冰片经鼻引药上行入脑与鼻黏膜黏液纤毛传输系统关系

Owing to the presence of blood-brain barrier, lots of medicines can not enter brain parenchyma by normal delivery way, which restrains their effect on brain diseases. The special pathway between nasal mucosa and brain make it possible for medicines to bypass blood-brain barrier and reach the brain. Our study showed that: borneol promoted nasal absorption of ligustrazine into brain. And its mechanism was connected with prolonging mucous cilia transmission time (MCT). Nasal administration did not increase systemic and brain side effects. Borneol did not cause inreversible damage of nasal mucous cilia on condition that its dosage was limited. In this research, the influence of borneol will be evaluated on concentration of ligustrazine nasal administrated in cerebrospinal fluid at different time point, MCT, Ciliary beat frequency, mucin expression level of goblet cells, concentration of Ca2+ and ATP in ciliated epithelial cells, and ultrastructure of nasal mucous membrane. In this way, the relationship between borneol promoting lingustrazine nasal administrated absorbed into brain and nasal membrane mucus cillia transmission system were investigated. According to the theory of "aromatic stimulant for resucscitation guiding medicine upward", the mechanism of borneol promoting lingustrazine absorbed by nasal membrane targeting brain was investigated. And this study will provide a powerful instrument for developing brain target adminstration system, broaden the application range of borneol, richen mordern connotation of the theory of "aromatic stimulant for resucscitation guiding medicine upward".

因血脑屏障的存在，许多药物经常规递药途径无法进入脑实质，限制了对脑部疾病的治疗；鼻黏膜和脑之间存在特殊通路，使药物经鼻入脑成为可能。研究发现：冰片能促进川芎嗪经鼻吸收迅速入脑，其机制与延长鼻黏膜黏液纤毛传送时间有关；经鼻腔给药不会额外增加药物的全身性和脑部不良反应；在严格控制用量和时间的情况下，冰片不会对鼻黏膜纤毛造成不可逆的损害。本研究拟通过测定经鼻腔递送的川芎嗪在不同时间点进入脑脊液的药量、纤毛摆动频率、杯状细胞黏蛋白表达水平、纤毛上皮细胞内Ca2+和ATP浓度、鼻黏膜超微结构等指标变化，评估冰片对它们的影响，从多层次对冰片促进川芎嗪经鼻吸收入脑与鼻黏膜黏液纤毛传输系统关系进行探讨。根据开窍药"引药上行"理论，在现有研究基础上，探讨冰片促进川芎嗪经鼻黏膜吸收靶向脑部的机制，为开发脑靶向给药系统提供一种有力的工具，拓宽冰片的应用范围，丰富开窍药引药上行的现代内涵。

由于血脑屏障的存在，不少药物经常规给药途径不能进入脑实质，限制了对脑部疾病的治疗；鼻黏膜在解剖生理上与脑部存在着独特的联系，经鼻腔将药物递送入脑的可能性日渐引起人们的关注。.鼻黏膜黏液纤毛系统（MTS）通过纤毛有规律的摆动可以清除进入鼻腔的微小异物，同样进入鼻腔的药物也被视为异物予以清除。鼻黏膜清除药物和吸收药物是一对矛盾，清除增加则吸收减少，反之则吸收增加。影响MTS功能的因素主要为鼻黏膜黏液的黏滞度和纤毛摆动频率。.我们前期研究发现：与川芎嗪鼻腔喷雾剂相比，冰片和川芎嗪组成的鼻腔喷雾剂经鼻腔给药可以提高川芎嗪入脑的速度吸收率；进一步研究发现冰片对人鼻黏膜纤毛传输系统功能有一定的抑制作用，这可能是冰片促进其他药物经鼻给药入脑的作用机制之一。.鼻黏膜黏液黏滞度的调控主要与黏蛋白有关，黏蛋白的少量增加会导致黏液黏滞度的明显增强。本研究发现冰片可抑制NCI-H292细胞黏蛋白MUC5AC 及其mRNA的表达，从而降低鼻黏膜黏液的黏滞度，有利于药物经鼻腔吸收入脑。.调控纤毛摆动的机制主要以cAMP和eNOS通路为主。cAMP激活位于轴丝上的蛋白激酶A(PKA)，PKA使靶细胞蛋白磷酸化，增加纤毛摆动频率(CBF)，eNOS可激活cGMP通路，直接激活PKG或间接激活PKA，从而增加纤毛摆动频率。本研究结果显示冰片可抑制小鼠鼻黏膜纤毛上皮细胞AC-PKA及eNOS-GC-PKG的表达，提示冰片可抑制AC-PKA及eNOS-GC-PKG信号通路，从而减慢纤毛摆动频率。.本项目通过对冰片经鼻“引药上行”入脑机制的深入研究，从实验研究的角度为该理论提供了科学的依据，丰富开窍药“引药上行”的理论内涵；有助于进一步阐明冰片的药效，拓宽冰片的应用范围；有利于促进冰片在治疗脑部疾病中的运用，提高中医药治疗脑部疾病特别是脑部急/重症的疗效。