CN117298126A - 一种天然五碳糖在制备抗抑郁药物中的应用 - Google Patents
一种天然五碳糖在制备抗抑郁药物中的应用 Download PDFInfo
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- CN117298126A CN117298126A CN202311165606.6A CN202311165606A CN117298126A CN 117298126 A CN117298126 A CN 117298126A CN 202311165606 A CN202311165606 A CN 202311165606A CN 117298126 A CN117298126 A CN 117298126A
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Abstract
本发明属于医药技术领域,具体涉及一种天然五碳糖在制备抗抑郁药物中的应用。本发明通过行为学和药理实验研究首次发现并证实天然五碳糖中的D‑阿拉伯糖具有抗抑郁活性,其无明显毒副作用,表明其具有开发成抗抑郁药物的前景。本发明为D‑阿拉伯糖开辟了新的药物用途,也为开发高效特异的抗抑郁药物奠定实验基础并提供新的视野,因此具有重要的临床意义和社会效益,同时也具有潜在的实际应用之价值。
Description
技术领域
本发明属于医药技术领域,具体涉及一种天然五碳糖在制备抗抑郁药物中的应用。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解,而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
重度抑郁症(Major depressive disorder,MDD)作为一种心理和神经免疫紊乱性疾病是目前危害人类身心健康最主要的疾病之一,临床表现为情绪低落,思维迟钝,言语动作减少,对生活和工作失去兴趣等。每年全球大约有3.5亿人深受其害并且其发病率仍在逐年攀升。抑郁症的危害是及其高的,是全球四大致残病之一,以及它的复发率和自杀率是及其高的,还增加了其他疾病发生的风险。目前认为是基因和坏境等多种因素导致抑郁产生,而关于机制的研究现在仍然是不清楚的,主要围绕三个假说研究,其一是神经营养因子假说,认为神经营养因子(BDNF、NGF、EGF、IGF-I)异常减少导致神经元萎缩、突触减少进而导致抑郁产生;其次是神经递质假说认为突触间单胺类递质(5-HT、NE、DA)异常减少或是功能不足导致;其三是神经炎症假说,认为IL-6等活性增加可能通过激活下丘脑-垂体-肾上腺轴或影响神经递质代谢而导致抑郁。然而目前临床上的抗抑郁药物主要通过改善单胺类递质异常起到改善抑郁的效果。但是仍然有很多不足,例如作用靶点单一、副作用大、起效慢甚至没有效果。因此需要寻求一个新的靶点,可能会作用多个靶点并且安全性高,效果强。
最近的研究表明,CRTC1作为CREB的转录辅激活因子,在抑郁症的病理生理学中起作用。它可以增强CREB活性以及介导的转录,促进下游BDNF的表达;其次研究也发现CRTC1下游会影响突触可塑性,以及调节树突生长,精氨酸代谢,神经炎症等。因此发现CRTC1可以同时作用多条通路来抵抗抑郁,然而对于CRTC1的调控还不是很清楚。
众所周知,糖代谢对于体内的各个组织、器官均是很重要的。并且在抑郁小鼠以及人体内糖代谢是紊乱的。据文献报道,阿拉伯糖是一种天然存在的五碳糖,作为添加剂时可以补充人体所需要的营养,是理想的食品添加剂和代茶冲剂。目前研究较多的是L-阿拉伯糖,能有效抑制肠道中的蔗糖酶,可以抑制肠道吸收蔗糖,从而被高血压、高脂肪、高血脂患者所喜爱。然而对于D-阿拉伯糖的生物学功能很大程度上未知,仅知道D-阿拉伯糖可能干扰核糖代谢,并且在神经疾病患者的脑脊液中D-阿拉伯糖含量是异常的,以及D-阿拉伯糖是组成分枝杆菌细胞壁阿拉伯半乳聚糖的成分,也是酵母中D-红抗坏血酸合成的底物。而D-阿拉伯糖对神经系统疾病的影响,如抑郁症,目前还未见报道。
发明内容
