CN115463169A - 一种核桃多酚在抗抑郁药物及抗抑郁保健食品中的应用 - Google Patents
一种核桃多酚在抗抑郁药物及抗抑郁保健食品中的应用 Download PDFInfo
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Abstract
本发明涉及生物医药技术领域,尤其涉及一种核桃多酚在制备抗抑郁药物或抗抑郁保健食品中的应用。提供核桃多酚在制备抗抑郁药物或抗抑郁保健食品中的应用。长期应激性生活事件会引起糖皮质类固醇激素水平持续升高,进而诱发神经元神经营养障碍,是抑郁症发生的重要机制。核桃多酚可有效抑制皮质酮诱导的PC12细胞损伤,并特异性的改善皮质酮诱导的神经营养缺乏,增加神经营养作用,显著增加脑源性神经营养因子(BDNF)表达及PKA/CREB/BDNF神经营养通路活性,从而发挥抗抑郁作用。本专利可为核桃多酚作为抑郁症干预的药物及保健食品提供科学依据。
Description
技术领域
本发明涉及生物医药技术领域,尤其涉及一种核桃多酚在制备抗抑郁药物和抗抑郁保健食品中的应用。
背景技术
抑郁症是一种以显著而持久的心境低落为主要特征的情感性精神障碍,其症状复杂,危害性高。随着现代社会的高速发展,竞争日益激烈,抑郁症的发病率逐年递增,已成为“21世纪的流行病”。据世界卫生组织(WHO)公布的调查预计,抑郁症目前为世界第4大疾患,在我国,约有20%的人有抑郁症状,有7%的人患有重度抑郁症,抑郁症已占我国疾病负担的第二位。
目前临床上一线的抗抑郁剂主要有选择性5-HT重摄取抑制剂、5-HT/NA双重重摄取抑制剂及三环类等,这些药物普遍存在不良反应多、耐受性差等不足,严重制约了抑郁症的临床治疗。近年来,植物活性成分在抗抑郁治疗中显示出独特优势,如,如贯叶连翘(St.John′s wort)在德国用于抑郁症的治疗用量超过其他任何一种抗抑郁药物,金丝桃提取物在欧美已经上市。因此,获取一种植物源且耐受性好的抗抑郁药物或抗抑郁保健食品具有重要的应用价值。
应激性生活事件可诱发抑郁症已成为不争的事实。压力应激会引起胞内信号传导及基因转录过程变化,从而引起特定脑区神经营养障碍,神经可塑性下降,是抑郁症病理机制的神经营养缺乏假说。环磷酸腺苷(cAMP)反应元件结合蛋白(cAMP-responsiveelement-binding protein,CREB)和脑源性神经营养因子(brain-derived neurotrophicfactor,BDNF)是抑郁症发生与转归的关键神经营养因子。CREB是调控BDNF转录活性的关键核转录因子。CREB133位点丝氨酸(S133)的磷酸化是激活CREB转录活性的关键,cAMP特异性蛋白激酶A(cAMP-dependent protein kinase A,PKA)是调控这一过程的主要激酶。抗抑郁剂可特异性的激活PKA活性,增强CREB的磷酸化水平,进一步介导BDNF的功能。CREB及其靶蛋白BDNF被认为是抗抑郁剂起效的重要靶标。
核桃多酚是核桃及核桃油加工副产物核桃粕中重要的生物活性物质之一,其活性的进一步开发对核桃资源高值化利用具有重要意义。核桃中的多酚类化合物主要为鞣花单宁水解多酚,具有较强的抗氧化作用,文献报道表明其抗氧化活性优于其他坚果包括杏仁、榛子、开心果和花生来源的多酚。最近,流行病学证据显示增加核桃摄食量可能减少抑郁症的发生。但目前关于核桃抗抑郁的功效组分研究并未见报道,并且目前尚无核桃多酚抗抑郁方面的报道。
