CN110464721A - 青蒿素衍生物在制备治疗失眠的药物或助眠食品中的应用 - Google Patents
青蒿素衍生物在制备治疗失眠的药物或助眠食品中的应用 Download PDFInfo
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Abstract
本发明公开了蒿甲醚的新用途,具体是蒿甲醚在制备安神促眠的药物或食品中的应用,可期望成为新型的安神促眠药物或食品。蒿甲醚可单独使用,也可与其它药物联合使用,或者与其它食品组合使用。本发明通过实验证实,蒿甲醚能够显著性减少小鼠的自主活动时间,延长其睡眠持续时间,并明显增加小鼠非快眼动睡眠时间。本发明通过记录神经元突触活动发现,蒿甲醚能增强中枢神经系统抑制性突触传递,促进抑制性突触前膜神经递质γ‑氨基丁酸(GABA)的释放。证明:蒿甲醚能通过促进中枢神经系统抑制性突触前膜囊泡释放来发挥稳定的安神促眠作用,可用于安神促眠药物或其它有助于缓解失眠表现的保健食品及功能性食品的制备。
Description
技术领域
本发明涉及一种青蒿素衍生物的新用途,尤其涉及青蒿素衍生物在制备治疗失眠的药物或助眠食品中的应用。
背景技术
失眠又称为睡眠障碍(sleep deprivation,SD),是指睡眠的始发和维持发生障碍导致睡眠缺失,使得睡眠质量不能满足个体生理需求,导致患者白天疲乏,萎靡等一系列神经精神状态,显著影响患者的日间活动。随着社会经济的发展,生活节奏的加快,人们工作学习的压力日益增大,失眠的发生率呈现逐年上升的趋势。调查研究发现,我国有38.4%的人存在睡眠障碍,而30%~50%的意外事故是由睡眠障碍引起的,10%~15%的人表示失眠会影响日间的学习和工作。失眠会导致疲劳,精神疾病(如抑郁症),甚至认知功能障碍,直接导致生活质量下降。同时,对心脏功能,免疫功能和血糖调节产生不良影响,增加死亡率。
目前,治疗失眠的药物主要是镇静催眠药。镇静催眠药能使人处于安静或思睡状态,对中枢神经系统有抑制作用。临床常用的镇静催眠药按化学结构分为三类:巴比妥类、苯二氮卓类和其它类。由于巴比妥类药物的毒副作用较大,已逐渐被苯二氮卓类药物替代,目前仅有少数药物在临床上使用,如苯巴比妥。苯二氮卓类为第二代镇静催眠药,其典型药物为地西泮。苯二氮卓类药物能增强中枢神经系统抑制性突触传递功能和对兴奋性突触抑制效应。其它类型的镇静催眠药也可以选择性增强抑制性突触传递功能,从而达到镇静催眠的效果。良好的镇静催眠药需要具备毒副作用低、提高睡眠效率、不产生肌松作用、不影响记忆功能、无呼吸抑制作用以及无依赖或戒断症状等特点。随着制药技术的发展,尽管诸多新型镇静催眠药的研究取得了一些进步,逐步从传统的巴比妥类和苯二氮卓类药物向高效抗失眠药、抗焦虑药发展,但临床上依然缺乏十分理想的镇静催眠药物。
青蒿素(Artemisinin)是我国药学人员于20世纪70年代从菊科植物黄花蒿叶中提取的一种含过氧化基团结构的倍半萜内酯化合物,其分子式为C15H22O5。青蒿素是继乙氨嘧啶、氯喹、伯喹之后最有效的抗疟特效药,尤其是对于脑型疟疾和抗氯喹疟疾,具有速效和低毒的特点,曾被世界卫生组织称做是“世界上唯一有效的疟疾治疗药物”。
蒿甲醚(Artemether,ART)是青蒿素的甲基醚衍生物。蒿甲醚的抗疟疾效果是其先导化合物青蒿素的6倍,目前被广泛用于制备抗疟疾药物,具有安全性高,毒副作用小的特点。此外,蒿甲醚还有抗炎和抗肿瘤等功效,并且可通过血脑屏障分布到中枢神经系统内。经临床试验证明,蒿甲醚同时具有水溶性和脂溶性的特点,化学性能比其它衍生物更为稳定,临床上常用肌肉注射作为其治疗疟疾的方法。
