CN109364097A - 瓜尔豆胶在制备抗抑郁症药物及保健品中的应用 - Google Patents
瓜尔豆胶在制备抗抑郁症药物及保健品中的应用 Download PDFInfo
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Abstract
本发明提供一种部分水解的瓜尔豆胶（PHGG）在制备抗抑郁症药物及保健品中的应用，属于天然植物活性成分的功能与应用领域。通过采用慢性不可预知性温和应激结合单笼饲养的模式创建小鼠抑郁症模型，并进行PHGG对抑郁小鼠行为学的影响和抗抑郁的药效机制研究等系列实验，结果显示，PHGG可改善抑郁症小鼠的快感缺乏和在应激状态下的绝望不动状态，如在糖水偏爱测试实验中PHGG能够提高抑郁小鼠对糖水的偏爱，减少强迫游泳试验中的不动时间，生理指标上，PHGG提高小鼠海马体中神经递质多巴胺和5‑羟色胺的水平，这些指标的改善表明PHGG能够缓解小鼠的抑郁症。因此，将PHGG开发成功能性保健品或者药物可有效防治抑郁症。
Description
技术领域
本发明属于天然植物活性成分的功能与应用领域，具体涉及PHGG在制备抗抑郁症药物及保健品中的应用。
背景技术
部分水解的瓜尔豆胶(PHGG，partially hydrolyzed guar gum)是一种天然的水溶性膳食纤维，其通过瓜尔豆胶种子的受控部分酶水解而生产。PHGG不能被哺乳动物消化吸收，但容易在肠道中被细菌发酵，增加有益菌和有害菌的比例，从而起到调节肠道菌群的作用。PHGG多用作食品添加剂，还具有修复创伤、改善便秘、改善肠道应激综合症、抑制小肠对脂肪和胆固醇的吸收等功能。
神经性障碍疾病患病率在我国疾速增加，尤其是抑郁症已经成为我国疾病负担的第二大病，抑郁症是一种与各种遗传、生物和环境因素有关的发病机制的慢性综合征，主要表现为情感低落，伴有相应的行为和认知改变。据世界卫生组织(WHO)统计，全球约有3.4亿人口遭受抑郁症的折磨，终生患病率高达10～20％，一年中分别约有5.8%的男性和9.5%的女性发病。据WHO预测，到2020年抑郁症将成为继心血管疾病之后的第二大影响人类生活质量的疾病。抑郁症发病率高、发病年龄跨度大、难治愈、复发率高、对患者生活质量易造成长期的影响。市场上流行的抗抑郁药物均具有副作用和过量时的毒性作用。如三环类抗抑郁药氯米帕明、丙咪嗪和阿米替林等，会导致口干、心跳过速、视力模糊、青光眼、便秘、认知障碍等。因此，研发无毒副作用的天然活性成分以作为防治抑郁症的药物刻不容缓。
当前新的抗抑郁药作用靶点和抑郁症发病机制研究的主要方向为单胺类神经递质异常假说和下丘脑-垂体-肾上腺素轴假说(HPA)，其中单胺类神经递质异常假说是目前新抗抑郁药治疗抑郁症的主要依据。近年来，许多研究认为肠道菌群与神经相关疾病有一定的联系，而通过一些膳食补充剂调整肠道菌群代谢产物，可能对治疗或改善神经相关疾病具有积极意义。
本发明通过大量的应用基础性实验证明PHGG能改善慢性不可预知性温和应激(CUMS, chronic unpredictable mild stress)导致的各种行为学异常和抑郁症相关单胺类神经递质表达异常，从而起到缓解抑郁症的作用。因此，可将PHGG用于抑郁症等相关精神性疾病的治疗。
发明内容
抑郁症是受各种遗传或环境因素影响的疾病，目前在预防和治疗上仍有很大缺陷和不足，而且抑郁症相关治疗药物对人体的脏器损伤较为严重。本发明的目的在于提供PHGG在制备抗抑郁症药物及保健品中的应用。
为实现上述目的，本发明采用如下技术方案：
本发明要保护的内容是部分水解的PHGG在制备抗抑郁症药物中的应用。
患有抑郁症的小鼠海马体神经递质多巴胺（DA, dopamine）和5-羟色胺(5-HT)等单胺类神经递质减少，对应激的反应下降、快感缺乏，行为学表现为强迫游泳不动时间增加，对糖水的偏爱减少。我们经研究表明，PHGG处理能够减少抑郁小鼠强迫游泳实验中的不动时间，并显著增加抑郁小鼠对糖水的偏爱百分比，小鼠对糖水偏爱百分比的增加表明小鼠对奖赏的反应性升高，这说明PHGG能够缓解抑郁小鼠的快感缺乏和提高小鼠对应激的反应。另外，我们还发现PHGG这种抗抑郁作用和小鼠体内单胺类神经递质的释放有关，CUMS会导致小鼠体内DA、5-HT等单胺类神经递质含量下降，而PHGG能够刺激DA、5-HT的释放，从而达到改善小鼠抑郁的效果。