申请公布号CN201811021999.2的中国发病专利申请公开了一种核桃多酚制备工艺及其神经保护用途,提供了核桃多酚以活性为导向的制备工艺方法及该核桃多酚对活性氧H2O2和毒性肽Aβ淀粉肽诱导的人神经母细胞瘤(SH-SY5Y)细胞损伤具有明显的保护作用。而对核桃多酚通过增加神经营养作用发挥抗抑郁活性不清楚,与本专利所述权利要求无关。
发明内容
本申请的目的在于提供一种核桃多酚在制备抗抑郁药物和抗抑郁保健食品中的应用,旨在解决缺乏一种能够通过增加神经营养水平改善抑郁症状且副作用小的药物和保健食品的现有技术问题。
第一方面,本申请提供了核桃多酚在制备抗抑郁药物和抗抑郁保健食品中的应用。
进一步,所述核桃多酚通过保护皮质酮诱导大鼠嗜铬瘤PC12细胞损伤,包括增加细胞活力,抑制细胞凋亡,乳酸脱氢酶(LDH)释放量和钙离子水平升高,发挥抗抑郁作用。
进一步,所述核桃多酚通过上调皮质酮诱导的PC12细胞中PKA/CREB/BDNF神经营养通路发挥抗抑郁作用,包括上调脑源性神经营养因子(BDNF)和磷酸化蛋白激酶A(PKA)底物的表达量,并增加cAMP反应元件结合蛋白CREB133位点丝氨酸(S133)的磷酸化。
进一步,所述核桃多酚作为所述抗抑郁药物或抗抑郁保健食品的唯一活性成分。
进一步,所述抗抑郁药物或抗抑郁保健食品还包括药学或保健食品上可接受的辅料。
进一步,所述辅料包括药学及保健食品领域常规的稀释剂、赋形剂、填充剂、粘合剂、湿润剂、吸收促进剂、表面活性剂、润滑剂、稳定剂、香味剂、甜味剂、色素中的至少一种。
进一步,所述抗抑郁药物或抗抑郁保健食品可被制成任意一种药学或保健食品上可接受的剂型,如液体制剂(注射剂、混悬剂、乳剂、溶液剂、糖浆剂等)、固体制剂(片剂、胶囊剂、颗粒剂、冲剂等)、喷剂、气雾剂等。
第二方面,所述核桃多酚作为所述抗抑郁药物或抗抑郁保健食品的活性成分之一。
附图说明
图1不同浓度核桃多酚对PC12细胞活力的影响.**P<0.01,与对照组比较.
图2不同浓度核桃多酚对皮质酮损伤PC12细胞的保护作用.##P<0.01,与对照组相比;**P<0.01,与模型组比较。
图3核桃多酚对皮质酮损伤PC12细胞凋亡的影响.a对照组;b模型组;c核桃多酚(75μg/ml)+皮质酮(200μM);d核桃多酚(150μg/ml)+皮质酮(200μM)
图4核桃多酚对皮质酮损伤PC12细胞乳酸脱氢酶(LDH)漏出情况的影响.##P<0.01,与对照组相比;**P<0.01,与模型组比较.
图5核桃多酚对皮质酮损伤PC12细胞内钙离子水平的影响.##P<0.01,与对照组相比;**P<0.01,与模型组比较.
图6核桃多酚对皮质酮损伤PC12细胞BDNF表达量的影响.##P<0.01,与对照组相比;**P<0.01,与模型组比较.
图7核桃多酚对皮质酮损伤PC12细胞CREB磷酸化水平的影响.##P<0.01,与对照组相比;*P<0.05,**P<0.01,与模型组比较.
图8核桃多酚对皮质酮损伤PC12细胞p-PKA底物表达量的影响.#P<0.05,与对照组比较;*P<0.05,与模型组比较.