针对上述现有技术中存在的不足,发明人经长期的技术与实践探索,提供天然五碳糖在制备抗抑郁药物中的应用。本发明通过行为学和药理实验研究首次发现并证实,天然五碳糖即D-阿拉伯糖具有抗抑郁活性,其无明显毒副作用,且抗抑郁效果显著。基于上述研究成果,从而完成本发明。
为实现上述技术目的,本发明采用如下技术方案:
本发明的第一个方面,提供天然五碳糖在制备抗抑郁产品中的应用。所述天然五碳糖为D-阿拉伯糖。并因此,D-阿拉伯糖在对于预防和/或治疗与抑郁相关的疾病是有效的。
所述产品可以为药品或食品。
根据本发明,不仅公开了D-阿拉伯糖在制备抗抑郁产品(尤其是药物)中的应用,而且还公开了,施用D-阿拉伯糖与其它至少一种药物活性成分的组合时,可以增强这种作用。作为其它药物活性成分的替代或补充,D-阿拉伯糖还可以与其它非药物活性成分组合使用。
因此,本发明的第二个方面,提供一种抗抑郁的药物组合物,所述药物组合物其活性成分至少包含D-阿拉伯糖。
本发明的第三个方面,提供一种用于预防和/或治疗与抑郁相关疾病的方法,所述方法包括向受试者施用治疗有效量的上述D-阿拉伯糖或上述药物组合物。
与现有技术方案相比,上述一个或多个技术方案具有如下有益效果:
上述技术方案首次发现D-阿拉伯糖具有抗抑郁活性,表明其具有开发成抗抑郁药物的前景,为D-阿拉伯糖开辟了新的药物用途,也为开发高效特异的抗抑郁药物奠定实验基础并提供新的视野,因此具有重要的临床意义和社会效益。
附图说明
构成本发明的一部分的说明书附图用来提供对本发明的进一步理解,本发明的示意性实施例及其说明用于解释本发明,并不构成对本发明的不当限定。
图1为将FITC-D-阿拉伯糖注射到小鼠体内3min、12h用小动物三维活体成像系统检测红色荧光的强度和分布图。
图2为小鼠行为学检测结果图;其中,a为悬尾实验结果;b为强迫游泳实验结果;c为蔗糖水偏好实验结果。
图3为小鼠海马组织中神经递质5-HT含量检测结果图。
图4为小鼠海马以及前额叶中CRTC1含量检测结果图;其中,A为小鼠海马组织CRTC1的mRNA水平变化结果图;B为小鼠海马组织CRTC1的蛋白水平变化结果图;C为小鼠前额叶中CRTC1的mRNA水平变化结果图;D为小鼠前额叶中CRTC1的mRNA水平变化结果图。
图5为小鼠海马以及前额叶神经营养因子BDNF的含量变化;其中,A为小鼠海马组织BDNF的mRNA水平变化结果图;B为小鼠海马组织BDNF的蛋白水平变化结果图;C为小鼠前额叶中BDNF的mRNA水平变化结果图;D为小鼠前额叶中BDNF的mRNA水平变化结果图。
具体实施方式
应该指出,以下详细说明都是例示性的,旨在对本申请提供进一步的说明。除非另有指明,本文使用的所有技术和科学术语具有与本申请所属技术领域的普通技术人员通常理解的相同含义。
需要注意的是,这里所使用的术语仅是为了描述具体实施方式,而非意图限制根据本申请的示例性实施方式。如在这里所使用的,除非上下文另外明确指出,否则单数形式也意图包括复数形式,此外,还应当理解的是,当在本说明书中使用术语“包含”和/或“包括”时,其指明存在特征、步骤、操作、器件、组件和/或它们的组合。
如前所述,D-阿拉伯糖的生物学功能很大程度上未知,D-阿拉伯糖对神经系统疾病的影响,如抑郁症,目前还未见报道
有鉴于此,本发明的一个典型具体实施方式中,提供天然五碳糖在制备抗抑郁产品中的应用。所述天然五碳糖为D-阿拉伯糖。并因此,D-阿拉伯糖在对于预防和/或治疗与抑郁相关的疾病是有效的,所述抑郁为通过慢性限制(如束缚)应激诱导的抑郁。
所述产品可以为药品或食品。
所述药品可以单位剂量形式给药,给药剂型可以是液体剂型、固体剂型。液体剂型可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混悬剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、乳剂、颗粒剂、栓剂、冻干粉针剂、包合物、填埋剂和贴剂等。
本发明的药品中还可以含有非药物活性成分,所述非药物活性成分可以是常用的载体,这里所述可药用载体包括但不局限于:离子交换剂,氧化铝,硬脂酸铝,卵磷脂,血清蛋白如人血清蛋白,缓冲物质如磷酸盐,甘油,山梨酯,山梨酸钾,饱和植物脂肪酸的部分甘油酯混合物,水,盐或电解质,如硫酸鱼精蛋白,磷酸氢二钠,磷酸氢钾,氯化钠,锌盐,胶态氧化硅,三硅酸镁,聚乙烯吡咯烷酮,纤维素物质,聚乙二醇,羧甲基纤维素钠,聚丙烯酸酯,蜂蜡,羊毛酯等。载体在药物组合物中的含量可以是1%重量-98%重量,通常大约占到80%重量。为方便起见,局部麻醉剂,防腐剂,缓冲剂等可直接溶于载体中。
