CN114191422A - 根皮素在制备抗抑郁药物中的应用 - Google Patents
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Abstract
本发明公开了根皮素在制备抗抑郁药物中的用途,属于医药技术领域。本发明通过慢性不可预见温和刺激建立小鼠抑郁模型,采用旷场实验、糖水偏好实验、悬尾实验以及强迫游泳实验等行为学检测手段评价了根皮素的抗抑郁作用,通过免疫荧光实验以及ELISA试剂盒检测证明了根皮素能够抑制小胶质细胞激活,缓解神经炎症,发挥神经保护作用,可以用于制备抗抑郁的药物。
Description
技术领域
本发明属于医药技术领域,具体涉及根皮素在制备抗抑郁药物中的应用。
背景技术
抑郁症是一种全球性的人类精神疾病,临床上以显著而持久的心境低落为主要特征,具有高患病率和高复发率,且抑郁症患者的自杀率逐年持续增长。抑郁症受遗传、生物、环境和心理因素等共同作用引起,治疗也因人而异。抑郁症的发病机制较为复杂,迄今尚未完全阐明。目前常用的抗抑郁药主要是通过调节大脑中控制情绪或压力的某些化学物质发挥作用,其疗效尚不能令人满意,且副作用较大。因此,研究抑郁症的发病机制,并针对不同发病机制研究有效的治疗药物具有重要意义。
抑郁症的病理生理过程与海马内小胶质细胞激活密切相关,应激(包括社会应激和环境应激)可以诱发抑郁症,也可以通过作用于交感神经和副交感神经系统促进小胶质细胞激活,进一步释放促炎性细胞因子,诱发神经炎症,而促炎性细胞因子作为关键的反应介质反过来可以诱发甚至加重抑郁样行为。高迁移率族蛋白(High mobility group box1,HMGB1)是一种表达广泛、含量丰富的蛋白,在生理和病理过程中发挥多种作用,与人类健康和疾病密切相关,特别是老化和炎症相关的疾病。HMGB1作为一种损伤相关分子模式,可以绑定到模式识别受体,移位到小胶质细胞并转化为促炎表型,调解促炎细胞因子的释放。目前国内外关于天然药物活性成分的神经保护作用已有了大量研究。根皮素作为一种二氢查耳酮,广泛分布于苹果皮、梨皮、石榴皮等果皮中,属于黄酮类化合物。研究表明,根皮素具有多种药理活性,包括抗氧化、降血糖、抗菌、抗炎等作用。最新研究报导,根皮素能够作用于中枢神经系统,发挥神经保护作用。但目前关于根皮素抗抑郁作用的研究还未见报道。
发明内容
本发明的目的是提供根皮素在制备抗抑郁药物中的应用。
本发明通过慢性不可预见温和刺激建立小鼠抑郁模型,采用旷场实验、糖水偏好实验、悬尾实验以及强迫游泳实验等行为学检测手段评价了根皮素的抗抑郁作用,通过免疫荧光实验以及ELISA试剂盒检测证明了根皮素能够抑制小胶质细胞激活,缓解神经炎症,发挥神经保护作用,可以用于制备抗抑郁的药物。到目前为止,未见任何关于根皮素抗抑郁作用的文献报道。
附图说明
图1为根皮素在糖水偏好实验、旷场实验、悬尾实验以及强迫游泳实验中对慢性应激诱导的小鼠抑郁样行为的影响;
图2为根皮素对慢性应激引起的小胶质细胞激活及HMGB1蛋白表达的影响;
图3为根皮素对慢性应激引起的促炎性细胞因子释放的影响。
具体实施方式
下面将结合附图和具体实施例对本发明进行详细说明。但此处所描述的具体实施例仅用以解释本发明,并不用于限制本发明的范围。
实施例1
根皮素对慢性应激诱导的小鼠抑郁样行为的影响
1.实验方法
1.1慢性应激抑郁小鼠模型的建立
采用多种方式交替刺激小鼠,每天1~2种刺激,每周刺激顺序不同,持续刺激6周后建立小鼠慢性不可预知温和刺激(Chronic unpredictable mild stress,CUMS)抑郁小鼠模型。小鼠接受的不可预知温和刺激如下:
1.2动物分组及给药
实验开始前将小鼠适应性喂养7天,然后随机分为五组:空白组(Control)、慢性应激模型组(CUMS)、慢性应激+氟西汀组[CUMS+Flu(20mg/kg)]、慢性应激+根皮素低剂量组[CUMS+Phi(40mg/kg)]以及慢性应激+根皮素高剂量组[CUMS+Phi(80mg/kg)]。CUMS造模三周后,从第四周开始,各组均按0.1ml/10g的给药体积灌胃给药,每日给药一次,连续给药3周,均于每日上午9时灌胃给药。空白对照组和模型组均给与相应体积的生理盐水。每周对各组小鼠称重并记录。
1.3行为学检测
1.3.1糖水偏好实验
测试前小鼠进行糖水饮用训练,每笼放置2个水瓶。训练第一天,两瓶均为1%(w/v)的蔗糖水;训练第二天,1瓶为1%蔗糖水,另1瓶换为纯水。然后禁食禁水12小时,之后开始测试,且测试时小鼠单笼饲养,每只给予1瓶1%蔗糖水和1瓶纯水,称重记录,12h后再次称重,记录各组小鼠的蔗糖水、纯水及总液体的消耗量(g)。
糖水偏好率(Sucrose Preference,SP)=蔗糖水的消耗量(g)/总液体的消耗量(g)×100%
