结构域样受体蛋白3（NLRP3）/半胱氨酸蛋白酶-1（Caspase-1）/白细胞介素-1β（IL-1β）信号通路调控的机制研究。方法 采用结扎双侧颈总动脉建立血管性认知障碍大鼠模型。大鼠随机分为假手术组、模型组、尼莫地平组、同仁牛黄清心丸（0.6、1.2、2.4 g/kg）组。苏木精-伊红（HE）染色检测模型大鼠大脑皮质及海马组织病理变化；镀银染色检测模型大鼠脑组织中神经原纤维缠结病理改变；免疫组化检测脑组织中β-淀粉样蛋白（Aβ）表达水平；ELISA检测脑组织中肿瘤坏死因子-α（TNF-α）的水平；Western blotting检测大鼠脑组织中NLRP3、Caspase1、IL-1β蛋白表达水平。结果 同仁牛黄清心丸能明显改善模型大鼠大脑皮质及海马神经元减少、神经元变性、坏死等病理损伤；同仁牛黄清心丸能明显改善模型大鼠脑组织中神经元排列散乱、神经原纤维增粗、银染加深等病理改变。与模型组比较，同仁牛黄清心丸各剂量组能明显降模型大鼠脑组织中Aβ、TNF-α、NLRP3、IL-1β表达水平（P＜0.05、0.01）；同仁牛黄清心丸0.6 g/kg组能明显下调模型大鼠脑组织中Caspase1蛋白表达（P＜0.01）。结论 同仁牛黄清心丸对血管性认知障碍造成的脑组织损伤具有较好的改善作用。其中抑制NLRP3/Caspase1/IL-1β信号通路活化，改善神经炎症反应可能是药物发挥治疗血管性认知障碍效应机制的关键环节。

Objective To explore the protective effect of Tongren Niuhuang Qingxin Pills on brain tissue of vascular cognitive impairment model rats, and the mechanism of its effect on NLRP3/Caspase1/IL-1β signaling pathway regulation. Methods Establishing a vascular cognitive impairment rat model by ligating bilateral common carotid arteries. The rats were randomly divided into sham operation group, model group, Tongren Niuhuang Qingxin Pills (0.6, 1.2, and 2.4 g/kg) groups. Pathological changes in the cerebral cortex and hippocampus of model rats were detected by HE staining detection, pathological changes of neurofibrillary tangles in the brain tissue of model rats were detected by silver staining. Immunohistochemical detection of Aβ expression levels in brain tissue, ELISA detection of TNF-α levels in brain tissue; Western blotting was used to detect the expression levels of NLRP3, Caspase1, and IL-1β proteins in rat brain tissue. Results Tongren Niuhuang Qingxin Pills could significantly improve pathological damage such as neuronal reduction, degeneration, and necrosis in the cerebral cortex and hippocampus of model rats, Tongren Niuhuang Qingxin Pills could significantly improve the pathological changes in the brain tissue of model rats, such as disordered arrangement of neurons, thickened nerve fibers, and deepened silver staining. Compared to the model group, Tongren Niuhuang Qingxin Pills (0.6, 1.2, and 2.4 g/kg) group could significantly reduce the expression level of Aβ, TNF-α, NLRP3, IL-1β in the brain tissue (P < 0.05, 0.01). Tongren Niuhuang Qingxin Pills 0.6 g/kg group could significantly downregulate the expression of Caspase1 protein in the brain tissue (P < 0.01). Conclusion Tongren Niuhuangqingxin Pills had a good effect on brain tissue injury caused by vascular cognitive impairment. Among them, inhibiting the activation of the NLRP3/Caspase1/IL-1β signaling pathway to improve the neuroinflammatory response might be a key link in the drug's effect mechanism of treating vascular cognitive impairment.

R285.5;R286.1

北京市中医药科技发展资金项目（BJZYYB-2023-51）