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合附图及实施例,对本发明进行进一步详细说明。本领域的技术人员应当理解的是,在不偏离本发明的精神和范围下可以对本发明技术方案的细节和形式进行修改或替换,但这些修改和替换均在本发明的保护范围。本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1 核桃多酚的制备与组分鉴定
(一)实验方法
核桃多酚样品制备:将去壳的核桃仁粉碎,按料液比1∶3加入石油醚,在室温下持续搅拌浸提6h后,抽滤取滤液,重复三次去除油脂;脱脂后的核桃仁粕按料液比1∶5加入75%乙醇溶液,在室温(25℃)下持续搅拌浸提6h,抽滤取滤液,重复三次,将三次得到的提取液合并在45℃旋蒸浓缩得到核桃粗多酚;将粗多酚和乙酸乙酯按1∶1混合萃取得到粗多酚的乙酸乙酯部位。采用极性树脂NKA-9对样品进行纯化,采用50%乙醇对浓缩液进行洗脱,然后应用中等极性树脂HP-20进一步纯化,先用75%乙醇洗脱浓缩液3次,然后用100%乙醇洗脱3次,收集合并100%乙醇洗脱物浓缩干燥得到核桃多酚。
核桃多酚活性组分鉴定:取核桃多酚样品用高纯水溶解,配成5mg/ml,过0.22μm的滤膜,待液相色谱分析。超高效液相色谱条件:色谱柱:Agilent InfinityLab Poroshell120 EC-C18(4.6×100mm,2.7μm粒度);流动相:A:0.1%甲酸高纯水,B:甲醇;柱温:20℃;流速:0.2μl/min;进样体积:5μl;检测波长:280nm。
表1 流动相洗脱表
注:A:0.1%甲酸高纯水,B:甲醇
质谱条件:
一级质谱条件:将Agilent 1290超高效液相色谱仪中色谱柱流出液,用T-型分流器(分流比1∶3)引入G6530A MS Q-TOF质谱检测器。电喷雾离子源:MS电喷雾离子化负离子模式;扫描范围100~1500u;扫描速率1.00mL/min;干燥气(N2)流速8.0L/min;干燥气温度360℃;喷雾气压力35psi;毛细管电压3000V;碎裂器电压100V。
二级质谱条件:质量扫描范围100~1500u;碰撞能量根据一级质谱所得化合物相对分子质量设定10~30eV。
(二)实验结果
通过一级质谱信息、二级质谱信息和美国国家标准与技术局数据库(NIST)及其与文献报道比较进行分析,结果见表1,结果显示核桃多酚活性组分中主要存在花梗鞣素/木麻黄鞣质异构体、trictinin/isostrictinin isomers、特里马素异构体、木麻黄鞣宁异构体、Strictinin/isostrictinin isomers、三聚乙酰-葡萄糖、四聚乙酰-葡萄糖、原花青素和Valoneic acid dilactone/sanguisorbic acid dilactone isomer、槲皮素戊糖苷异构体和鞣花酸等11种物质,这些化合物除原花青素外均含有六羟基联苯二甲酰基(hexahydroxydiphenoyl,HHDP)基团。这些结果初步阐明了本发明提供的提取方法得到的核桃多酚组成。
表2 核桃多酚活性组分中鉴定的多酚化合物的质谱数据
实施例2 核桃多酚对皮质酮所致PC12细胞的保护作用
应激激素糖皮质类固醇(人类为皮质醇,啮齿类动物为皮质酮)对大脑特别是海马神经元的损伤被认为是抑郁症发生的生理生化基础。体外实验发现皮质酮可导致PC12出现损伤和凋亡,模拟应激状态的海马神经元损伤状态,是目前最常用和最公认抑郁症的体外细胞模型。经典的抗抑郁药和抗抑郁植物有效成分在该模型上表现出很好的细胞保护作用。本实施例中采用皮质酮损伤的PC12细胞损伤模型评价核桃多酚潜在的抗抑郁作用,并采用细胞活力、细胞凋亡、乳酸脱氢酶(LDH)及钙超载等指标评价核桃多酚的细胞保护作用。
本实施中用到的PC12细胞购自美国标准生物品收藏中心(CRL-1721.1TM),使用含10%马血清、5%胎牛血清和1%双抗的RPMI 1640完全培养液培养。LDH试剂盒、钙离子试剂盒、细胞凋亡Hoechst33342染色试剂盒均购自碧云天生物技术有限公司。p-PKA底物抗体,CREB抗体购自美国Cell Signaling公司,p-CREB(Ser133)抗体购自Merck公司,皮质酮和BDNF抗体购自Sigma公司。