1.3.2旷场实验
将小鼠置于旷场实验箱中。实验箱大小为50×50×50cm。实验开始时把小鼠置于箱底中心位置,让小鼠自由探索开阔区域,在安静的环境中进行观察。记录5min内小鼠的行为。每只小鼠完成实验后,用75%乙醇清洗仪器。记录小鼠在中心区域停留时间以及总路程。
1.3.3悬尾实验
将小鼠尾端1cm的部位固定于水平铁架上,使小鼠倒挂在装置上,其头部离台面约15cm。在安静的环境下,观察6min并记录小鼠后4min内累计不动时间。不动的判断标准为小鼠无挣扎和任何试图逃离悬挂装置的动作。
1.3.4强迫游泳实验
将小鼠放在装满水(深度13厘米)的玻璃桶(高30厘米,直径15厘米)中,让小鼠自由游泳。适应2分钟后开始记录不动时间。记录小鼠在后4min内的累计不动时间。当实验老鼠停止挣扎并漂浮在水面上时,则判定为小鼠静止不动。
2.实验结果
如图1所示,在旷场实验(open field test,OFT)中,与空白组相比,CUMS模型组小鼠在旷场中心区域停留时间以及移动总路程显著降低,给予阳性药氟西汀(20mg/kg)以及根皮素低高剂量之后,能够显著升高中心区域停留时间以及总路程。与旷场实验结果一致,在糖水偏好实验(sucrose preference test,SPT)中,给予氟西汀以及根皮素低高剂量之后能够显著改善CUMS小鼠的糖水消耗率。在悬尾实验(tail suspension test,TST)以及强迫游泳实验(forced swimming test,FST)中,给予氟西汀以及根皮素低高剂量之后能够显著减少不动时间。这些结果表明根皮素能够逆转慢性应激引起的小鼠抑郁样行为。
实施例2
根皮素对慢性应激引起的HMGB1的表达升高及小胶质细胞激活的影响
1.实验方法
1.1取全脑
采用10%的水合氯醛腹腔注射麻醉小鼠,待小鼠完全麻醉后,用针头固定小鼠四肢,打开胸腔,暴露心脏,用PBS以及4%多聚甲醛心脏灌流,取出全脑,将脑组织浸泡在4%的多聚甲醛中备用。
1.2免疫荧光染色
将脑组织更换溶液,采用10%、20%及30%的蔗糖溶液梯度脱水,待全脑完全沉底,说明脱水成功。将脑组织用冰冻切片机进行冰冻切片,切成厚度为20μm的脑片。用0.3%的Triton-100溶液透化脑片20min,然后采用10%的山羊血清封闭2h,之后孵育一抗Iba-1以及HMGB1,4℃过夜。用PBS洗3次,孵育荧光二抗Alexa-488以及Alexa-594,孵育1h。PBS清洗3次,孵育DAPI溶液15min。最后荧光抗淬灭剂封片,共聚焦观察。
2.结果
如图2所示,Iba-1为小胶质细胞的标志性蛋白,主要用于标记激活的小胶质细胞,与空白组(Control)相比,CUMS模型组(CUMS)小鼠海马内Iba-1以及HMGB1蛋白表达显著升高,而给予氟西汀(Flu)以及根皮素(Phi)低高剂量治疗之后能够显著降低这些蛋白的表达。结果表明根皮素能够抑制海马内HMGB1的表达以及小胶质细胞的激活。
实施例3
根皮素对慢性应激引起的促炎性细胞因子释放的影响
1.实验方法
1.1海马组织匀浆制备
小鼠行为学结束后,脱颈椎处死,在冰浴上取出海马组织,液氮速冻。将海马组织与生理盐水按1:9的比例混合,匀浆器研磨匀浆,直至看不见组织碎块为止。将海马组织匀浆液放置于4℃备用。
1.2炎症因子的检测
采用ELISA试剂盒检测海马组织中IL-1β、IL-6以及TNF-α的含量。操作步骤按照试剂盒说明书进行,于指定波长处测定各孔的OD值,然后根据公式计算出样品中IL-1β、IL-6及TNF-α的蛋白表达含量。单位含量以pg/mgprot表示。
2.结果
如图3所示,与空白组(Control)相比,CUMS模型组小鼠海马内促炎性细胞因子IL-1β、IL-6以及TNF-α的含量显著升高,而给予氟西汀(Flu)以及根皮素(Phi)低高剂量治疗之后能够显著降低这些炎症因子的表达。结果表明根皮素能够抑制慢性应激引起的促炎性细胞因子的释放。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,不脱离本发明范畴所做出的改进和修改都应该在本发明的保护范围之内。
Claims (4)
1.根皮素在制备抗抑郁症药物中的应用。
2.根据权利要求1所述的应用,其特征在于,所述抗抑郁症药物能够减少HMGB1的表达、抑制小胶质细胞激活及缓解神经炎症。
3.根据权利要求1所述的应用,其特征在于,所述抗抑郁症药物是以根皮素为主要成分,加上药学上可接受的辅料制备而成的药物制剂。
4.根据权利要求3所述的应用,其特征在于,所述的药物制剂为片剂、颗粒剂、胶囊剂或注射制剂。
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