青蒿素衍生物的安全性较高,毒副作用小,在拓展其他疾病方向的研究有很好的应用前景。目前尚未见青蒿素衍生物在治疗失眠方面的研究报道。本发明首次探索青蒿素衍生物在失眠病症中的作用,并通过实验研究证实了蒿甲醚具有安神促眠作用,并进一步证明了蒿甲醚的安神促眠作用机制是通过促进中枢神经系统抑制性突触前膜囊泡释放,增强中枢神经系统抑制性突触传递功能。本发明为失眠患者提供了一种价格低廉、安全、高效的新药物,也拓宽了青蒿素衍生物在药用方面的临床价值。
发明内容
本发明的目的在于提供青蒿素衍生物在神经系统的新用途,具体是青蒿素衍生物在制备治疗失眠的药物或助眠食品中的应用。进一步地,所述青蒿素衍生物包括蒿甲醚。本发明中,蒿甲醚可单独直接使用,也可与其他药物联合使用,或者与其它食品组合使用。
本发明还提供了所述青蒿素衍生物作为一种提高中枢抑制性突触传递及促进抑制性突触前膜释放神经递质的作用剂在制备治疗失眠的药物或助眠食品中的应用。
本发明还提供了一种治疗失眠的药物,其含有有效剂量的所述青蒿素衍生物及其药用盐。
优选地,所述治疗失眠的药物还含有药学上可接受的载体和/或辅料。
优选地,所述治疗失眠的药物的剂型为口服制剂或注射制剂。
优选地,所述口服制剂选自片剂、胶囊剂、软胶囊剂、颗粒剂、混悬剂、滴丸、丸剂、口服液体制剂中的至少一种。
优选地,所述片剂为普通片剂、分散片、口腔崩解片或缓释片。
优选地,所述注射制剂为注射液或粉针剂。
此外,本发明还提供了一种助眠食品,其含有有效量的所述青蒿素衍生物。优选地,所述助眠食品还含有食品上可接受的载体和/或辅料。
本发明通过对小鼠进行脑皮层电图(ECoGs)记录,并结合视频对小鼠睡眠进行分期和分析,发现蒿甲醚能显著降低小鼠的清醒时间,并延长小鼠非快动眼期睡眠时间,证明了蒿甲醚具有安神促眠作用。本发明还通过膜片钳全细胞技术检测神经元突触传递功能,发现蒿甲醚能显著提高小鼠中枢神经系统抑制性的突触传递功能,促进抑制性突触前膜囊泡释放,可用于安神促眠药物或其它有助于缓解失眠表现的保健食品及功能性食品的制备。蒿甲醚安神促眠的效果显著,安全性高、价格低廉,具有良好的应用前景,以代替现有的治疗药物。
附图说明
图1为本发明实施例1中的采用脑皮层电图(ECoGs)记录小鼠睡眠并结合行为视频对睡眠时期进行分析,发现蒿甲醚能延长以非快动眼为主的睡眠持续时间。A为进行埋植手术定位、电极埋植,分别在额叶以及顶叶埋植4颗颅钉(EEG1、EEG2、EEG 3、EEG4);B为ECoGs记录小鼠清醒及睡眠时期的不同脑电波,分别为清醒期(wake)、快眼动时期(Rapid EyeMovement,REM)、非快眼动时期(Non-Rapid Eye Movement,NREM);C为青蒿素衍生物蒿甲醚以及对照溶剂甲基纤维素对正常小鼠睡眠各阶段ECoGs热图的结果;D、E、F、G图为本发明实施例1的蒿甲醚以及对照溶剂甲基纤维素对正常小鼠睡眠各时期饼状图例图及统计结果;
图2为利用膜片钳全细胞记录技术发现蒿甲醚增加海马脑片CA1区锥体神经元mIPSCs的频率并且抑制eIPSCs双脉冲比值。A为海马CA1区锥体神经元mIPSCs的代表性例图;B提示蒿甲醚能显著提高mIPSCs的频率;C提示蒿甲醚不改变mIPSCs的幅度;D为双脉冲诱发的eIPSCs的例图;E提示蒿甲醚显著抑制eIPSCs双脉冲比值。
具体实施方式
