CN112294821B - 5-甲基四氢叶酸的用途及其组合物 - Google Patents
5-甲基四氢叶酸的用途及其组合物 Download PDFInfo
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Abstract
本发明提供5‑甲基四氢叶酸的用途及其组合物。所述5‑甲基四氢叶酸或其组合物用于治疗、缓解或预防因急性酒精中毒和慢性酒精中毒导致的各种疾病或症状。所述急性酒精中毒带来的伤害或引发的疾病包括:饮酒导致的头疼;饮酒导致的负面情绪,或者抑郁症;饮酒后的宿醉症状。所述慢性酒精中毒带来的伤害或引发的疾病包括:酒精性脂肪肝、中枢神经系统(CNS)炎症等。
Description
技术领域
本发明属于医药领域,涉及含5-甲基四氢叶酸的药物或保健食品组合物,及其用途。
背景技术
叶酸(folic acid)是维生素B9,也叫蝶酰谷氨酸(pteroylglutamic acid,PGA)。其具有多种生化功能,例如聚有促进骨髓中幼细胞成熟的作用,人类如缺乏叶酸可引起巨红细胞性贫血以及白细胞减少症,对孕妇尤其重要。作为营养补充剂,成人的叶酸建议用量为400μg,由于合成叶酸需要经过复杂的人体转化为5-甲基四氢叶酸进入血液循环参与人体的各项生理活动,超过该推荐剂量可能会对人体产生各种副作用。
叶酸在人体的血液和组织中主要以5-甲基四氢叶酸(5-MTHF)的方式存在,参与人体当中的很多生化反应,因此5-MTHF是叶酸在体内发挥作用的主要形式,不需要经过复杂的酶促反应,就可以直接被人体吸收和利用。叶酸被小肠吸收后,在辅酶还原型烟酰胺腺嘌呤二核苷酸(NADPH)以及二氢叶酸还原酶的共同作用下还原得到二氢叶酸,二氢叶酸再被还原型辅酶II和抗坏血酸还原,代谢生成具有生物活性的四氢叶酸(THF),最后THF在肝脏中减少并甲基化为5-MTHF。
5-甲基四氢叶酸的化学命名为N-[4-[[(2-氨基-1,4,5,6,7,8-六氢-4-氧-5-甲基-(6S),-(6R),和(6R,S)-喋啶基)甲基]氨基]甲苯酰-谷氨酸,其可以形成多种形式的盐。
目前5-甲基四氢叶酸已经成为国际市场上一种新型的维生素保健产品,它能够作为食品添加剂和营养保健品的主要成分,不产生任何副作用,同时还具有很好的功能。因此科学家们对于开发5-甲基四氢叶酸的新用途具有较高热情和期待。
饮酒是人类文化精神生活中的一种重要行为,然而长期或一次过度饮酒会对人体带来极大危害。酒主要通过肝脏代谢、解毒,其进入人体后会加重肝脏负担,严重影响肝脏正常的功能,造成肝损伤;此外,酒精对人的心、脑、血管产生很强的刺激作用,对人体神经系统产生不良影响,因此长期或过度饮酒会大大提高心脑血管系统疾病的机率,并且产生头晕、头疼、偏头疼、恶心、困倦、厌食、认知模糊等不舒适症状。饮酒后也会产生人的情绪状态的改变,其中包括很多负面情绪,包括酒后产生消沉、抑郁的精神状态,对于其发生的机制也不明确。
长时间以来,对于宿醉没有一个确定的定义,在2016年美国新奥尔良举行的第八次酒精宿醉研究会议上,专家小组将酒精宿醉定义为“一次饮酒后第二天出现的,血液酒精浓度(BAC)接近零开始后,精神和身体的综合表现的症状。”关于酒精宿醉,人们有许多理论解释,但是这些机制无法解释宿醉的全部,有很多的局限性。对于宿醉的解释包括:急性酒精戒断;乙醛产生的不良反应;酒精导致的电解质失衡;神经炎症;酒精中的甲醇;心理因素。