本发明的显著优点在于：
本发明首次发现了PHGG能够通过改善小鼠海马体中DA和5-HT等单胺类神经递质异常，以及缓解小鼠的快感缺乏和增强小鼠对应激的反应，达到改善小鼠抑郁症的效果，这对今后开发、制备预防和治疗抑郁症的药物提供了重要的实验基础和科学依据。
附图说明
图1是抑郁症造模阶段小鼠的体重变化结果图，与对照组相比，CUMS组小鼠体重增长缓慢，在造模第28天时，CUMS组小鼠体重显著低于正常小鼠，说明CUMS抑制了小鼠体重的正常增长。*，p<0.05，基于student’s t-test。
图2是抑郁症造模阶段小鼠对糖水偏爱实验的结果图，从图中看出，造模第二周开始，CUMS组小鼠对糖水的偏爱百分比相对于对照组显著降低。*，p<0.05，基于student’s t-test。
图3是抑郁症造模第28天时小鼠强迫游泳实验不动时间的结果图，从图中可以看出，与对照组相比，CUMS组小鼠的强迫游泳不动时间显著增加。*，p<0.05，基于student’st-test。
图4是造模抑郁症成功之后，经PHGG、阳性药物氟西汀及其两者复配物干预后抑郁小鼠的体重变化情况，从图中可以看出，经PHGG处理可以缓解CUMS对小鼠体重增长的抑制作用，而且，PHGG和氟西汀的复配物缓解效果更好。*，p<0.05，基于student’s t-test。
图5 是造模抑郁症成功之后，经PHGG、氟西汀、PHGG与氟西汀的复配物干预后小鼠对糖水的偏爱实验结果，如图所示，相比于抑郁组，PHGG处理能显著提高小鼠对糖水的偏爱百分比，氟西汀、氟西汀与PHGG的复配物干预都有显著效果，且前期阳性药物氟西汀的干预效果最好，直至干预后期即实验第56天时，PHGG干预效果高于药物氟西汀组和复配物组。*，p<0.05，基于student’s t-test。
图6 是造模抑郁症成功之后，抑郁小鼠经PHGG、氟西汀及其复配物干预后的强迫游泳不动时间结果图，如图所示，相对于抑郁组，PHGG与氟西汀的复配处理和单独的氟西汀处理能显著减少小鼠的强迫游泳不动时间，而单独的PHGG处理没有显著效果。*，p<0.05，基于student’s t-test。
图7是造模成功后的抑郁小鼠经过PHGG、氟西汀、PHGG与氟西汀的复配物干预后海马体多巴胺的浓度，如图所示，与抑郁组相比，氟西汀的干预可以显著升高小鼠海马体多巴胺的浓度， PHGG与氟西汀的复配物干预效果更好，而单独的PHGG处理在一定程度上能升高小鼠海马体多巴胺的浓度。*，p<0.05，基于t-test。
图8是造模成功后的抑郁小鼠经过PHGG、氟西汀、PHGG与氟西汀的复配物干预后海马体5-羟色胺的浓度，从图中可以看出，相对于抑郁小鼠， PHGG、氟西汀、PHGG与氟西汀的复配物处理均能显著提高小鼠海马体5-羟色胺的浓度。*，p<0.05，基于t-test。
具体实施方式
为了使本发明所述的内容更加便于理解，下面结合具体实施方式对本发明所述的技术方案做进一步的说明，但是本发明不仅限于此。
实施例1
部分水解的PHGG的制备，瓜尔豆胶通过内切-β-D甘露聚糖酶，在pH=6，温度为50℃条件下，孵育2~3小时，进行降解。随后，采用D315大孔树脂-732阳离子交换树脂-717阴离子交换树脂的树脂组合对降解液进行脱盐、脱色、脱味的提纯处理。提纯液经冷冻干燥得样品。利用液相色谱检测样品的分子量（平均分子量在20kDa）。制得样本用于后续的抑郁小鼠干预实验。
实验对象为体重相近的36只雄性C57BL/6小鼠，其中6只作为对照组，正常饲养；其余30只用慢性不可预知性温和应激(CUMS)结合单笼饲养进行抑郁症造模，实验进行28天，对小鼠进行行为学评价以判断模型是否成功，有糖水偏爱实验（SPT）和强迫游泳实验（FST）。所有行为测试在上午9点和13点之间进行，若造模组和对照组的数据差异(p<0.05)具有统计学意义，则说明抑郁症模型建立成功。
表1 慢性不可预知性温和应激抑郁症模型计划
注： SPT：糖水偏爱实验 FST：强迫游泳实验 OFT：矿场实验
一糖一水表示SPT适应期的前两天，两个水瓶中，一瓶装纯水，一瓶装1%的糖水。两糖表示SPT适应期的前一天，两个水瓶中都装1%的糖水。