口服片剂和胶囊可以含有赋形剂如粘合剂,如糖浆,山梨醇,黄芪胶,或聚乙烯吡咯烷酮,填充剂,如乳糖,蔗糖,玉米淀粉,磷酸钙,山梨醇,氨基乙酸,润滑剂,如硬脂酸镁,滑石,聚乙二醇,硅土,崩解剂,如马铃薯淀粉,或可接受的增润剂,如月桂醇钠硫酸盐。片剂可以用制药学上公知的方法包衣。
口服液可以制成水和油的悬浮液,溶液,乳浊液,糖浆,也可以制成干品,用前补充水或其它合适的媒质。这种液体制剂可以包含常规的添加剂,如悬浮剂,山梨醇,纤维素甲醚,葡萄糖糖浆,凝胶,羟乙基纤维素,羧甲基纤维素,硬脂酸铝凝胶,氢化的食用油脂,乳化剂,如卵磷脂,山梨聚糖单油酸盐;或非水载体(可包含可食用油),如杏仁油,油脂如甘油,乙二醇,或乙醇;防腐剂,如对羟基苯甲酸甲酯或丙酯,山梨酸。如需要可添加调味剂或着色剂。
所使用的术语“食品”应做广义的理解,其可以理解为可以使任何可以被食用的形式,例如,本发明中的食品包括普通食品和特殊食品,本发明所述特殊食品包括保健食品和特殊医学用途配方食品;而普通食品时相对于特殊食品而言的,是适合所有人的食品。进一步的,本申请中所述产品为保健食品。
根据本发明,不仅公开了D-阿拉伯糖在制备抗抑郁产品(尤其是药物)中的应用,而且还公开了,施用D-阿拉伯糖与其它至少一种药物活性成分的组合时,可以增强这种作用。作为其它药物活性成分的替代或补充,D-阿拉伯糖还可以与其它非药物活性成分组合使用。
因此,本发明的第二个方面,提供一种抗抑郁的药物组合物,所述药物组合物其活性成分至少包含D-阿拉伯糖。
更具体的,所述药物组合物由D-阿拉伯糖与至少一种其它药物活性成分和/或至少一种其它非药物活性成分组成。
所述其它药物活性成分包括任意已知的具有抗抑郁功效的物质;
所述非药物活性成分包括药学上可接受的载体,具体可详见第一方面,在此不再赘述。
本发明的又一具体实施方式中,提供一种用于预防和/或治疗与抑郁相关疾病的方法,所述方法包括向受试者施用治疗有效量的上述D-阿拉伯糖或上述药物组合物。
所述受试者是指已经是治疗、观察或实验的对象的动物,优选指哺乳动物,如大鼠、小鼠、豚鼠、猩猩、猴、狗等,最优选指人。所述“治疗有效量”是指包括本发明化合物在内的活性化合物或药剂的量,该量可引起研究者、兽医、医生或其他医疗人员所追求的组织系统、动物的生物学或医学响应,这包括减轻或部分减轻受治疗的疾病、综合征、病症或障碍的症状。必须认识到,本发明所述活性成分的最佳给药剂量和间隔是由其性质和诸如给药的形式、路径和部位以及所治疗的特定哺乳动物等外部条件决定的,而这一最佳给药剂量可用常规的技术确定。同时也必须认识到,最佳的疗程,即同时化合物在额定的时间内每日的剂量,可用本领域内公知的方法确定。
以下结合具体实例对本发明作进一步的说明,以下实例仅是为了解释本发明,并不对其内容进行限定。凡是依据本发明的技术实质对实施方式所做的任何简单修改,等同变化与修饰,均属于本发明技术方案的范围内。
实施例1
在本实施例中,为了证明D-阿拉伯糖能够穿越血脑屏障入脑,用FITC标记的D-阿拉伯糖以直观地跟踪此糖在体内的运动,然后将FITC标记的D-阿拉伯糖通过尾静脉注射到小鼠体内,通过成像系统捕获FITC荧光信号以追踪D-阿拉伯糖在体内的分布。结果表明,静脉注射后3min就在脑中检测到一小部分荧光(图1),持续观察了其12h脑内荧光情况,即说明此糖能够穿越血脑屏障入脑。
实施例2:构建小鼠抑郁模型
通过慢性束缚应激建立小鼠抑郁样疾病模型,具体操作为将小鼠束缚于特制的束缚器上,每日上午9点开始束缚,每次束缚3小时,一共束缚4周。其中治疗组饮用2.5%与5%D-阿拉伯糖。四周后进行小鼠抑郁样行为检测。
实施例3:小鼠行为学检测
行为学测试均在慢性束缚应激四周后进行检测,测试时间为9:00~15:00。实验均在光线良好的安静房间内进行且实验前两小时将小鼠放入测试房间适应环境。
(1)抑郁样相关行为检测
