CN116650455A - 墙草碱在制备抗焦虑症药物中的应用 - Google Patents
墙草碱在制备抗焦虑症药物中的应用 Download PDFInfo
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Abstract
本发明属于生物医药技术领域，涉及墙草碱在制备抗焦虑症药物中的应用。墙草碱能增加小鼠在新环境下的探究行为和自发活动，减少紧张度。墙草碱干预后，高架十字迷宫实验中小鼠进臂的总次数以及开臂进入时间的百分比均增加，而闭臂进入时间的百分比减少。墙草碱干预后，小鼠进入明箱次数增多。墙草碱干预后，小鼠海马组织MDA含量降低，SOD、GSH‑Px活性升高。墙草碱能降低CRS诱导的小鼠海马组织抑制氧化应激。墙草碱干预后，小鼠海马组织Bcl‑2表达升高，Bax表达下降。墙草碱能抑制CRS诱导的小鼠海马组织细胞凋亡。
Description
技术领域
本发明属于生物医药技术领域，涉及墙草碱在制备抗焦虑症药物中的应用。
背景技术
焦虑症是临床常见精神类疾病，常常会导致人的情绪状态和中枢神经系统的精神障碍，并且正在导致全球健康负担不断增加[1]。据流行病学报道，焦虑症是影响普通人群中所有年龄组的最常见的精神疾病之一，且发病率逐年上升[2]。相关数据统计，我国焦虑障碍患病率最高，年患病率4.98％，终生患病率已达7.57％[3]。目前，临床上常用于治疗焦虑的药物有苯二氮卓类药物，如地西泮；选择性5-HT与去甲肾上腺素再摄取抑制药(SNRIs)，如文拉法辛(venlafaxine)和度洛西汀(duloxetine)；选择性5-HT再摄取抑制药(SSRIs)，如氟西汀和舍曲林等[4]。尽管这些药物治疗焦虑症显示出一定的疗效，但遗憾的是，长期服用这些药物易产生耐药性、成瘾性和停药易复发现象等[5]。此外，患者还常常伴有头晕、头痛、胃肠功能紊乱和性功能障碍等不良反应[6]。因此，开发临床疗效好、副作用小的抗焦虑药物是十分必要的。
中医药已经形成了治疗焦虑症的一系列疗法，在精神疾病领域发挥着重要作用，比西医具有一定的优势。与西医相比，中医药在治疗焦虑方面更安全、更有效，副作用更少。酸枣仁汤、逍遥散、柴胡加龙骨牡蛎汤和半夏厚朴汤等因其对焦虑疾病的显著疗效而被认为是重要的替代疗法[7-8]。随着分子中药的研究深入，中药活性组分的抗焦虑作用，越来越受到关注。缬草素、酸枣仁皂苷A、积雪草苷、槲皮苷等抗焦虑作用机理的研究，为焦虑的治疗开辟了新的策略[9]。
墙草碱(Pellitorine，PEL)是中药蓍草中的一种活性成分[10]。蓍草为菊科植物蓍Achillea alpina L.的全草，又名一枝蒿、乱头发、千条蜈蚣。在我国贵州、江西、内蒙古、东北等地均有作为民间药物应用的记载。墙草碱的结构式如下：
蓍草作为中药，使用历史悠久，始载于《神农本草经》，2020版《中国药典》收载有蓍草中药材。蓍草味苦、酸、平，归肺、脾、膀胱经。具有解毒利湿、活血化瘀的功能。现代研究表明，蓍草具有抗炎、抗氧化、抗菌、降血压、保肝治肝等作用，但蓍草的化学成分研究非常少。到目前为止，墙草碱抗焦虑的作用及应用国内外尚无人报道。
参考文献：
[1]Liu J,Shi J L,Guo J Y,et al.Anxiolytic-like effect of Suanzaoren-Wuweizi herb-pair and evidence for the involvement of the monoaminergicsystem in mice based on network pharmacology[J].BMC complementary medicineand therapies,2023,23(1):7.
[2]Zhao C B W,Liu J,Shi J L,et al.Anxiolytic Effect of Alcohol-WaterExtracted Suanzaoren-Wuweizi Herb-Pair by Regulating ECS-BDNF-ERK SignalingPathway Expression in Acute Restraint Stress Male Rats[J].Evidence-basedComplementary and Alternative Medicine,2020,2020(12):1-13.
