CN104288142B - 木果楝素h及其类似物在制备抗抑郁症药物或食品中的用途 - Google Patents
木果楝素h及其类似物在制备抗抑郁症药物或食品中的用途 Download PDFInfo
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Abstract
本发明涉及一种木果楝素H及其类似物的新用途,具体的涉及其在制备抗抑郁症药物或食品中的用途,所述的木果楝素H的结构如结构式(1)所示。实验证明,木果楝素H及其类似物对抑郁症具有确切的疗效,基本与抗抑郁的常用药文拉法辛的效果相当;同时,由于其为天然产物提取成分,对人体的副作用小,可以长期使用。
Description
技术领域
本发明涉及一种木果楝素H及其类似物的新用途,具体的涉及其在制备抗抑郁症药物或食品中的用途。
背景技术
木果楝(lian)(XylocarpusgranatumKoenig.)为楝科木果楝属植物,传统上作为收敛剂、解热药使用,并可用于治疗疟疾、鹅口疮、霍乱、痢疾和腹泻等疾病。木果楝中富含的柠檬苦素类化合物(limonoids)是自然界中存在的一大类拥有复杂三维拓扑结构的三萜类次生代谢产物,此类化合物的结构复杂多变柠檬苦素类化合物显示出的广谱的生物活性,如抗菌、抗HIV、杀虫、抗疟、抗肉毒菌、抗过敏、抑制黑色素形成、抗炎、抗肿瘤和神经保护等活性。目前关于木果楝的提取物开展了多项研究,如专利CN200680041586.X公开了木果楝属提取物用于治疗糖尿病和血脂异常的,其中生物活性部分包括木果楝素H(xylocarpinH,又名granaxylocarpinB)等多种组分;专利CN201210552780.1公开了木果楝庚素(xylogranatuminG)具有明显的抑制肿瘤细胞的活性;专利CN201210564022.1公开了木果楝碱甲素(granatumineA)作为蛋白酪氨酸磷酸酶抑制剂在治疗糖尿病、肥胖症及其并发症中的应用。可见,现有技术中尚无将木果楝或木果楝柠檬苦素类成分用于治疗或预防抑郁症的用途。
抑郁症是一种严重危及人类身心健康的精神疾病,主要表现为快感缺乏、兴趣丧失,伴有焦虑、睡眠障碍等其他不同程度的心理和(或)躯体症状。世界卫生组织(WHO)预测到2020年抑郁症将成为第二大致残疾病,前中国抑郁症患病率达3%—5%,患者约达2600万人。抑郁症症状多变、发病机制至今不明。比较一致的是,应激是抑郁症发生的重要触发器,海马、皮层、下丘脑等多个脑区,共同组成了情绪调节的神经回路。涉及下丘脑-垂体-肾上腺(HPA)轴的功能失常,神经元再生损伤等可能机制。目前临床上抑郁症的治疗主要以药物治疗为主,现有药物绝大部分存在起效延迟、症状缓解不彻底、复发率高和副作用大等局限性。开发新型、高效、安全的新型抗抑郁药物成为当前研究的热点。
天然植物药具有安全、低毒性、副作用少、高效、无耐药性从而可重复使用等特点。我国的天然药物资源丰富,需求广泛,有着很好的发展基础。大量研究表明,天然植物提取物具有抗炎、抗肿瘤、抗衰老等活性,在抗抑郁方面也表现出良好的开发和应用前景。已发现的抗抑郁活性植物成分主要有苯并二蒽酮类、黄酮类、低聚糖类、生物碱类、间苯三酚类、倍半萜类、二萜类、三萜类、皂苷、有机酸等类型化合物。贯叶金丝桃中的黄酮类化合物可通过提高中枢单胺类含量、抑制突触体对单胺再摄取发挥抗抑郁作用表现为明显缩短强迫游泳测试(forcedswimmingtestFST)和悬尾测试(tailsuspensiontestTST)实验中的小鼠不动时间,由其提取物生产的制剂已在欧美诸国临床上广泛用于治疗中、轻度抑郁症。生姜提取物姜黄素已被证实有一定的抗抑郁作用,其作用可能与单胺神经系统有关,进一步研究发现,姜黄素能显著增加额叶皮层、海马及下丘脑的单胺递质含量,其抗抑郁作用可能通过Erk-BDNF-CREB信号途径有关。其他如从槟榔、巴戟天等的提取物也发现了抗抑郁有效成分。天然药物抗抑郁活性成分筛选成为了抗抑郁药物研发的重要领域和研究热点。