急性酒精戒断导致宿醉的论据是基于它们之间存在几个共同症状,例如恶心、呕吐、出汗、焦虑[Swift R,Davidson D.Alcohol hangover:mechanisms andmediators.Alcohol Health Res World.1998;22(1):54-60.]。但是宿醉会在饮酒后几个小时出现,并且持续最多24小时,而急性酒精戒断的症状发生在戒酒后的1-5天,并且具有宿醉不常出现的症状,例如幻觉、癫痫,因此可以确定的是宿醉和戒断是不同的现象,其次观察到戒酒期间的激素和血液动力学变化与宿醉中观察到的不同[Wiese JG,Shlipak MG,Browner WS.The alcohol hangover.Ann Intern Med.2000;132(11):897-902.],此外,产生戒酒综合症需要长时间连续大量饮酒,而单次饮酒或非习惯性饮酒的人都会出现宿醉的现象,最后在宿醉期间脑活动减少,而戒酒期间观察到中枢神经系统过度兴奋[Fadda F,Rossetti ZL.Chronic ethanol consumption:from neuroadaptation toneurodegeneration.Prog Neurobiol.1998;56(4):385-431.]。因此,尽管观察到酗酒的人容易宿醉,但是可以确定宿醉与戒酒反应是不同的。
乙醛理论也存在很大缺陷,乙醇会在乙醇脱氢酶作用下代谢成乙醛,很多研究人员推测该酒精代谢物会导致宿醉。乙醛脱氢酶(ALDH)快速代谢乙醛转为乙酸盐,虽然乙醛是剧毒,但是ALDH的反应非常迅速。36%的东亚人的乙醛脱氢酶基因变异导致代谢不足,许多中国人会因为喝酒而引起脸部潮红和头痛。这也导致很多人认为乙醛是导致宿醉的原因。第一,必须指出即使在酒精中毒患者的血液中检测到的乙醛含量也非常低,中低剂量的饮酒血液系统中难以检测出乙醛,并且也不存在生物体内的积累;第二,欧美人中有关乙醛脱氢酶的基因变异的较少,却依然存在大量的宿醉病例,在中国喝酒不脸红的人同样也会产生宿醉的现象;第三,宿醉往往发生在饮酒后第二天,血液中酒精含量已经接近为零,乙醛导致的潮红和头痛却往往在喝酒期间发生;第四,乙醛很难通过血脑屏障,而脑中的乙醇脱氢酶却很少,这就导致大脑中乙醛的含量会比血液中乙醛的含量低很多,在大脑中难以可靠的检测到乙醛的产生。因此宿醉与乙醛的关系应该不大。
也有学者认为乙酸盐是导致宿醉的主要因素,主要原因在于饮酒后6个小时后血液乙酸盐含量显著增加,但是乙酸盐难以通过血脑屏障,此外乙酸盐在大脑中也产于乙酰胆碱的合成代谢和一些其他代谢。宿醉发生率与酒精摄入量并没有显著的关联,中低剂量的酒精摄入依然会导致宿醉的发生,因此该理论依然存在缺陷,或者说乙酸盐可能仅是宿醉的一个影响因素而不是主要原因。
乙醇暴露于免疫反应之间存在复杂的的关系,乙醇会提高海马和皮质层中细胞因子的表达,炎症反应可能导致多种症状,可能是宿醉的主要因素。宿醉状态下人体静脉血中IL-12和IFN-γ显著增加,然而有研究表明[Marshall SA,McClain JA,Kelso ML,HopkinsDM,Pauly JR,Nixon K.Microglial activation is not equivalent toneuroinflammation in alcohol-induced neurodegeneration:The importance ofmicroglia phenotype.Neurobiol Dis.2013;54:239-251.]乙醇不会经典的激活小胶质细胞,不符合炎症的经典定义,酒精诱导的小胶质细胞激活是酒精诱导的细胞死亡的结果,尤其是迄今为止尚无报道称酒精中毒者大脑中有完全激活的小胶质细胞。如果小胶质细胞只能局限于部分激活,那么它们可能对酒诱导的神经变性后的内源性修复有益。