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发明内容
本发明的目的在于提供墙草碱在制备抗焦虑症药物中的应用。
本发明的实现过程如下：
墙草碱在制备抗焦虑症药物中的应用。
进一步，墙草碱能增加小鼠在新环境下的探究行为和自发活动，减少紧张度。
进一步，墙草碱干预后，高架十字迷宫实验中小鼠进臂的总次数以及开臂进入时间的百分比均增加，而闭臂进入时间的百分比减少。
进一步，墙草碱干预后，小鼠进入明箱次数增多。
进一步，墙草碱干预后，小鼠海马组织MDA含量降低，SOD、GSH-Px活性升高。
进一步，墙草碱能降低CRS诱导的小鼠海马组织抑制氧化应激。
进一步，墙草碱干预后，小鼠海马组织Bcl-2表达升高，Bax表达下降。
进一步，墙草碱能抑制CRS诱导的小鼠海马组织细胞凋亡。
进一步，所述抗焦虑症药物至少包含墙草碱。
进一步，所述抗焦虑症药物包括墙草碱和药物载体，所述抗焦虑症药物为片剂、胶囊、丸剂、注射剂、缓释制剂、控释制剂或各种微粒给药系统。
本发明的积极效果：
(1)旷场实验结果表明，PEL(10mg/kg)组效果较优，有统计学差异明显，说明PEL可改善小鼠的焦虑样行为。
(2)高架十字迷宫实验结果表明，DIA及PEL(高、低剂量)干预后，进臂的总次数以及开臂进入时间的百分比均增加，而闭臂进入时间的百分比减少，说明PEL可改善小鼠的焦虑样行为。
(3)明暗箱实验结果表明，DIA组及PEL高剂量组小鼠进入明箱次数增多，说明PEL可改善小鼠的焦虑样行为。
(4)DIA组及PEL高剂量组小鼠海马组织MDA含量明显降低，SOD、GSH-Px活性明显升高。PEL高剂量(10mg/kg)可以降低CRS诱导的小鼠海马组织抑制氧化应激。说明PEL可改善小鼠的焦虑样行为。
(5)Western blot实验结果表明，DIA组、PEL低剂量组、PEL高剂量组小鼠海马组织Bcl-2表达显著升高，Bax表达显著下降，具有统计学意义。PEL可以显著抑制CRS诱导的小鼠海马组织细胞凋亡。说明PEL可改善小鼠的焦虑样行为。
附图说明
图1为各组小鼠旷场实验结果图，n＝6，与Control组相比，##P<0.01，###P<0.001；与CRS组相比，*P<0.05,**P<0.01,***P<0.001；
图2为各组小鼠高架十字迷宫实验结果图，n＝6，与Control组相比，##P<0.01，###P<0.001；与CRS组相比，*P<0.05,**P<0.01,***P<0.001；
图3为各组小鼠明暗箱实验结果，n＝6，与Control组相比，###P<0.001；与CRS组相比，**P<0.01,***P<0.001；
图4为各组小鼠海马组织中MDA含量及SOD、GSH-Px活性，n＝6，与Control组相比，#P<0.001，###P<0.001；与CRS组相比，*P<0.05，**P<0.01,***P<0.001；
图5为各组小鼠海马组织中Bcl-2和Bax表达，n＝4。
具体实施方式
下面结合实施例对本发明做进一步说明。
1.实验动物
雄性C57BL/6小鼠50只，体重22～24g，购于空军军医大学动物中心(合格证编号：0009241)饲养条件为温度25±1℃、相对湿度50±5％，实验前适应性饲养一周。
2.药物配制
墙草碱、地西泮均用纯净水溶解。
墙草碱(Pellitorine，PEL)给药浓度：5mg/kg、10mg/kg
地西泮片(Diazepam，DIA)药浓度：1.3mg/kg
3.动物分组
实验动物随机分为Control(空白对照组)、CRS(急性束缚应激组)、DIA(急性束缚应激+地西泮组)、PEL-L(急性束缚应激+墙草碱低剂量组)、PEL-H(急性束缚应激+墙草碱高剂量组)。
4.CRS模型的建立