本实施中数据结果以均值±标准查表示,数据应用软件GraphPad Prism 6.0版本分析,多组间采用单因素方差分析(one-way analysis of variance,one-way ANOVA)Dunnett′s t-test检验进行分析,当P<0.05认为组间存在显著性差异。
(一)实验方法
核桃多酚对PC12细胞生长的影响:用无血清培养基稀释核桃多酚母液,配制成浓度为50、75、100、150、200μg/mL的核桃多酚培养液,孵育12h。每组设置6个复孔。采用MTT法测定细胞活力,在多功能酶标仪490nm处测量各孔的吸光值。按照公式(1)计算其相对细胞活力:
核桃多酚对皮质酮损伤PC12细胞活力的影响:取对数生长期PC12细胞,按照1×104个/孔的密度接种子96孔板中,孵育过夜。用无血清培养基配置75、150μg/mL的核桃多酚培养液,孵育12h。弃原培养液,模型组与加药组加入含有200μM浓度皮质酮的无血清培养液,孵育24h,用MTT法测定细胞活力,相对细胞活力计算同上。
核桃多酚对皮质酮损伤PC12细胞凋亡的影响:PC12细胞按照1×105个/mL接种于6孔板中,孵育过夜。用无血清培养基配置75和150μg/mL的核桃多酚溶液,孵育12h。弃原培养液,模型组与加药组加入含有200μM浓度皮质酮的无血清培养液,孵育24h,弃去原培养液,加入含有Hoechst 33342染色液的无血清培养液,在37℃下孵育10min。用PBS溶液洗涤三次后在荧光显微镜下观察细胞并拍照。
核桃多酚对皮质酮损伤PC12细胞LDH释放的影响:PC12细胞按照1×105个/mL接种于6孔板中,孵育过夜。用无血清培养基配置75、150μg/mL的核桃多酚溶液,孵育12h。弃原培养液,模型组与加药组加入含有200μM浓度皮质酮的无血清培养液,孵育24h,每孔取1mL细胞培养液,离心后取上清液按试剂盒说明书测定LDH水平。
核桃多酚对皮质酮损伤PC12细胞内钙离子浓度的影响:PC12按照1×104个/孔的密度接种于96孔黑边透明底板,孵育过夜。用无血清培养液将核桃多酚母液稀释成75、150μg/mL,孵育12h。弃原培养液,加入含有200μM浓度皮质酮的无血清培养液,孵育24h。弃去培养液,加入无血清培养液配制的含有5μM Fluo-2 AM荧光探针的培养液,37℃培养30min。用PBS洗三次除去未装载的探针。双波长检测,激发波长为340nm和380nm,发射波长510nm。
蛋白免疫印迹法测定核桃多酚对PKA/CREB/BDNF神经营养通路的影响:取对数生长期PC12细胞,按照1×105个/mL接种于6孔板中,孵育过夜。用无血清培养基配置75、150μg/mL的核桃多酚溶液,孵育12h。弃原培养液,模型组与加药组加入含有200μM浓度皮质酮的无血清培养液,孵育24h,用RIPA裂解液在冰上裂解细胞,离心收集蛋白,采用BCA蛋白定量试剂盒测定蛋白浓度。蛋白样品经SDS-PAGE凝胶电泳分离,湿转法将蛋白转至PVDF膜上,5%脱脂奶粉室温封闭1h。再分别加入一抗p-PKA底物(1∶2 000),p-CREB(1∶2 000),CREB(1∶4 000),BDNF(1∶4 000),β-actin(1∶4000)在4℃摇床孵育过夜。PBST缓冲液洗涤10min×3次,加入二抗室温孵育1h,PBST缓冲液洗涤10min×3次。加入ECL化学发光液显影。采用凝胶成像仪检测,以Image Lab软件进行分析,以β-actin为内参计算相对灰度值,用来表示目标蛋白的表达水平。
(二)实验结果
