柴贝止痫汤有效组分干预难治性癫痫大鼠BBB和P-gp/mdr1变化的机理研究

Epilepsy is a common chronic neurological disorder，and over 30% of patients with epilepsy do not have seizure control even with the best available AEDs, and thus, develop medically intractable epilepsy (IE). A main reason of IE is the blood-brain barrier (BBB) blocks the drug's transport into the brain, caused the effective concentration cannot be reached to influence the damaged brain tissue. Therefore, promoting the drug to permeate BBB has become a key problem asking for solution. Based on the previous studies, we suggest that the pathogeneses of IE are the stagnation of liver-qi, wind-phlegm obstructing orifices, and toxins damaging brain collaterals. With the foundation of treating qi-stagnation, wind and phlegm, we tried to commence with toxins, designed syndrome differentiation therapy using Chai Bei Zhi Xian Decoction, and has got good clinical effect. Guided by this result, we introduce epilepsy rat models, taking activating the drug transporters on BBB to increase the concentration of drugs as a cut-in point, to study the relationship between the brain transport of the effective constituents of Chai Bei Zhi Xian Decoction and the morphology and function of BBB, and to analyze the influence of effective constituents on the expression and function of P-glycoprotein/mdr1, so as to reveal the anti-epilepsy effect of effective constituents combination of Chinese medicine by improving the active transport function of BBB, and at the same time, to explore the possible molecular mechanism of Chinese medicine in treating IE.

癫痫是神经科常见疾病，约30％的患者对抗癫痫药不敏感而成为难治性癫痫，其主要原因之一是由于血脑屏障（blood-brain barrier， BBB）的阻挡，使得受损脑组织无法获得有效的药物浓度，因此，促进有效药物的脑部转运便成为一个亟待解决的关键问题。在以往研究工作基础上，提出难治性癫痫肝郁气滞、风痰闭窍、毒滞脑络的发病机制，在从郁、风、痰论治的基础上，从毒着手，以中药复方柴贝止痫汤进行辨证论治，收到了较好的临床疗效。并在此理论指导下，引入难治性癫痫动物模型，以有效开启BBB转运功能以提高脑内药物浓度为切入点，研究柴贝止痫汤有效组分脑部转运与BBB结构与功能的关系，并分析有效组分对P-糖蛋白/mdr1功能表达的影响，从而开展中药组分配伍以增加BBB主动转运功能而发挥抗癫痫作用的研究，同时探讨中药干预难治性癫痫的可能的分子病理机制。

癫痫是神经科常见疾病，约30％的患者对抗癫痫药不敏感而成为难治性癫痫，其主要原因 之一是由于血脑屏障（BBB）的阻挡，使得受损脑组织无法获得 有效的药物浓度，因此，促进有效药物的脑部转运便成为一个亟待解决的关键问题。在以往研究工作基础上，提出难治性癫痫肝郁气滞、风痰闭窍、毒滞脑络的发病机制，在从郁 、风、痰论治的基础上，从毒着手，以中药复方柴贝止痫汤进行辨证论治，收到了较好的临床疗效。并在此理论指导下，引入难治性癫痫动物模型，以有效开启BBB转运功能以提 高脑内药物浓度为切入点，研究柴贝止痫汤有效组分脑部转运与BBB结构与功能的关系， 并分析有效组分对P-糖蛋白/mdr1功能表达的影响，从而开展中药组分配伍以增加BBB主动转运功能而发挥抗癫痫作用的研究，同时探讨中药干预难治性癫痫的可能的分子病理机制 。对难治性癫痫大鼠血脑屏障的研究表明，难治性癫痫大鼠神经细胞形态结构严重受损，尼氏体受到损伤，椎体细胞出现凋亡。难治性癫痫大鼠血脑屏障过表达耐药基因及蛋白，对不同时点大鼠血脑屏障耐药蛋白及基因表达的研究表明，MDR1基因转录升高先于P糖蛋白表达升高。研究发现柴贝止痫汤入血成分十余种，由多到少依次为：天麻素、对羟基苯甲醛、胡芦巴碱、天麻素苷元、原儿茶醛、香草醛、β细辛醚、柴胡皂苷A、贝母素乙、茴香脑、β细辛醚、柴胡皂苷C、贝母素甲、贝母辛。机制研究发现天麻素和柴贝止痫汤均可抑制MDR1基因转录影响P-gp蛋白表达，减少脑组织神经损伤，柴贝止痫汤入血成分可能是其发挥抗癫痫作用的物质基础。进一步研究将针对其主要入血成分的疗效及机制开展，以便挖掘中药抗癫痫的物质基础，更好的为临床服务。