WO2022088656A1 - 黑果腺肋花楸叶多酚提取物在制备抗抑郁药物中的应用 - Google Patents
黑果腺肋花楸叶多酚提取物在制备抗抑郁药物中的应用 Download PDFInfo
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- WO2022088656A1 WO2022088656A1 PCT/CN2021/095178 CN2021095178W WO2022088656A1 WO 2022088656 A1 WO2022088656 A1 WO 2022088656A1 CN 2021095178 W CN2021095178 W CN 2021095178W WO 2022088656 A1 WO2022088656 A1 WO 2022088656A1
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Abstract
一种黑果腺肋花楸叶多酚提取物在制备预防、调节或治疗抑郁症的药物、功能性食品或补剂中的应用。该提取物含有芦丁、绿原酸及异构体、3-O-咖啡酰奎宁酸、槲皮素及其衍生物槲皮素3-O-α-L吡喃阿糖基-(1→6)β-D-吡喃葡糖苷、咖啡酸及其衍生物金丝桃苷。该提取物能通过调节抑郁症小鼠肠道菌群丰富度与多样性至正常水平，显著提高抑郁症小鼠大脑海马区BDNF(脑源性神经营养因子)水平，对小鼠抑郁症状具有显著改善作用。该提取物属于无毒无害的天然成分，不产生副作用。
Description
本发明公开一种黑果腺肋花楸叶多酚提取物在预防、调节或治疗抑郁症领域中的应用，属于药品、功能性食品、补剂等相关产品领域。
抑郁症是一种特征为显著持久的情绪低落，对日常令人愉快的活动失去兴趣的情感障碍。随着人们生活压力的增大，抑郁症的发病率也逐年增加，据世界卫生组织统计，预计到2020年，抑郁症将超过心血管疾病成为威胁人类健康的第二大疾病。2019年北大团队在《柳叶刀》子刊发表的研究，全球估计预计有3.5亿人患抑郁症，中国患者超过9500万。2020年9月11日，国家卫健委发布的《探索抑郁症防治特色服务工作方案》要求，“抑郁症筛查”可能成为体检固定项目。这无不表明抑郁症对人们身心健康、生活工作产生巨大影响。
抑郁症的发病机制十分复杂，目前单胺学说受到广泛的认可。单胺学说认为由于神经递质如5-羟色胺与去甲肾上腺素的水平低下而引起抑郁，据此研发提高两者水平的抗抑郁药物，但此类药物仅仅有益于部分患者，并且患者可能出现耐药性等不良反应。
人类肠道中微生物数量庞大且种类丰富，参与着人体许多生理活动，影响宿主的健康。近年来研究发现，肠道微生物的结构和多样性与抑郁症联系紧密，肠道微生物与抑郁症通过“脑-肠-微生物”轴相互影响。而且，抑郁动物模型与抑郁症患者存在相似的微生物结构。据研究证实肠道菌群的改变能够引起大脑海马区中脑源性神经营养因子(brain-derived neurotrophic factor，BDNF)的改变。BDNF是神经生长的重要调节因子，BDNF水平降低，神经凋亡增加会引起抑郁症状；脑中BDNF和其他神经营养含量的增加，能够减少海马神经元的凋亡，促进神经元生长，改善认知和情绪。研究表明乳酸菌与双歧杆菌可通过改变肠道组成和肠道菌群多样性、降低炎症因子、调节中枢神经系统等机制缓解抑郁症。