宿醉症状可能是酒精饮料中存在的几种同系物引起的,这些物质(胺,酰胺,丙酮,多酚,甲醇),红酒中存在高浓度的甲醇,果胶在发酵过程中脱甲基会释放出甲醇。甲醇被认为是宿醉的主要因素,国家标准规定,以粮谷类为原料的白酒中甲醇含量不得超过0.6g/L,以其他原料生产的白酒中甲醇含量不得超过2.0g/L。(甲醇指标按100%酒精度折算)。总所周知的是,水果酿造的果酒与粮食酿造的白酒相比会增加宿醉的频率和强度,有研究也表明[Young-Sup,Woo,Su-Jung,el.Concentration changes of methanol in bloodsamples during an experimentally induced alcohol hangover state[J].AddictionBiology,2005.]甲醇浓度的变化与宿醉的主观评分的变化具有很好的相关性。需要指出的是,甲醇本身对人体细胞无毒,然而其氧化产物甲醛和甲酸盐是一种剧毒素,被认为在神经损伤中起作用,乙醇会竞争性的抑制甲醇代谢,当血液乙醇含量接近于零时,甲醇代谢增加,氧化为甲醛或甲酸盐,上述解释很好的契合了宿醉症状的时间过程,即宿醉一般发生在第二天,当血液酒精浓度接近零之后产生的身体和精神上的不适。尽管如此,仍有数据与甲醇理论背道而驰,比如[Mackus M,Van de Loo AJ,Korte-Bouws GA,et al.Urinemethanol concentration and alcohol hangover severity.Alcohol.2017;59:37-41.]文中说明尿中甲醇浓度与宿醉严重程度之间没有相关性。显然有必要进一步研究甲醇对宿醉的相关作用。
长期以来,人们认为甲醇是一种外源性的化合物,主要来源于酒精和一些水果中,研究人员没有关注内源性甲醇和甲醛在人体的作用和影响。随着检测手段的提高和进步,直到最近人们发现了甲醇和甲醛实际上是正常健康人体内的天然化合物。长期以来人们均观察到饮酒后,血液中甲醇含量的提升,酒水制造商也努力降低其产品中甲醇的浓度,尽管如此,最近的研究发现即使喝不含甲醇的酒精饮料时,血液甲醇含量迅速提高,研究人员观察到人饮用50-90毫升的40%浓度的乙醇时(不含甲醇),他们血液中甲醇含量依然提高[Shindyapina AV,Petrunia IV,Komarova TV,et al.Dietary methanol regulateshuman gene activity.PLoS One.2014;9(7):e102837.],认为是由于内源性甲醇的代谢收到了乙醇的抑制而导致血液中甲醇的含量增加。
酒精性肝病是长期或过度饮酒所致的肝脏疾病。在病理组织学上按照肝细胞发生脂肪病变的过程分为酒精性脂肪肝、肝炎、肝纤维化、肝硬化。四者是渐进性的过程,即可不同类型同时存在。调查显示,酒精性肝病在人群中数多发病和常见病也是最严重的的酗酒并发症。