发明内容
本发明的目的在于提供一种木果楝素H及其类似物在制备抗抑郁症药物或食品中的用途,木果楝素H作为一种天然植物提取物具有更高的安全性和人体适应性,并且由于毒副作用小,可添加至食品中长期使用。
本发明的技术方案如下:
本发明的木果楝素H在制备抗抑郁症药物或食品中的用途,其中木果楝素H的结构如结构式(1)所示,
结构式(1)。
本发明的木果楝素H类似物在制备抗抑郁症药物或食品中的用途,其中木果楝素H类似物的结构如结构式(2)所示;
结构式(2),
其中R1选自氢、羰基化合物、C1~C18取代或非取代的烷基、取代或非取代的芳基,
R2选自氢、羰基化合物、C1~C18取代或非取代的烷基、取代或非取代的芳基,
R3选自氢、羰基化合物、C1~C18取代或非取代的烷基、取代或非取代的芳基。
本发明所述的抑郁症包括临床上的单项抑郁症或双向抑郁症。
本发明所述的药物包括基于治疗目的的药物以及基于预防目的的保健品。
本发明保护了木果楝素H在制备治疗抑郁症的药物或食品中的用途,因此只要是基于抗抑郁的目的添加木果楝素H的组合物或产品都属于本发明所保护的范围,而并不特别限定该产品中只有木果楝素H一种组分。并且作为本领域所公知的,在制备为药物或食品时可以添加其它有效成分或辅料,形成最终产品。可以添加的辅料包括赋形剂、药用载体、崩解剂、填充剂等。
本发明保护了木果楝素H的衍生物在制备治疗抑郁症的药物或食品中的用途,所述的衍生物为以结构式(2)为母核,R1、R2和R3选自氢、羰基化合物、C1~C18取代或非取代的烷基、取代或非取代的芳基得到的化合物。
本发明提供了一种木果楝素H的新用途,其可应用于制备抗抑郁症的药物、保健品或食品。当制备为药品时,木果楝素H的有效剂量为口服0.5-5mg/kg,(或注射0.1-2mg/Kg);当制备为保健品时,木果楝素H的有效剂量为口服0.1-1mg/kg;当制备为食品时,可以选择添加0.1-1mg/kg的木果楝素H至饮品或食物中。
本发明的有益效果为:
本发明提供了一种木果楝素H的新用途,其可应用于制备抗抑郁症的药物、保健品或食品。实验证明,木果楝素H及其类似物对抑郁症具有确切的疗效,基本与抗抑郁的常用药文拉法辛的效果相当;同时,由于其为天然产物提取成分,对人体的副作用小,可以长期使用。
附图说明
图1为实施例1木果楝素H的1H-NMR谱图,
图2为实施例1木果楝素H的13CNMR谱图,
图3为实施例1木果楝素H的1H-1HCOSY谱图,
图4为实施例1木果楝素H的HMQC谱图,
图5为实施例1木果楝素H的和HMBC谱图,
图6为实施例1木果楝素H的NOESY谱图,
图7为实施例试验方法的流程图,
图8为实施例2的小鼠强迫游泳实验的实验结果,
图9为实施例3的小鼠悬尾实验的实验结果,
图10为实施例4的小鼠自发活动实验的实验结果。
具体实施方式
实施例1木果楝素H的制备
木果楝素H为从木果楝中分离提取出来的单体,经纯度鉴定达到98%以上。
木果楝素H的提取分离纯化方法
取粉碎后的木果楝药材(果实或种子)约20Kg,用95%乙醇冷浸提取,每次浸泡时间为一周,提取3次。提取液过滤,减压浓缩至膏状,得浸膏。将浸膏悬浮于水中,分别用石油醚、二氯甲烷和乙酸乙酯萃取,萃取液减压浓缩,得到石油醚部分浸膏、二氯甲烷部分浸膏和乙酸乙酯部分浸膏。采用硅胶柱层析、葡聚糖凝胶、制备薄层法和制备高效液相色谱法对以上部位的化学成分进行分离,得到的木果楝素H单体化合物为白色粉末状固体。采用HR-ESI-MS、1HNMR、13CNMR、1H-1HCOSY、HMQC、HMBC和NOESY鉴定化合物结构。
