目的 酸枣仁提取物经鼻、经口途径的体内、外入脑行为分析及镇静催眠作用比较。方法 建立Calu-3/BMEC和Caco-2/BMEC细胞模型，分别从体外模拟酸枣仁指标成分斯皮诺素经鼻黏膜和经胃肠道吸收入血、入脑过程；考察大鼠经鼻和ig给药，指标成分在体内的血浆和脑组织分布过程；进一步比较2种给药方式对酸枣仁提取物镇静、催眠作用的影响。结果 鼻腔的Calu-3、肠道的Caco-2和血脑屏障的BMEC细胞层对斯皮诺素的跨细胞转运都有阻滞作用，而且模拟体内的多细胞转运过程，进一步加强了阻滞作用；经鼻给药增加斯皮诺素的入血、入脑分布，其药时曲线下面积（area under curve，AUC_0～t）分别是ig给药的4.8倍（血浆）和5.1倍（脑组织）；与ig给药相比，鼻腔给药显著减少了模型小鼠的运动距离（P＜0.05），延长了静止时间和睡眠持续时间（P＜0.05）。结论 经鼻给药可通过直接、间接方式的多种入脑通路增加酸枣仁提取物入脑含量，并增强其镇静催眠作用。

Objective To analyze the behavior of Suanzaoren (Zizyphi Spinosae Semen) extract penetrating into brain in vivo and in vitro through intranasal and gavage administration, and compare the corresponding sedative-hypnotic effects. Methods Calu-3/BMEC and Caco-2/BMEC cell models were established to simulate the process of spinosin, an index component of Zizyphi Spinosae Semen extract, being absorbed into the bloodstream and brain through nasal mucosa and gastrointestinal tract in vitro, respectively. The distribution process of index component in the plasma and brain tissue of rats after intranasal and gavage administration was investigated. The effects of the two administration routes on the sedative and hypnotic action of Zizyphi Spinosae Semen extract were further compared. Results The cellular layers representing Calu-3 in the nasal cavity, Caco-2 in the intestinal tract and the BMEC in the blood-brain barrier all blocked the transcellular transport of spinosin. The multicellular transport process, which imitated in vivo physiological conditions, further strengthened the blocking effect. The distribution of spinosin in the blood and brain was increased when administered intranasally, and the area under curve (AUC_0～t) value was 4.8 times (plasma) and 5.1 times (brain tissue) higher than those of gavage administration, respectively. Compared with gavage administration, intranasal administration significantly reduced the movement distance (P < 0.05), prolonged the immobility time and sleep duration in the model mice (P < 0.05). Conclusion Intranasal administration could increase the brain uptake of Zizyphi Spinosae Semen extract through multiple brain entry pathways in a direct and indirect manner, and enhance its sedative and hypnotic effects.

R285.61

陕西省重点研发计划项目(2024SF-YBXM-486)