长期以来人们建立了酒精摄入与脂肪性肝炎之间的联系机制,包括代谢的乙醛对肝组织的损伤等等,但是值得注意的是仅有30%的酗酒者会发展至酒精性肝炎或其他肝病[Grant BF,Dufour MC,Harford TC.Epidemiology of alcoholic liver disease.SeminLiver Dis.1988;8(1):12-25.],因此除了大量摄入酒精会导致脂肪性肝炎外,还应该存在另一种主要机制促进肝病理的进展,肠道来源的内毒素是酒精之外最可能的影响因素。早期的研究已经证明了补充燕麦能够防止肠渗透预防酒精性肝损伤[Keshavarzian A,Choudhary S,Holmes EW,et al.Preventing gut leakiness by oats supplementationameliorates alcohol-induced liver damage in rats.J Pharmacol Exp Ther.2001;299(2):442-448.],此外还有很多证据,包括在动物模型中成功的使用抗生素预防肝损伤,益生元对肝脏的保护作用等等。这些研究均证明了肠道的生理功能是肝损伤的重要机制。
非酒精脂肪肝(NAFLD)主要是除外酒精和其他明确的损肝因素所致的肝细胞内脂肪过度沉积为主要特征的临床病理综合征,随着人们生活水平的提高,非酒精脂肪肝在我国的发病率不断提升,作为“富贵病”的一种,临床上最常见的原因是肥胖及营养过剩导致的肝脏的脂肪蓄积。经常服用叶酸的人群患有非酒精脂肪肝也很常见。根据症状,非酒精性脂肪肝可以分为表型状态-良性的非酒精单纯脂肪肝(NAFL)以及非酒精脂肪肝炎(NASH),非酒精性脂肪肝炎(NASH)占整个非酒精脂肪肝(NAFLD)的比例大约44%,主要以脂质积聚、炎症、肝细胞损伤以及肝纤维化为特征的病理状态进行,严重的可发展为肝癌。发病机制原因复杂,目前人们还无法完全认清NASH的发病的分子机制。发病机制可能包括脂质代谢失调、胰岛素抵抗、免疫反应、炎症、氧化应激、细胞凋亡、肝星状细胞的活化等。
目前国家食品药品监督管理总局网站公布的对化学性肝损伤有辅助保护功能的保健食品,约86.8%为含有中药类的产品。由于中药成分复杂,难以分辨其中是否有成分具有肝毒性成分,长期服用存在药物性肝损伤的可能。
发明内容
本发明经潜心研究,发现5-甲基四氢叶酸具有新的药用或辅助药用活性,其对因长期或过度饮酒引发的各种疾病能产生缓解或治疗作用,因此本发明提供一种含有5-甲基四氢叶酸的药物组合物或保健食品组合物,及其新用途。本发明的技术方案如下所述:
一种药物组合物或保健食品组合物,其含有有效量的5-甲基四氢叶酸,所述组合物用于治疗或缓解因饮酒或酒精引发的各种疾病或症状。
根据本发明的组合物,其用于治疗、缓解或预防急性酒精中毒带来的伤害或引发的疾病。
根据本发明的组合物,所述急性酒精中毒带来的伤害或引发的疾病包括:饮酒导致的头疼;饮酒导致的负面情绪,或者抑郁症;饮酒后的宿醉症状。
根据本发明的组合物,所述饮酒后的宿醉症状包括:头痛、眩晕、疲劳、恶心、胃部不适、困倦、发汗、过极度口渴和认知模糊等症状。
根据本发明的组合物,其用于治疗、缓解或预防慢性酒精中毒带来的伤害或引发的疾病。
根据本发明的组合物,所述慢性酒精中毒带来的伤害或引发的疾病包括:酒精性脂肪肝、中枢神经系统(CNS)炎症等。
根据本发明的组合物,所述中枢神经系统炎症包括由其引发的偏头疼、头疼。
根据本发明的组合物,其用于治疗或缓解非酒精性脂肪肝。所述非酒精性脂肪肝包括非酒精性单纯性脂肪肝(NAFL)以及非酒精性脂肪肝炎(NASH)。
根据本发明的组合物,其用于缩短醒酒时间。
根据本发明的组合物,其用于降低因饮酒带来的心脑血管系统疾病的风险。
根据本发明的组合物,其还含有药学上可接受的辅料或助剂。