因此，通过食品中的营养物质干预调节抑郁症与开发高效、对人体无毒害与副作用的抑郁调节营养体系成为了人们关注的重点。近年来研究发现，许多食品例如桔梗、黄花菜、肉豆蔻等具有缓解抑郁症的功能。黑果腺肋花楸(简称黑果)是一种富含多酚类物质的可食用浆果，具有抗氧化、免疫调节、抗炎等多种功效。黑果腺肋花楸叶多酚提取物主要为原花青素、花色苷、酚酸等，如芦丁、绿原酸及异构体、3-O-咖啡酰奎宁酸、槲皮素及其衍生物槲皮素3-O-α-L吡喃阿糖基-(1→6)β-D-吡喃葡糖苷、咖啡酸及其衍生物金丝桃苷。具体物质并且黑果中所含有的多酚总量高于许多其他种类的浆果。多酚对慢性不可预知应激引起的 小鼠抑郁具有改善作用，其机制可能与抑制脑组织氧化应激反应有关。此外，多酚可提高人体内的肠道细菌对多酚代谢物的生物利用能力，而这些多酚的代谢物能够促进心理状况。
目前，对于黑果腺肋花楸叶多酚提取物的研究较少，同时，亦未见黑果腺肋花楸叶多酚提取物在预防、调节或治疗抑郁症方面的应用报道，因此，开展黑果腺肋花楸叶多酚提取物在抗抑郁的药物、功能性食品或补剂方面的应用具有重要意义。
发明内容
本发明提供一种黑果腺肋花楸叶多酚提取物及其制备方法和应用，具有预防、调节或治疗抑郁症作用，可应用于药品、功能性食品、补剂以及药食同源的食品领域。
本发明所述的黑果腺肋花楸叶多酚提取物可以从黑果中提取得到，其提取方法也有大量的现有文献报道，而黑果可以通过商业购买获得。所述的黑果腺肋花楸叶多酚提取物，其组成为芦丁、绿原酸及异构体、3-O-咖啡酰奎宁酸、槲皮素及其衍生物槲皮素3-O-α-L吡喃阿糖基-(1→6)β-D-吡喃葡糖苷、咖啡酸及其衍生物金丝桃苷。
优选的，所述黑果腺肋花楸叶多酚提取物应用剂量为15-25mL/kg体重。
优选的，适当剂量的黑果腺肋花楸叶多酚提取物可以有效降低肠道微生物中某些有害菌的相对丰度，调节肠道微环境，维持肠道菌群多样性和丰富度在正常水平。对降低抑郁症小鼠肠道菌群多样性具有积极影响。可以调节肠道微生物菌群结构，显著提高抑郁症小鼠大脑海马区BDNF的表达水平。
优选的，黑果腺肋花楸叶多酚提取物对有害菌拟杆菌门中有一定的抑制作用，且有益于有益菌厚壁菌门的增殖。
优选的，黑果腺肋花楸叶多酚提取物能够将抑郁小鼠的肠道菌群丰富度与多样性恢复到正常水平，有利于BDNF的释放，改善抑郁症状。
优选的，所述的黑果腺肋花楸叶多酚提取物在制备预防、调节或治疗抑郁症的功能性食品、补剂中的应用。
优选的，所述的黑果腺肋花楸叶多酚提取物在制备预防、调节或治疗抑郁症的药物中的应用。
进一步的，上述药物、功能性食品或补剂中，可根据需要加入合适的载体、辅料或辅助成分。所述抗抑郁症药物、功能性食品或补剂的剂型可以是任何一种药剂学上的剂型。
1.本发明验证了黑果腺肋花楸叶多酚提取物可以降低小鼠肠道有害菌群相对丰度，抑制拟杆菌门的增殖，防止炎症产生。同时，黑果腺肋花楸叶多酚提取物有益于厚壁菌门的增殖，从 而保证了肠道上皮细胞的能量获取，防止致病菌的进入，并促进了5-HT分泌。黑果腺肋花楸叶多酚提取物可以减少因肠道微生物紊乱而造成的不良影响，调节肠道微生物菌群丰富度和多样性到正常水平。
2.本发明的黑果腺肋花楸叶多酚提取物具有调节肠道微环境，改善肠道菌群结构，提高大脑海马区BDNF表达水平的作用。
3.本发明提供了一种黑果腺肋花楸叶多酚提取物在抗抑郁的药物、功能性食品或补剂中的应用，属于黑果新型产品的开发，可以将黑果腺肋花楸叶多酚提取物作为添加剂添加到药物、功能性食品或补剂中提升其价值，黑果腺肋花楸叶多酚提取物可以有效改善肠道菌群，用于预防、调节或治疗抑郁症，并避免了传统药物产生的毒副作用。
