基于大麻素受体CB1的固体脂质纳米粒治疗抑郁症研究

Depression is a serious mental diseases to human life and health, however,the existing chemical drugs have many shotcomings, such as side effects,slow onset, narrow spectrum of antidepressant and easy to relapse. Nowdays the demands of new drugs and new targets grow with each passing day.Curcumnin is a kind of plant extracts, which is considered as safe and experiments have proved its antidepressant effect.But curcumin has some shortcomings, including the extremely low avalabilityemely, short half-life, not easy to pass the blood brain barrier, and its mechanism is not clear. The CB1 receptor is one of the G protein-coupled receptors that mainly distributes in the central nervous system, and is also one of the recent hot spots of new target for antidepression.Our researches have confirmed that solid lipid nanoparticles (SLN) can help the curcumin cross the blood-brain barrier, improve the brain distribution up to 18 folds as original curcumin. Therefore, we design the ligand Hu-211 to modify SLN- curcumin, which makes its targeting to CB1 receptor, and then achieve antidepressant effects. To determine the treatment effect and comfirm the targeting effect of Hu211-SLN- curcumin, the project will be undertake using depression rats. And after treatments,the the expression, distribution and function of CB1 receptor will be studied via different methods.This study is the first to apply SLN- curcumin to antidepression treatment, while further validate the function and mechanism of CB1 receptor as new target, and will provide a novel idea and new drug targets for the treatment of depression.

抑郁症是严重危害人类生活与健康的精神类疾病, 已有的化学药物起效慢、毒副作用高、抗抑郁谱窄、易复发，对新药物及新靶点的需求与日俱增。姜黄素是一种植物提取物，安全性好，实验证明具有较好的抗抑郁效果，但是生物利用率极低、半衰期短、不易透过血脑屏障，其作用机制也不明确。CB1受体是主要分布于中枢神经系统的G蛋白偶联受体，也是近年研究的抗抑郁新靶点之一。本课题组已经证实，固体脂质纳米粒（SLN）能够帮助姜黄素穿越血脑屏障，提高其在脑部的分布高达18倍。因此，我们设计配基Hu-211来修饰SLN-姜黄素，从而使其靶向作用于CB1受体，达到抗抑郁的作用。为证实Hu211-SLN-姜黄素的治疗效果和靶向性，本项目将对抑郁大鼠进行分组给药，并对大鼠脑部CB1受体的表达、分布及功能进行研究。本研究首次将SLN-姜黄素用于抑郁症治疗，同时进一步验证CB1作为新靶点的机制，为抑郁症的治疗提供新思路和药物新靶点。

抑郁症是严重危害人类生活与健康的精神类疾病, 已有的化学药物起效慢、毒副作用高、抗抑郁谱窄、易复发，对新药物及新靶点的需求与日俱增。姜黄素是一种植物提取物，安全性好，实验证明具有较好的抗抑郁效果，但是生物利用率极低、半衰期短、不易透过血脑屏障，其作用机制也不明确。CB1受体是主要分布于中枢神经系统的G蛋白偶联受体，也是近年研究的抗抑郁新靶点之一。通过课题的开展，已经成功合成纳米SLN-姜黄素-HU211，粒径范围60—200nm，呈圆球形，易分散，药物在其中可提高热稳定性；在体内外实验已经证实，SLN-姜黄素-HU211和单纯的姜黄素相比，具有更好的穿膜性能以及显著的脑靶向性，同时药物利用度提高了10倍以上；通过皮质酮建立抑郁症小鼠模型，并设组给药，发现SLN-姜黄素-HU211能够提高小鼠的行为学得分，可以提高提高5-HT和多巴胺等神经递质在纹状体和海马组织中的表达；同时通过蛋白印迹、免疫荧光等手段，发现SLN-姜黄素-HU211能够激活CB1受体，并通过PI3K/AKT、MAPK/ERK信号通路发挥治疗作用；并进一步通过CB1受体抑制剂利莫那班验证了CB1受体在SLN-姜黄素-HU211治疗抑郁症治疗作用的靶点效应。本研究首次将SLN-姜黄素用于抑郁症治疗，同时进一步验证CB1作为新靶点的机制，为抑郁症的治疗提供新思路和药物新靶点。