另外,本发明的组合物还可含有单独起作用或具有协同作用的活性化合物。
根据本发明的组合物,其包括有效量的5-甲基四氢叶酸和姜黄素。
根据本发明的上述组合物,其5-甲基四氢叶酸:姜黄素的质量比为:3~1:1~100,示例性的,3~1:1~3,例如1:1。
根据本发明的组合物,其可以制成本领域已知的各种剂型。例如经肠给药剂型,例如口服、舌下含服或直肠给药;示例性的,口服剂型可以是片剂、胶囊、口服液、滴剂、丸剂、粉剂、颗粒剂。
根据本发明的组合物,所述5-甲基四氢叶酸的人用剂量为5~50mg/日,优选的,为10-50mg/日。
第二方面,本发明提供一种药物组合物或保健食品组合物,其含有有效量的5-甲基四氢叶酸,所述组合物能够显著降低血清中总胆固醇(TC)、甘油三酯(TG)、丙二醛(MDA)的水平并提高超氧化物歧化酶(SOD)水平。
根据本发明的组合物,所述组合物可用于治疗或预防高血脂及由高血脂引发的疾病。
根据本发明,所述由高血脂引发的疾病包括:脂肪肝、动脉粥样硬化、冠心病、脑梗塞、糖尿病、血管血栓、胰腺炎等。
第三方面,本发明提供5-甲基四氢叶酸的用途,其用于制备治疗、预防或缓解上述疾病的药物或保健食品。
发明详述
本发明中,术语“5-甲基四氢叶酸”包括5-甲基-(6S)四氢叶酸,5-甲基-(6R)四氢叶酸,5-甲基-(6R,S)四氢叶酸,即包括5-甲基四氢叶酸的旋光异构体、特别是纯旋光学天然异构体,旋光异构体的混合物、例如是外消旋混合物,以及它们生理学上可接受的盐。其中5-甲基-(6S)四氢叶酸(也称为L-5-甲基四氢叶酸)是特别优选的。
所述生理上可接受的盐,是指5-甲基四氢叶酸中的碱性基团转化为相应的酸加成盐,所述酸可以是无机酸,例如盐酸、硫酸、硝酸、磷酸;有机酸,例如甲酸、乙酸、丙酸、二乙基乙酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸,酒石酸、苹果酸、柠檬酸、葡糖酸、抗坏血酸或烟酸等。
所述生理上可接受的盐,也可指5-甲基四氢叶酸中的酸性基团转化为相应的碱加成盐,合适的盐,例如是钠、钾、镁、钙和铵盐,取代的铵盐,以及与精氨酸或赖氨酸形成的盐。
本发明所称的“急性酒精中毒”是本领域常规的术语,俗称酒醉,是由一次饮入过量的酒精或酒类饮料引起的神经精神症状为主的疾病,多表现行为和意识异常。一般将临床表现分为III期,①兴奋期,出现头痛、头昏、欣快、兴奋、饶舌、情绪不稳定、易激惹、或有攻击行为,少数人可表现为沉默,孤僻。②共济失调期,出现动作不协调,语无伦次,眼球震颤、骚动,视力模糊,复视,恶心、呕吐及困倦感。③昏睡(或昏迷)期,患者表现为昏睡,颜面苍白,皮肤湿冷,口唇微绀,严重者可出现深昏迷症状,表现为瞳孔中度散大,心率增快,血压下降,二便失禁,可因呼吸衰竭及循环衰竭而死忙,也可因咽部反射减弱,饱餐后呕吐,导致吸入性肺炎或窒息而死。
本发明所称的宿醉(hangover),是指一次饮酒后第二天出现的,血液酒精浓度(BAC)接近零时,但精神和身体仍然不适,表现出的各种症状,例如头痛、眩晕、疲劳、恶心、胃部不适、困倦、发汗、过极度口渴和认知模糊等症状。目前科学家们认为对于宿醉的神经机制与神经炎症因素、神经递质、受体的改变、线粒体功能障碍、和酒精代谢物有关,有作者认为炎症因素,神经递质和受体的改变,线粒体功能障碍是最有可能与宿醉病理有关的因素[Palmer E,Tyacke R,Sastre M,Lingford-Hughes A,Nutt D,Ward RJ.AlcoholHangover:Underlying Biochemical,Inflammatory and NeurochemicalMechanisms.Alcohol Alcohol.2019;54(3):196-203.]。然而上述解释均难以解释宿醉的时间过程,即饮酒后数小时后或第二天,人体血液酒精浓度降低至接近零之后产生的各种精神和身体的不适。