ESI-MSm/z:583[M+H],分子式为C32H38O10。
1HNMR(500MHz,TMS,CDCl3,δ,ppm,J/Hz):7.01(1H,s,H-3),2.29(1H,o,H-5),2.48(1H,d,J=14.5Hz,H-6a),2.29(1H,o,H-6b),2.28(1H,o,H-10),3.08(1H,dd,J=20.0,7.2Hz,H-11a),2.53(1H,o,H-11b),2.69(1H,td,J=12.9,7.0Hz,H-12a),1.65(1H,o,H-12b),6.10(1H,s,H-15),5.37(1H,s,H-17),0.97(3H,s,H-18),1.04(3H,d,J=5.3Hz,H-19),7.56(1H,s,H-21),6.47(1H,br,H-22),7.45(1H,s,H-23),1.14(3H,s,H-28),1.20(3H,s,H-29),6.60(1H,s,H-30),3.69(3H,s,7-OMe),3.90(1H,s,8-OH),6.96(1H,q,J=6.8Hz,H-3′),1.83(3H,dq,J=7.2,0.9Hz,H-4′),1.85(3H,q,J=0.9Hz,H-5′).13CNMR(125MHz,TMS,CDCl3,δ):198.78(C-1),128.83(C-2),161.85(C-3),36.82(C-4),45.22(C-5),34.62(C-6),173.38(C-7),80.29(C-8),208.81(C-9),42.79(C-10),33.01(C-11),25.54(C-12),38.33(C-13),163.54(C-14),118.46(C-15),163.31(C-16),80.07(C-17),18.50(C-18),11.58(C-19),119.69(C-20),141.41(C-21),109.80(C-22),143.19(C-23),20.49(C-28),27.86(C-29),67.56(C-30),51.96(7-OMe),166.82(C-1′),127.74(C-2′),139.89(C-3′),14.65(C-4′),12.06(C-5′)。
1H-NMR谱图见附图1,13CNMR谱图见附图2,1H-1HCOSY谱图见附图3,HMQC谱图见附图4,HMBC谱图见附图5,NOESY谱图见附图6。
实施例2小鼠强迫游泳实验模型
实验动物采用雄性昆明种小鼠,小鼠自由摄食饮水,实验时体重约30-40克。
将定量的木果楝素H置于研钵中,加入定量的0.5%羧甲基纤维素钠溶液研磨使成混悬液,制成木果楝素H-0.5%羧甲基纤维素钠混悬液;阳性对照药物为文拉法辛。给药方式为灌胃给药。
小鼠随机分为5组,分为阴性对照组(溶媒组)、木果楝素H低剂量组(XL组5mg/kg)、木果楝素H中剂量组(XM组15mg/kg)、木果楝素H高剂量组(XH组50mg/kg)、文拉法辛阳性对照组(VEN组15mg/kg),每组12只。
如图7所示,小鼠经过5天的适应性饲养后开始给药,第一次给药当天计为给药第一天,连续给药7天,末次给药后半小时进行行为学测试。
行为学检测方法:游泳装置由透明有机玻璃制成(玻璃缸高24㎝,直径15㎝,水深17㎝,水温24±2℃)将小鼠置于其中,适应2分钟后,记录后4分钟内小鼠漂浮不动时间。漂浮不动时间定义为小鼠微蜷躯体、呈漂浮状态的时间。