以下将结合实施例对本发明进行详细清楚的描述。
实施例1
黑果多酚提取物与试剂：
黑果取自淄博市铁山林场。黑果叶子多酚提取物制备方法：将新鲜黑果叶子洗净，打浆。称取5g浆液按照1:5料液比添加适量50％乙醇超声40min后，抽滤，滤液50℃减压除去乙醇后，经冷冻干燥后冷冻保存，备用。
皮质酮由江苏佳尔科药业集团有限公司提供；丙二醇由济南华赢化工有限公司提供；氟西汀由山东西亚化学工业有限公司提供。
实施例2
黑果腺肋花楸叶多酚提取物提取过程：
黑果腺肋花楸叶多酚提取物制备方法：将新鲜黑果腺肋花楸叶洗净，打浆。称取5g浆液按照1:5料液比添加适量50％乙醇超声40min后，抽滤，滤液50℃减压除去乙醇后，经冷冻干燥后冷冻保存，备用。实验室配制成0.15mg/mL黑果腺肋花楸叶多酚叶提取物。
建立抑郁症小鼠模型：
100只雄性BALB/C小鼠，通过皮下注射0.2mL皮质酮建立抑郁症小鼠模型。用正常小鼠构建正常组，建模成功的抑郁症小鼠分为模型组、溶剂组(0.2mL丙二醇)、药物组(0.2mL氟西汀)、黑果腺肋花楸叶多酚提取物低、中、高剂量组(0.2mL黑果腺肋花楸叶多酚提取物含量分别是0.15mg/mL、20mg/mL、25mg/mL)进行分组，每笼10只小鼠进行为期4周的灌胃实验，正常组与模型组灌取同等体积的生理盐水。喂养实验结束，取大鼠肠道粪便贮于灭菌EP管中，液氮中保存。测定肠道菌群多样性、菌群群落、PCA等分析。
实施例3
大鼠喂养实验结束后取其肠道粪便进行肠道菌群稀释曲线分析。与空白组相比，模型组Sobs值显著高于空白组，表明抑郁症会提高小鼠肠道菌群的多样性。与模型组相比，黑果腺肋花楸叶多酚提取物中剂量组肠道菌群的多样性显著降低，表明合适剂量的黑果腺肋花楸叶多酚提取物对降低抑郁症小鼠肠道菌群多样性具有积极影响。
实施例4
大鼠喂养实验结束后取其肠道粪便进行肠道菌群Alpha多样性分析(见表1)。与空白组相比，模型组Chao值与Ace值显著下降，表明抑郁症会降低小鼠肠道菌群的丰富度；而药物组的肠道菌群丰富度显著下降，表明药物对提高小鼠肠道菌群丰富度不具有积极影响；与模型组相比，黑果腺肋花楸叶多酚提取物低剂量组肠道菌群丰富度即显著提高，表明适当剂量的黑果腺肋花楸叶多酚提取物对提高抑郁症小鼠肠道菌群丰富度有积极影响。黑果腺肋花楸叶多酚提取物高剂量组的小鼠肠道菌群丰富度与多样性与空白组较相近，表明高剂量的黑果腺肋花楸叶多酚提取物可以将小鼠的肠道菌群维持在正常水平。
表1黑果腺肋花楸叶多酚提取物对抑郁症小鼠肠道菌群影响的ALPHA多样性分析
注：与空白组比较，*p<0.05。D：空白组；M：模型组；Y：药物组；HYd、HYz、HYg：分别表示黑果腺肋花楸叶多酚提取物低、中、高剂量组。
实施例5
大鼠喂养实验结束后取其肠道粪便进行肠道菌群群落组成测定分析(见表2)。模型组小鼠肠道菌群中拟杆菌门比例较空白组显著提高，黑果腺肋花楸叶多酚提取物组拟杆菌门的比例均低于模型组，表明黑果腺肋花楸叶多酚提取物对拟杆菌门中有一定的抑制作用。模型组肠道菌群中厚壁菌门比例较空白组显著降低，黑果腺肋花楸叶多酚提取物组中厚壁菌门比例均高 于模型组，表明黑果中的多酚化合物有益于厚壁菌门的增殖。
表2小鼠肠道菌群门水平群落组成
注：与空白组比较，*p<0.05。D：空白组；M：模型组；Y：药物组；HYd、HYz、HYg：分别表示黑果腺肋花楸叶多酚提取物低、中、高剂量组。
