百花花楸果中β-谷甾醇及其衍生物的制备及抗抑郁活性研究
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篇名: 百花花楸果中β-谷甾醇及其衍生物的制备及抗抑郁活性研究
TITLE: Preparation and Antidepressant Activity Study of β-sitosterol and Its Derivatives from the Fruit of Sorbus pohuashanensis
摘要: 目的:制备百花花楸果中β-谷甾醇(简称为“Sit”)及其衍生物,并考察其抗抑郁活性。方法:以百花花楸果实为原料,经过75%乙醇和20%KOH溶液提取,并经萃取结晶后得到Sit。以Sit的C3位羟基作为结构修饰位点,以二氯甲烷为反应溶剂、4-二甲氨基吡啶为催化剂、1-(3-二甲胺基丙基)-3-乙基碳二亚胺为脱水剂,分别加入4种有机酸(水杨酸、2-四氢糠酸、苯丙氨酸、山梨酸),通过羧合反应生成相应的酯类衍生物Sit-S、Sit-T、Sit-P、Sit-Sr,并采用红外和核磁共振等波谱技术鉴定其化学结构。根据悬尾实验和强迫游泳实验初步探讨Sit及其4种衍生物的抗抑郁活性,然后再根据悬尾实验和自发运动能力实验筛选抗抑郁活性较好的化合物的有效剂量。将筛选出的该化合物单用以及分别与阿戈美拉汀[40mg/kg,5-羟基色胺(5-HT)和5-HT2C受体拮抗剂]、氟哌啶醇[0.2mg/kg,非选择性D2受体拮抗剂]和荷包牡丹碱[4mg/kg,竞争性γ-氨基丁酸(GABA)拮抗剂]联用,腹腔注射给药60min后,进行悬尾实验,然后通过酶联免疫吸附法检测小鼠脑组织中5-HT、多巴胺(DA)、GABA水平,初步探索该化合物的抗抑郁作用机制。实验均设置空白对照组,腹腔注射等量10%丙二醇溶液。结果:经波谱技术鉴定,Sit与4种有机酸成功地反应生成了相应的酯类衍生物。在Sit及其4种衍生物中,Sit-S组小鼠在悬尾实验和强迫游泳实验中的不动时间均最短,且显著短于空白对照组(P<0.05)。Sit-S的筛选结果显示,其抗抑郁的有效剂量为4mg/kg,且与空白对照组比较不影响小鼠的自发活动(P>0.05)。该剂量作用下,Sit-S可显著缩短小鼠在悬尾实验中的不动时间(P<0.01),显著提高小鼠脑组织中5-HT、DA和GABA水平(P<0.05或P<0.01),但该作用效果可被阿戈美拉汀、氟哌啶醇和荷包牡丹碱不同程度地逆转。结论:Sit的水杨酸酯衍生物Sit-S具有良好的抗抑郁活性,其作用机制可能是通过提高脑组织中5-HT、DA和GABA水平所介导的。
ABSTRACT: OBJECTIVE: To prepare β-sitosterol (shorted fo r “Sit”) and its deri vatives from the fruit of Sorbus pohuashanensis,and to investigte their antidepressant activities. METHODS :Using the fruit of S. pohuashanensis as raw material , extracted with 75% ethanol and 20%KOH solution ,Sit was obtained after extraction and crystallization. C 3 hydroxyl group of Sit was used as the structural modification site ,CH2Cl2 was used as the reaction solvent ,DMAP was used as catalyst ,EDCI was used as dehydrating agent ,4 kinds of organic acids (salicylic acid ,2-tetrahydrofuranic acid ,phenylalanine,sorbic acid )were added to make the carboxylation reaction to produce ester derivatives Sit-S ,Sit-T,Sit-P and Sit-Sr. The chemical structure of its derivatives were elucidated by IR and NMR. The tail suspension test and the forced swimming model were used to preliminarily explore the antidepressant active components of Sit and 4 kinds of derivatives ;tail suspension test and the spontaneous exercise capacity test were used to screen effective dose of the compounds with antidepressant active. The compound was used alone or in combination with agomelatin [ 40 mg/kg,5-hydroxytryptamine(5-HT)and 5-HT 2C receptor antagonist] ,haloperidol [ 0.2 mg/kg,non-selective D2 receptor antagonist] and bicuculline [ 4 mg/kg,competitive γ-aminobutyric acid(GABA)antagonist],respectively. Sixty minutes after intraperitoneal injection ,tail suspension test was performed. The levels of 5-HT,dopamine(DA)and GABA in brain tissues of mice were detected by ELISA. The blank control group was given intraperitoneal injection of 10% propylene glycol solution. RESULTS:By spectrum technology ,the corresponding ester compounds were synthesized by the reaction of Sit with four kinds of organic acids. Among Sit and its four derivatives ,the immobility time of Sit-S group was the shortest in tail suspension test and forced swimming test ,which was significantly shorter than that of blank control group (P<0.05). Screening results of Sit-S showed that the effective antidepressant dose was 4 mg/kg, * and it did not affect the spontaneous activity of mice compared with the blank control group (P>0.05). With this dose ,Sit-S could significantly shorten the immobility time of mice in tail hua1666@163.com suspension test (P<0.01),and can s ignificantly increase the ·64levels of 5-HT,DA and GABA in the brain tissue of mice (P<0.05 or P<0.01),but its effect can be reversed by agomelatine , haloperidol and bicuculline to different extent. CONCLUSIONS :Sit salicylate derivatives Sit-S exhibits good antidepressant activity,and its mechanism of action may be mediated by increasing the levels of 5-HT,DA and GABA.
期刊: 2021年第32卷第01期
作者: 刘晓峰,曹馨元,尹永霞,王波,黄文华
AUTHORS: LIU Xiaofeng ,CAO Xinyuan ,YIN Yongxia ,WANG Bo,HUANG Wenhua
关键字: 百花花楸果;β-谷甾醇;衍生物;抗抑郁活性
KEYWORDS: Fruit of Sorbus pohuashanensis ;β-sitosterol;Derivative;Antidepressant activities
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