实验结果以平均值±标准误差表示,以t检验统计处理。
强迫游泳实验为经典抗抑郁药筛选模型,有效的抗抑郁药会使小鼠游泳的漂浮不动时间,如图8的实验结果所示,木果楝素H具有显著的抗抑郁效果,与溶媒对照组相比,15、50mg/kg7天连续灌胃给药能显著降低小鼠漂浮不动时间(p<0.05,p<0.01),与阳性对照组相比两组木果楝素H给药组均无显著差异。说明木果楝素H可以显著降低小鼠漂浮不动时间,其作用效果与文拉法辛相当。
实施例3小鼠悬尾实验
实验动物采用雄性昆明种小鼠,小鼠自由摄食饮水,实验时体重约30-40克。
以0.5%羧甲基纤维素钠作为溶媒,于实验前制备新鲜木果楝素H-0.5%羧甲基纤维素钠混悬液;阳性对照药物为文拉法辛。给药方式为灌胃给药。
小鼠随机分为5组,分为阴性对照组(溶媒组)、木果楝素H低剂量组(XL组5mg/kg)、木果楝素H中剂量组(XM组15mg/kg)、木果楝素H高剂量组(XH组50mg/kg)、文拉法辛阳性对照组(VEN组15mg/kg),每组12只。如图7所示,小鼠经过5天的适应性饲养后开始给药,第一次给药当天计为给药第一天,连续给药7天,连续给药7天,末次灌胃给药后半小时进行行为学测试。
实验结果以平均值±标准误差表示,以t检验统计处理。
根据EuropeanJournalofPharmacology,2001,415:197中记载的实验方法构建小鼠悬尾实验模型,将小鼠倒吊于距地面60cm的横杆上6分钟,小鼠的固定位点为距尾稍1cm处,适应2分钟后,观察后4分钟小鼠不动时间,不动状态定义为小鼠停止挣扎,躯体呈放松状态。
实验结果以平均值±标准误差表示,以t检验统计处理。
小鼠悬尾实验为经典的筛选抗抑郁药实验模型,小鼠悬尾一段时间后呈现绝望状态,停止挣扎。有效的抗抑郁药物会使小鼠悬尾过程中不动时间缩短。本实验表明,木果楝素H具有显著的抗抑郁效果,如图9的实验结果所示,与溶媒对照组相比,50mg/kg木果楝素H给药能显著降低小鼠悬尾不动时间(p<0.05);与阳性对照组相比,木果楝素H高剂量给药组差异不具有显著性。
说明木果楝素H可以显著降低小鼠悬尾不动时间,当剂量达到50mg/kg时作用效果与文拉法辛相当。
实施例4小鼠自发活动
实验动物采用雄性昆明种小鼠,小鼠自由摄食饮水,实验时体重约30-40克。
以0.5%羧甲基纤维素钠作为溶媒,于实验前制备新鲜木果楝素H-0.5%羧甲基纤维素钠混悬液;阳性对照药物为文拉法辛。给药方式为灌胃给药。
小鼠随机分为5组,分为阴性对照组(溶媒组)、木果楝素H低剂量组(XL组5mg/kg)、木果楝素H中剂量组(XM组15mg/kg)、木果楝素H高剂量组(XH组50mg/kg)、文拉法辛阳性对照组(VEN组15mg/kg),每组12只。如图7所示,小鼠经过5天的适应性饲养后开始给药,第一次给药当天计为给药第一天,连续给药7天,连续给药7天,末次灌胃给药后半小时进行行为学测试。
实验结果以平均值±标准误差表示,以t检验统计处理。
将小鼠放于自发活动箱,观察10分钟,记录后6分钟内小鼠自发活动情况,实验结果以平均值±标准误差表示,以t检验统计处理。
如图10的实验结果所示,与对照组相比,木果楝素H给药组小鼠自发活动没有显著变化。说明木果楝素H对小鼠的自发活动没有显著影响,在实验剂量内对小鼠的神经活性没有显著作用,不具有神经毒性。
Claims (1)
1.一种木果楝素H在制备抗抑郁症药物或食品中的用途,所述的木果楝素H的结构如结构式(1)所示,
结构式(1)。
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