抑郁症模型创模成功后，将抑郁小鼠随机分为以下几组，按照计划表继续创模并同时灌胃生理盐水组（抑郁），按照计划表继续创模并同时灌胃0.01 g/mL PHGG组（抑郁+PHGG），按照计划表继续创模并同时灌胃0.01 g/mL PHGG和1 mg/mL氟西汀组（抑郁+PHGG+氟西汀），按照计划表继续创模并同时灌胃1 mg/kg氟西汀组（抑郁+氟西汀），每组6只，干预阶段实验进行28天。
小鼠行为学评价：
糖水偏爱测试实验
实验前2天，小鼠进行糖水适应，每笼同时给予2个装有1%蔗糖水的水瓶，24小时后(8：00～8：00)，再换另外2瓶水，一瓶装1%蔗糖水，一瓶装纯水。正式测试时，测量蔗糖水和纯水的质量，开始测试前3个小时内每隔半小时进行一次双瓶位置交换，24 h后测量蔗糖水和纯水的质量，称量每只小鼠体重。每周进行一次上述试验。小鼠糖水偏爱百分比=糖水偏爱量/(糖水偏爱量+纯水消耗量)/小鼠体重 × 100%。
强迫游泳实验
实验室地点：要保证测试小鼠不被其他小鼠看见。如果测试地点较远，则需要使用带有新鲜寝具的临时干笼。实验室的窗帘拉上，采用照明灯(40 W)，保持实验室内灯光不变。实验在一个安静的场地，注意避免人员走动，每次测试在固定时间段进行。
在测试前1天，在25 cm×16 cm圆柱型玻璃容器内注入15 cm高的水，水温约为23±2℃，将小鼠放入水中适应15 min，适应结束后将小鼠用已灭菌的吸水毛巾擦干，避免小鼠感冒。正式测试时，将小鼠放入圆柱型玻璃容器，计时6 min。将记录设备放置在圆柱上至少30 cm，并对图像进行聚焦，以提供下面圆柱体的完整直径的清晰，清晰的图像。记录小鼠后4 min的不动时间(在水面漂浮只有轻微的活动或是身体垂直于水面只有鼻子露出水面的时间记录为不动时间)。每周进行一次。
海马体中DA和5-HT检测
海马体样品前处理：小鼠处死后，摘取脑袋，从脑组织中剥离海马体后，将组织裂解液与海马体脑组织按照10:1(ml:g)混合，将玻璃匀浆器置于碎冰中低温匀浆，低温静置30min，15,000 r/min低温离心15 min，弃去沉淀，吸取上清液，加入等体积的高氯酸沉淀剂，在碎冰中静置10 min 后15,000 r/min低温离心15 min，用0.22 μm水系滤膜过滤，弃去沉淀，取上清液20 μL进行上样分析。
HPLC条件：高效液相-荧光检测器，色谱柱Hypersil GOLD C18 (5 μm, 250 ×4.6 mm) (SN: 10512640)，流速为1.0 mL/min，进样量为20 μL，发射波长为330 nm，激发波长为280 nm。采集时间为40 min，等度洗脱。
统计学处理
采用Excel进行统计分析，各组数据以平均数±标准误(Mean±SEM)表示，实验数据均采用t-test检验，统计学意义差异设定在0.05(即P<0.05)。采用GraphPad Software 5.0软件完成图表的绘制。
结果如图1-8所示：图1-3揭示了创模组的体重下降，糖水偏爱实验的糖水饮用量减少，和不动时间的提高，说明抑郁模型创建成功。图4-8表明通过PHGG的干预，可以使抑郁小鼠的体重回升，恢复味觉，增加活动时间，以及提升海马体神经递质量。
上述结果表明，抑郁小鼠经过PHGG干预后对小鼠的抑郁症有所改善。在本实验中，利用CUMS结合单笼饲养，模仿人类去除社会援助，模拟人类离开社会支持的状态，增加无望感和无助感，从而增强抑郁情绪，长期身心应激导致HPA轴功能持续活跃，其中海马体对应激最为敏感，是HPA轴应激反应的高位调节中枢，与情绪、情感密切相关，持续应激导致海马体结构损伤和功能改变、行为学异常和单胺类神经递质表达紊乱，这是CUMS导致抑郁的主要理论基础。经上述实验发现，PHGG可以通过以下两个途径达到缓解CUMS导致小鼠抑郁的目的：一是调节小鼠的中枢神经系统，减少其在持续应激下的无助感和无望感，增加其对应激的反应；另一方面，也通过增加小鼠海马体中单胺类神经递质的浓度，从而达到抗抑郁的效果。因此，可将PHGG开发用于抗抑郁药物或相关保健品的制备。
以上所述仅为本发明的较佳实施例，凡依本发明申请专利范围所做的均等变化与修饰，皆应属本发明的涵盖范围。
Claims (2)
1.瓜尔豆胶在制备抗抑郁症药物及保健品中的应用。
2.根据权利要求1所述的应用，其特征在于：瓜尔豆胶为部分水解的瓜尔豆胶。
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