饮酒后血液甲醇的消除会滞后,乙醇的消除约6至8个小时,有数据表明饮酒后数小时内,血液甲醇浓度会不断升高。主要原因在于大脑以外的甲醇代谢系统受到了乙醇的抑制,而人体内会产出内源性的甲醇,从而造成一定程度的甲醇蓄积,内源性甲醇的产生速度至少约1.66mg/kg/h,一个成人在1小时内可以形成116mg的甲醇,这相当于摄入了250至300ml的红酒。由此可见,内源性的甲醇的产生量并不是能够让人忽略不计。
本发明的一个实施例中,发现急性饮酒后会导致大鼠尿液中甲醇和甲醛的含量急剧升高,甲醇浓度在饮酒后8小时达到高峰,而甲醛和甲酸盐的高峰则会延后于甲醇。值得注意的是甲酸盐的浓度远远高于甲醛和甲醇,高达数十倍或数百倍。由于大鼠甲醇代谢能力远远超过人类,因此甲酸蓄积在人类和猴子身上多见。饮酒后内源性甲醇,甲醛,甲酸的蓄积在人类中应该会更为严重,发明人回顾了关于宿醉的现有的、零碎的知识,宿醉有许多解释性的假说,这些假说基于饮酒的潜在直接影响或戒酒影响,几乎所有的解释都存在缺陷。正如背景技术所述的,人们往往关注在酒精代谢物而忽视了酒精对内源性甲醇和甲醛的代谢的影响,本发明的实验结果表明饮酒后大脑中甲醛及甲酸盐会出现蓄积现象,众所周知甲醛及甲酸盐具有神经毒性,甲醛在脑功能障碍的病理发展中起着一定的作用,甲醇和甲醛及代谢的甲酸盐很可能是最重要的宿醉因素,本发明的数据支持这一结论。
本发明的另一个实施例中,考察了饮酒24小时后,大鼠大脑中甲醛和甲酸盐以及一些神经递质(5-羟色胺、多巴胺)的含量,令人惊奇的是大脑甲醛和甲酸盐存在蓄积的现象,大鼠在24小时左右,尿液中的甲醛和甲酸盐的浓度已经基本下降至基线水平,而脑组织的甲醛和甲酸的含量水平依然较高。甲醇和乙醇可以比较容易的穿过血脑屏障,作用于大脑,而甲醛和乙醛则难以通过血脑屏障,此外大脑中没有ADH1的活性,从而减少内源性甲醛在大脑中的产生。对于在大脑中甲醇经过氧化而产生的甲醛,则通过FDH和ALDH2等酶迅速的解毒,正常情况下通过上述二种策略可以保护中枢神经细胞不受甲醛的危害,但是在急性饮酒期间,上述两种策略会受到挑战,特别是饮酒后发现大脑中脑组织中SOD酶和GSH含量的下降,增加了大脑中甲醇氧化成甲醛的可能性。此外乙醇作为脱水剂,同样也会导致脑组织甲醛的升高。本发明发现5-甲基四氢叶酸能够促进脑组织中甲醛和甲酸盐的代谢,降低甲醛和甲酸盐的浓度,从而预防和治疗宿醉。
本发明所称的负面情绪是指情绪低沉、失落、食欲不振、失眠、易感疲劳、注意力涣散、对周边事物失去兴趣、罪恶感或厌恶感的自我强化等消极情绪,这类情绪如果持续性出现,并伴随严重的心情郁闷,则形成抑郁症。而有些饮酒者,酒后会出现以上负面情绪,或者饮酒会使得本来具有以上负面情绪或抑郁症的患者症状加重,本发明的一个实施例发现,饮酒后24小时大鼠脑组织中5-羟色胺水平下降,这可能是导致酒后抑郁感的原因,而5-甲基四氢叶酸能够改善5-羟色胺的分泌。