实施例6
大鼠喂养实验结束后取其肠道粪便进行肠道菌群PCA分析。空白组与其他组的差异主要在PC2方向上，PC2可以解释23.83％的差异性，空白组与药物组、黑果腺肋花楸叶多酚提取物组的相似性极高。以上表明模型组小鼠肠道菌群失调，黑果腺肋花楸叶多酚提取物可以调节改善抑郁症小鼠肠道菌群，且高剂量组的调节功效最佳。
实施例7
大鼠喂养实验结束后进行BDNF测定。小鼠脱颈致死后，剪开头骨，用解剖刀片将小鼠脑切开，将位于大脑皮层底部的海马组织取出，处理后的样品加入适量浓缩SDS-PAGE蛋白缓冲液进行蛋白分离，电压120V。用PVDF膜进行膜转化，完成后清洗2次，4℃密封过夜。在原稀释液中孵育1h，洗涤5min，洗涤3次，第2次抗体孵育步骤同上，最终曝光显影。
结果发现与空白组相比，模型组BDNF水平显著下降，抑郁症使小鼠的肠道菌群失衡，菌群的改变诱发了精神紊乱，使得小鼠大脑中BDNF表达降低。与模型组相比，黑果腺肋花楸叶多酚提取物低剂量组与高剂量组BDNF水平显著提高，表明合适剂量的黑果叶子提取物有利于BDNF的释放。
Claims (10)
- 一种黑果腺肋花楸叶多酚提取物在制备预防、调节或治疗抑郁症的药物、功能性食品或补剂中的应用，其特征在于，黑果腺肋花楸叶多酚提取物的组成为芦丁、绿原酸及异构体、3-O-咖啡酰奎宁酸、槲皮素及其衍生物槲皮素3-O-α-L吡喃阿糖基-(1→6)β-D-吡喃葡糖苷、咖啡酸及其衍生物金丝桃苷。
- 如权利要求1的应用，其特征在于，所述黑果腺肋花楸叶多酚提取物应用剂量为15-25mL/kg体重。
- 如权利要求1的应用，其特征在于，黑果腺肋花楸叶多酚提取物可以能够有效降低肠道微生物中某些有害菌的相对丰度，调节肠道微环境，维持肠道菌群多样性和丰富度在正常水平。
- 如权利要求1的应用，其特征在于，黑果腺肋花楸叶多酚提取物能够调节肠道微生物菌群结构，提高抑郁症小鼠大脑海马区BDNF的表达水平。
- 如权利要求1所述的黑果腺肋花楸叶多酚提取物的应用，其特征在于，所述的黑果腺肋花楸叶多酚提取物在抗抑郁症的药物中的应用。
- 如权利要求1所述的黑果腺肋花楸叶多酚提取物的应用，其特征在于，所述的黑果腺肋花楸叶多酚提取物在抗抑郁症的功能性食品、补剂中的应用。
- 如权利要求5或6的应用，其特征在于，所述抗抑郁症是指预防、调节或治疗抑郁症。
- 如权利要求5或6的应用，其特征在于，在所述药物、功能性食品或补剂中加入可接受的载体。
- 如权利要求5或6的应用，其特征在于，在所述抗抑郁药物、功能性食品或补剂中，加入可接受的辅料或辅助成分。
- 如权利要求5或6的应用，其特征在于，所述抗抑郁症药物、功能性食品或补剂的剂型是任何一种药剂学上的剂型。
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| CN108157968A (zh) * | 2018-03-15 | 2018-06-15 | 黑龙江绿知都生物科技开发有限公司 | 一种调节并改善人体内分泌系统的蓝莓复合冲剂及其制备方法 |
| CN112190618A (zh) * | 2020-11-02 | 2021-01-08 | 山东理工大学 | 黑果腺肋花楸叶多酚提取物在制备抗抑郁药物中的应用 |
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