为更好的说明本发明的目的、技术方案和优点,本发明通过下列实施例进一步说明。显然,下列实施例仅是本发明的一部分实施例,而不是全部的实施例。应理解,本发明实施例仅用于说明本发明的技术效果,而非用于限制本发明的保护范围。实施例中,所用方法如无特别说明,均为常规方法。
实施例1通过脑电记录蒿甲醚对正常小鼠睡眠的影响
一.实验动物饲养
SPF级C57BL/6小鼠:雄性,年龄6周,由济南朋悦实验动物繁育有限公司提供。SPF级动物中心饲养,饲养区温度一般在24-26℃之间,湿度控制在40%-70%之间,微电脑控制日光灯照明系统,12h明暗自动交替。动物中心定期打扫卫生、更换动物垫料、添加饲料,可自由摄取SPF级繁殖级饲料和饮水。
二.药品及主要试剂
蒿甲醚,购自上海阿拉丁生化科技股份有限公司;甲基纤维素(Methylcellulose,MC),购自Sigma-Aldrich公司(中国,上海);NaCl,购自Sigma-Aldrich公司(中国,上海);电极埋植时麻醉剂异氟烷购自瑞沃德生命科技有限公司(中国,深圳)。
三.实验方法
1.动物分组:每组6只小鼠,对照组(Vehicle)记录前腹腔注射1%MC;干预组记录前腹腔注射蒿甲醚(Art,50mg/kg)。
2.蒿甲醚(Art)的配制:
(1)配制1%甲基纤维素溶液(MC):用0.9%生理盐水,在水浴锅中加热至40℃,溶解MC粉末,搅拌均匀至完全溶解,无乳白色沉淀为止。
(2)蒿甲醚配制:用4℃冷藏的1%MC溶解配置浓度为50mg/kg的Art,混匀成混悬液,现配现用。
3.给药方法:蒿甲醚干预组实验前腹腔注射蒿甲醚50mg/kg,对照组同时间注射1%MC。
4.脑电记录方法:
(1)小鼠脑皮层电图电极(ECoGs)埋植手术:用异氟烷麻醉小鼠,用脑立体定位仪固定头骨,脱毛膏脱去头骨毛发,暴露颅骨;在双侧额叶及顶叶各埋植一颗导电性能良好的颅骨钉,坐标分别为(额叶:AP+2.0mm,ML±1.5mm;顶叶:AP-3.0mm,ML±2.5mm);另外在后脑部植入一颗颅骨钉作为地线。埋入电极后用牙科水泥进行固定;手术后第三天开始记录。
(2)记录时间及给药方式:记录时间为每天早上9点至晚上9点,共12小时,每天记录前腹腔注射给予蒿甲醚(50mg/kg)或相同体积的溶剂(1%MC),给予1%MC作为对照组,给予蒿甲醚作为干预组。
(3)ECoGs记录EEG及睡眠不同时期分析:1)将小鼠提前置于隔音的屏蔽房中适应1天,自由摄取饲料和饮水。2)睡眠脑电记录:应用在体多通道神经信号采集系统(MedusaBio-signal technologies,美国)对小鼠进行12小时无干扰睡眠脑电记录。同时运用高清摄像头同步采集小鼠的睡眠及活动行为。3)脑电分析:运用NeuroExplorer软件(NexTechnologies:Boston,MA,U.S.A.)对睡眠脑电信号进行频谱及功率谱分析,结合脑电信号波形特点(见图1B)、以及视频记录数据,判断小鼠的清醒和睡眠时期(清醒期、快眼动期、非快眼动期)。
5.实验结果:蒿甲醚能减少小鼠的清醒(活动)时间,显著增加了非快眼动睡眠阶段时间和总睡眠时间(见图1)。结果提示,蒿甲醚有较显著的安神促眠作用。
实施例2蒿甲醚对海马脑片CA1区锥体神经元抑制性突触电流的影响
1.实验动物饲养:同实施例1。
2.药品及主要试剂:氯化铯、甲磺酸铯、HEPES、EGTA、ATP-Mg、GTP-Na、犬尿喹啉酸、氯化镁、氯化钠、氯化钾、磷酸二氢钠、硫酸镁、氯化钙、碳酸氢钠、葡萄糖、蔗糖均购自Sigma-Aldrich公司(中国,上海);QX314购自TOCRIS(英国);河豚毒素购自河北省水产科技开发公司;蒿甲醚购自上海阿拉丁生化科技股份有限公司;二甲基亚砜购自广州瑞舒生物科技有限公司。