束缚应激(Chronic restraint stress，CRS)模型被证明是一种有效的焦虑应激模型。具体操作如下：实验小鼠被放置在通风良好的离心管(25mL容量)中，每天2小时，连续7天诱导急性束缚应激，而对照组小鼠被放置在同期自由移动的家庭笼子中。于束缚应激30分钟后，DIA组给予地西泮片(Diazepam，DIA)1.3mg/kg；PEL-L和PEL-H组分别给与墙草碱(5mg/kg、10mg/kg)；Control(空白对照组)和CRS组(模型组)分别给予等体积的生理盐水。末次给药30分钟后，进行行为学测试。
5.行为学实验
5.1旷场实验(OFT)
旷场是一个开放的盒子结构，大小为40厘米×40厘米×30厘米，底部为黑色。照相机设备被放置在该区域的中心。在实验开始前60分钟，小鼠被放在实验室里，以便适应。在整个试验过程中，保证了统一的照明和安静的环境。小鼠被轻轻地放在广场的中心，并允许在空地上自由移动10分钟。记录中心距离和时间。在测试之间，用20％的酒精对该区域进行清洁。在酒精气味散去，箱底没有明显的潮湿痕迹后，对下一只小鼠进行测试。
5.2高架十字迷宫实验(EPM)
高架迷宫由70厘米×5厘米×20厘米的黑色有机玻璃组成，表面为白色以提供对比。测试是在红光(<10勒克斯)下进行的，从外面看是隔音的。在测试之间，用20％的乙醇溶液来手动清洁EPM装置。将小鼠放在迷宫的中心，用视频跟踪系统(Ethovision)记录5分钟的开臂时间和开臂入口。
5.3明暗箱实验
将已适应环境的小鼠置于明暗箱(44cm×21cm×21cm，明箱占1/3，暗箱占2/3)的明箱中央，头朝暗箱。记录5min内小鼠进入明箱次数及明箱活动时间。
6.ELISA法检测氧化应激相关指标
行为学测试结束后，各组小鼠鼠断头取脑，快速取出小鼠海马组织，匀浆、离心后取上清，测定海马组织中的MDA含量及SOD、GSH-Px活性。所有操作严格按照试剂盒说明书进行。
7.Western Blot法检测小鼠海马组织中Bcl-2和Bax的表达
行为学测试结束后，断头取脑快速分离出小鼠海马组织，BCA法测定各组蛋白含量。SDS-PAGE凝胶电泳，转膜1h，封闭，Bcl-一抗(1:500)，Bax-抗(1:500)，β-actin一抗(1:1000)室温孵育1h，二抗(1:5000)室温孵育1h，将膜置于凝胶成像仪中，加入ECL发光剂显影。
8.结果
8.1墙草碱对CRS小鼠行为学的影响
8.1.1旷场试验结果
旷场实验的实验结果表明，与Control组相比，CRS模型组小鼠的总路程、中央路程占比及中央时间占比均显著减少，表明CRS模型组小鼠在新环境下的探究行为、自发活动明显减少，而紧张度明显增加，因此CRS诱导小鼠焦虑样行为成功。与CRS模型组相比，DIA组和PEL各剂量组小鼠的总路程、中央路程占比及中央时间占比均有变化，其PEL(10mg/kg)组效果较优，有统计学差异明显。PEL可改善小鼠的焦虑样行为，结果见图1，图1为各组小鼠旷场实验结果图，n＝6，与Control组相比，##P<0.01，###P<0.001；与CRS组相比，*P<0.05,**P<0.01,***P<0.001。
8.1.2高架十字迷宫实验结果
高架十字迷宫实验结果表明，与Control组相比，CRS组小鼠进臂的总次数以及开臂进入时间的百分比均显著减少，而闭臂进入时间的百分比明显增加，说明小鼠处于CRS造成的焦虑状态。与CRS应激组小鼠比较，DIA及PEL(高、低剂量)干预后，进臂的总次数以及开臂进入时间的百分比均增加，而闭臂进入时间的百分比减少，尤其是PEL高剂量统计学意义明显，PEL可改善小鼠的焦虑样行为，结果见图2，图2为各组小鼠高架十字迷宫实验结果图，n＝6，与Control组相比，##P<0.01，###P<0.001；与CRS组相比，*P<0.05,**P<0.01,***P<0.001。