a.强迫游泳实验:将小鼠单独放入装有16厘米水(22±0.5℃)的透明烧杯(直径30×18cm)中。统计小鼠在6min内放弃挣扎,不动时间,并对整个实验过程进行录像。
b.悬尾实验:小鼠尾巴的后部1/3用胶带固定,并挂在支架上,头部距离桌子15厘米。计算小鼠6分钟内不动的时间,不动被定义为没有以逃生为导向的运动。
c.蔗糖水偏好实验:蔗糖水偏好实验是评价动物快感缺乏的一种常用实验模型。小鼠禁水9h后,给予小鼠两个常规水瓶,一个装有水,一个装有1%蔗糖水。3h后取走两个水瓶,称量引用前后的两个水瓶重量,记录水和蔗糖水的消耗。第二天交换两个水瓶的位置,以防有位置偏好性。蔗糖水偏好指数%=蔗糖水消耗量/(蔗糖水消耗量+纯水消耗量)×100%。
实验结果如附图2-a,b,c所示,在未接受慢性束缚刺激组和接受了慢性束缚刺激的小鼠中,服用了D-阿拉伯糖的小鼠整体活动性较强,对蔗糖水偏好更强,整体表现出较低的抑郁水平,并具有统计意义。
实施例4:体外检测结果
处死小鼠,取出小鼠前额叶、海马等组织。前额叶及海马组织一部分提取出总RNA,逆转为CDNA,分别用CRTC1以及BDNF的引物扩增,检测每组样本中CRTC1以及BDNF的mRNA水平的变化。一部分提取前额叶及海马组织总蛋白,BCA法测蛋白浓度,定量制作蛋白样品。将每个样品中的蛋白质(30μg/泳道)在10%十二烷基硫酸钠-聚丙烯酰胺凝胶(SDS-PAGE)上通过电泳分离,然后使用半干转法(14V,1h)将蛋白质转移到聚偏二氟乙烯(PVDF,Millipore,MA,USA)膜上。在室温下用5%脱脂奶粉封闭1小时后,将膜与一抗在4℃孵育过夜。将二级HRP偶联抗体在室温下振荡孵育1小时。使用增强化学发光(ECL)对条带进行可视化。Elisa检测抑郁小鼠海马组织中5-HT的变化,往预先包被小鼠5-HT捕获抗体包被微孔中,依次加入标本,标准品,HRP标记的检测抗体,经过温育并彻底洗涤,用底物TMB显色。颜色深浅与样本中的5-HT的含量呈正相关。用酶标仪450nm波长下测定OD值,计算样品浓度,反应每组样品中5-HT的含量。
检测结果如附图4,5所示,在未接受慢性束缚刺激组和接受了慢性束缚刺激的小鼠中,服用了D-阿拉伯糖的小鼠脑组织中的CRTC1、神经营养因子BDNF变化水平表现出较低的抑郁水平。此外,如图3所示,D-阿拉伯糖对此神经递质的降低是没有改善作用的,说明D-阿拉伯糖不是调控神经递质5-HT的产生,而是靶向神经营养假说发挥抗抑郁功能的。
以上所述仅为本申请的优选实施例而已,并不用于限制本申请,对于本领域的技术人员来说,本申请可以有各种更改和变化。凡在本申请的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本申请的保护范围之内。
Claims (10)
1.天然五碳糖在制备抗抑郁产品中的应用;所述天然五碳糖为D-阿拉伯糖,所述抑郁为通过慢性限制应激诱导的抑郁。
2.如权利要求1所述应用,其特征在于,所述产品为药品或食品。
3.如权利要求2所述应用,其特征在于,所述药品的给药剂型是液体剂型或固体剂型。
4.如权利要求3所述应用,其特征在于,所述药品的给药剂型包括真溶液类、胶体类、微粒剂型、乳剂剂型、混悬剂型、片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、乳剂、颗粒剂、栓剂、冻干粉针剂、包合物、填埋剂和贴剂。
5.如权利要求4所述应用,其特征在于,所述药品中还含有非药物活性成分。
6.如权利要求2所述应用,其特征在于,所述食品包括普通食品和特殊食品,所述特殊食品包括保健食品和特殊医学用途配方食品。
7.一种抗抑郁的药物组合物,其特征在于,所述药物组合物其活性成分至少包含D-阿拉伯糖。
8.如权利要求7所述药物组合物,其特征在于,所述药物组合物由D-阿拉伯糖与至少一种其它药物活性成分和/或至少一种其它非药物活性成分组成。
9.如权利要求8所述药物组合物,其特征在于,所述其它药物活性成分包括任意已知的具有抗抑郁功效的物质。
10.如权利要求8所述药物组合物,其特征在于,所述非药物活性成分包括药学上可接受的载体。
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