3.蒿甲醚的配制用二甲基亚砜溶解配制浓度为10μM的蒿甲醚溶液。
4.给药方法:脑片记录液中灌流浓度为10μM的蒿甲醚溶液。
5.膜片钳记录方法:
(1)制备小鼠海马脑片:用1%戊巴比妥钠(50mg/kg)腹腔注射麻醉小鼠,迅速断头取脑,把取出的脑组织放入预先配制好的4℃切片液中。将脑组织固定在切片机底座上,使用震动切片机(LEICA VT1200S,德国)切取海马脑片,切片的厚度为300μm。切下来的海马脑片放置于32-34℃的孵育槽中孵育30分钟,随后在室温下孵育1小时。孵育完成后即可记录脑片电活动。使用Axon digidata 1550A数模转换器(Molecular Devices,美国)和Multiclamp 700B(Molecular Devices,美国)放大器。
(2)微小抑制性突触后电流(mIPSCs):使用Axon digidata 1550A数模转换器(Molecular Devices,美国)和Multiclamp 700B(Molecular Devices,美国)放大器。记录海马CA1区锥体神经元的微小抑制性突触后电流,在电压钳的模式下,电压钳制在-70mV,灌流液中加入河豚毒素和犬尿喹啉酸分别阻断动作电位及谷氨酸能兴奋性受体电流。
(3)诱发抑制性突触后电流(eIPSCs):记录海马CA1区锥体神经元诱发抑制性突触后电流,灌流液中加入犬尿喹啉酸阻断谷氨酸能兴奋性受体电流,把一根同心圆刺激电极放在CA1锥体细胞带下方辐射层,给予一个间隔分别为20ms、50ms、100ms、200ms的双脉冲刺激,比较两个脉冲刺激诱发的突触后电流的幅度,第二个eIPSC的幅度除以第一个eIPSC的幅度即为双脉冲比值(Paired-pulse ratio)。
6.实验结果:蒿甲醚能增加海马CA1区锥体神经元的mIPSC频率而对mIPSC的幅度没有影响,提示蒿甲醚的这种作用可能影响了抑制性突触前膜,双脉冲比值结果进一步证明了蒿甲醚能促进海马CA1区抑制性突触前膜囊泡释放(见图2)。
Claims (10)
1.青蒿素衍生物在制备治疗失眠的药物或助眠食品中的应用。
2.如权利要求1所述的应用,其特征在于,所述青蒿素衍生物包括蒿甲醚。
3.如权利要求1或2所述的应用,其特征在于,所述青蒿素衍生物作为一种提高中枢抑制性突触传递及促进抑制性突触前膜释放神经递质的作用剂在制备治疗失眠的药物或助眠食品中的应用。
4.一种治疗失眠的药物,其特征在于,含有有效剂量的青蒿素衍生物及其药用盐。
5.如权利要求4所述的治疗失眠的药物,所述青蒿素衍生物包括蒿甲醚。
6.如权利要求4或5所述的治疗失眠的药物,其特征在于,所述药物还含有药学上可接受的载体和/或辅料。
7.如权利要求4或5所述的治疗失眠的药物,其特征在于,所述药物的剂型为口服制剂或注射制剂;优选地,所述口服制剂选自片剂、胶囊剂、软胶囊剂、颗粒剂、混悬剂、滴丸、丸剂、口服液体制剂中的至少一种;优选地,所述片剂为普通片剂、分散片、口腔崩解片或缓释片;优选地,所述注射制剂为注射液或粉针剂。
8.一种助眠食品,其特征在于,含有有效量的青蒿素衍生物。
9.如权利要求8所述的助眠食品,所述青蒿素衍生物包括蒿甲醚。
10.如权利要求8或9所述的助眠食品,其特征在于,所述食品还含有食品上可接受的载体和/或辅料。
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