8.1.3明暗箱实验结果
明暗箱实验结果表明，与Control组相比，CRS组小鼠进入明箱次数少于Control组，明箱活动时间短于空白组，差异有统计学意义。与CRS组比较，DIA组及PEL高剂量组小鼠进入明箱次数增多，差异有统计学意义，说明PEL可改善小鼠的焦虑样行为。PEL低量组与CRS组比较，差异无统计学意义。结果见图3。图3为各组小鼠明暗箱实验结果，n＝6，与Control组相比，###P<0.001；与CRS组相比，**P<0.01,***P<0.001。
8.2墙草碱对CRS小鼠海马组织MDA含量及SOD、GSH-Px活性的影响
Elisa实验结果表明，与Control组相比，CRS组小鼠海马组织MDA含量明显升高，SOD、GSH-Px活性明显降低。与CRS组比较，DIA组及PEL高剂量组小鼠海马组织MDA含量明显降低，SOD、GSH-Px活性明显升高，具有统计学意义，见图4，图4为各组小鼠海马组织中MDA含量及SOD、GSH-Px活性，n＝6，与Control组相比，#P<0.001，###P<0.001；与CRS组相比，*P<0.05，**P<0.01,***P<0.001。PEL低量组与CRS组比较，差异无统计学意义。结果提示，PEL高剂量(10mg/kg)可以降低CRS诱导的小鼠海马组织抑制氧化应激。
表1各组小鼠鼠海马组织氧化应激指标的测定结果
8.3墙草碱对CRS小鼠海马组织中Bcl-2和Bax表达的影响
Western blot实验结果表明，与Control组相比，CRS组小鼠海马组织Bcl-2表达明显下降，Bax表达明显上升，而Bcl-2/Bax比值显著减小。与CRS组比较，DIA组、PEL低剂量组、PEL高剂量组小鼠海马组织Bcl-2表达显著升高，Bax表达显著下降，具有统计学意义，见图5，图5为各组小鼠海马组织中Bcl-2和Bax表达，n＝4。结果提示，PEL可以显著抑制CRS诱导的小鼠海马组织细胞凋亡。
综上所述，墙草碱(PEL)可以明显改善CRS诱导的小鼠焦虑样行为，其主要机制与PEL抑制海马中氧化应激和神经元凋亡有关。
以上内容是结合具体的优选实施方式对本发明所作出的进一步详细说明，不能认定本发明的具体实施仅限于这些说明。对于本发明所属领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以作出若干简单推演或替换，都应该视为属于本发明的保护范围。
Claims (10)
1.墙草碱在制备抗焦虑症药物中的应用。
2.根据权利要求1所述应用，其特征在于：墙草碱能增加小鼠在新环境下的探究行为和自发活动，减少紧张度。
3.根据权利要求1所述应用，其特征在于：墙草碱干预后，高架十字迷宫实验中小鼠进臂的总次数以及开臂进入时间的百分比均增加，而闭臂进入时间的百分比减少。
4.根据权利要求1所述应用，其特征在于：墙草碱干预后，小鼠进入明箱次数增多。
5.根据权利要求1所述应用，其特征在于：墙草碱干预后，小鼠海马组织MDA含量降低，SOD、GSH-Px活性升高。
6.根据权利要求1所述应用，其特征在于：墙草碱能降低CRS诱导的小鼠海马组织抑制氧化应激。
7.根据权利要求1所述应用，其特征在于：墙草碱干预后，小鼠海马组织Bcl-2表达升高，Bax表达下降。
8.根据权利要求1所述应用，其特征在于：墙草碱能抑制CRS诱导的小鼠海马组织细胞凋亡。
9.根据权利要求1所述应用，其特征在于：所述抗焦虑症药物至少包含墙草碱。
10.根据权利要求1所述应用，其特征在于：所述抗焦虑症药物包括墙草碱和药物载体，所述抗焦虑症药物为片剂、胶囊、丸剂、注射剂、缓释制剂、控释制剂或各种微粒给药系统。
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