核桃多酚对皮质酮损伤PC12细胞的保护作用:如图1所示,与对照组细胞活力相比较,浓度范围为50~150μg/mL的核桃多酚对正常培养的PC12细胞活力没有明显降低。而200μg/mL核桃多酚可显著降低PC12细胞活力,表现出细胞毒作用。如图2所示,核桃多酚50、75、100、150μg/mL浓度可显著逆转皮质酮诱导的PC12细胞活力的降低(P<0.01),表现出细胞保护作用。如图3所示,与对照组相比,皮质酮处理PC12细胞中凋亡细胞数量明显增加,表现为细胞核皱缩、染色质凝固,不均一,75和150μg/mL浓度核桃多酚预孵育12h可明显减少凋亡细胞数量和形态。如图4所示,与对照组相比,皮质酮处理可显著增加PC12细胞中LDH的释放,导致培养液中LDH水平显著升高(P<0.01)。75和150μg/mL核桃多酚处理的组可显著降低培养液中LDH水平(P<0.01)。如图5所示,与对照组相比,皮质酮引起PC12细胞内钙离子水平显著升高(P<0.01)。75和150μg/mL核桃多酚处理的组可显著降低细胞内钙离子水平(P<0.01)。以上结果显示核桃多酚可显著逆转皮质酮所致PC12细胞的损伤,从而发挥抗抑郁作用。
核桃多酚上调皮质酮损伤PC12细胞PKA/CREB/BDNF神经营养通路:如图6所示,与皮质酮模型组比较,核桃多酚75和150μg/mL处理的组可显著增加BDNF的表达量(P<0.01);如图7所示,与皮质酮模型组比较,核桃多酚75和150μg/mL处理的组可显著增加CREB133位点丝氨酸的磷酸化水平(P<0.05或P<0.01);PKA是CREB最主要的上游激酶,我们参考文献方法[S.Didier,F.Sauvé,M.Domise,et al.,AMP-activated protein kinase controlsimmediate early genes expression following synaptic activation through thePKA/CREB pathway,Int.J.Mol.Sci.19(2018).https://doi.org/10.3390/ijms19123716.],通过测定磷酸化PKA底物含量评价PKA活性,如图8所示,与皮质酮模型组比较,核桃多酚75和150μg/mL处理的组可显著增加磷酸化PKA底物的表达量(P<0.05),增加PKA活性。以上结果表明核桃多酚可显著增加PKA/CREB/BDNF神经营养通路活性,从而发挥抗抑郁作用。
Claims (9)
1.核桃多酚在制备抗抑郁药物和抗抑郁保健食品中的应用。
2.根据权利要求1所述的应用,其特征在于,所述核桃多酚通过保护皮质酮诱导的大鼠嗜铬瘤PC12细胞损伤,并上调PKA/CREB/BDNF神经营养通路活性,改善皮质酮引起的神经营养低下,发挥抗抑郁作用。
3.根据权利要求2所述的应用,其特征在于,上调PKA/CREB/BDNF神经营养通路表达步骤中,包括:所述核桃多酚可上调脑源性神经营养因子(BDNF)和磷酸化蛋白激酶A(PKA)底物的表达,并增加cAMP反应元件结合蛋白CREB133位点丝氨酸(S133)的磷酸化。
4.根据权利要求1~3任一所述的应用,其特征在于,所述核桃多酚作为所述抗抑郁药物或抗抑郁保健食品的唯一活性成分。
5.根据权利要求1~3任一所述的应用,其特征在于,所述抗抑郁药物或抗抑郁保健食品包括核桃多酚药学或保健食品上可接受的盐、共晶、立体异构体、前药、溶剂化物、代谢产物中的至少一种。
6.根据权利要求1~3任一所述的应用,其特征在于,所述抗抑郁药物或抗抑郁保健食品还包括药学或保健食品上可接受的辅料。
7.根据权利要求1~3任一所述的应用,其特征在于,所述辅料包括药学及保健食品领域常规的稀释剂、赋形剂、填充剂、粘合剂、湿润剂、吸收促进剂、表面活性剂、润滑剂、稳定剂、香味剂、甜味剂、色素中的至少一种。
8.根据权利要求1~3任一所述的应用,其特征在于,所述抗抑郁药物或抗抑郁保健食品可被制成任意一种药学或保健食品上可接受的剂型,如液体制剂(注射剂、混悬剂、乳剂、溶液剂、糖浆剂等)、固体制剂(片剂、胶囊剂、颗粒剂、冲剂等)、喷剂、气雾剂等。
9.根据权利要求1~3任一所述的应用,其特征在于,所述核桃多酚作为所述抗抑郁药物或抗抑郁保健食品的活性成分之一。
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