本发明所称的慢性酒精中毒(酒精依赖症),也是本领域常规技术术语,是指长期过量饮酒引起的中枢神经系统严重中毒,表现为对酒的渴求和经常需要饮酒的强迫性体验,停止饮酒后常感心中难受、坐立不安,或出现肢体震颤、恶心、呕吐、出汗等戒断症状,恢复饮酒则这类症状迅速消失。由于长期饮酒,多数合并躯体损害,以心、肝、神经系统为明显,最常见的是肝损伤,周围神经病变和癫痫性发作,有的则形成酒精中毒性精神障碍及酒精中毒性脑病。
本发明所称的酒精性脂肪肝,是由慢性酒精中毒,即长期饮酒导致的肝脏病变。脂肪肝大致可分为酒精性脂肪肝(AFLD)和非酒精性脂肪肝(NAFLD)。非酒精性脂肪肝是一种无过量饮酒史致肝实质细胞脂肪变性和脂肪储积,以炎症和纤维化为特征的疾病,和肥胖,高脂血症的发生密切相关。NAFLD定义为影像学和肝组织学证实肝脂肪变,并除外导致肝脂肪变的其他原因,如大量饮酒、长期应用促脂肪形成药物或单基因遗传紊乱等。NAFLD依据肝组织学变化分为NAFL及NASH:(1)NAFL:肝细胞脂肪变>5%,无肝细胞气球样变。(2)NASH:肝细胞脂肪变>5%,伴有炎症及肝细胞损伤(如气球样变),有或无纤维化。肝纤维化分期(stage,S)为S3(桥接纤维化)和S4(肝硬化)定义为进展期肝纤维化。
酒精性脂肪肝发展为酒精性脂肪肝炎的易感性是高度可变的,为什么有些人会得酒精性脂肪肝炎而有些人长期饮酒依然是良性的脂肪肝,有关原因受到酗酒的数量和时间、年龄、性别、种族、合并症、营养状况和环境的影响,遗传和表观遗传因素也会导致对酒精性脂肪肝炎的易感性差异。最近的证据支出了肠道菌群及其代谢产物在酒精性脂肪肝炎病理发展的作用[Meroni M,Longo M,Dongiovanni P.Alcohol or Gut Microbiota:WhoIs the Guilty.Int J Mol Sci.2019;20(18):4568.],具体而言,由于滥用酒精导致肠道通透性增加,导致进入门脉血流的脂多糖(LPS)浓度升高,从而与肝组织的Toll样受体4(TLR4)结合并激活活化的B细胞和NF-κB,促炎性细胞因子的释放,从而导致良性的脂肪肝转为脂肪肝炎。已经发现从酒精性肝炎患者中分离出的肠道菌群移植酒精饲养的无酒精性肝炎小鼠后会出现严重的肝脏炎症、坏死[Llopis M,Cassard A M,Wrzosek L,etal.Intestinal microbiota contributes to individual susceptibility toalcoholic liver disease[J].Gut,2016,65(5):830-839.]。
已经有几个实验模型表明,内毒素血症和酒精性肝炎可以被抗生素预防,然而抗生素在治疗中长期给药存在争议,包括抗生素的滥用导致的细菌抗性、药物本身的肝毒性、肠道微生物生态系统的破坏。但是上述研究也证明了肠道微生物对酒精性脂肪肝发展到肝炎的发病机制和进展密切相关。在本发明的一个实施例中发现,5-甲基四氢叶酸能够显著的保护肠屏障的生理功能,降低血清内毒素的水平。该结果表明5-甲基四氢叶酸能够阻止酒精性“渗透性肠”的产生,从而降低内毒素进入肝肠循环,进一步的预防和治疗酒精性脂肪肝炎。该机制的发现也可能同样适用与5-甲基四氢叶酸预防非酒精性脂肪肝炎的发生。
此外,日益增多的证据表明慢性酒精中毒影响胶质细胞,与中枢神经系统(CNS)炎症反应有密切关系,其主要表现为激活的脑内吞噬细胞(小胶质细胞)和其他胶质细胞,通过旁分泌途径,导致神经元的损伤。体外研究表明,慢性酒精中毒可抑制脑星形胶质细胞胶原纤维酸性蛋白和S100蛋白的表达,酒精可通过损伤脑星形胶质细胞的细胞膜和线粒体导致星形胶质细胞凋亡和坏死。
发明人经研究发现,一次大量饮酒会导致血清内叶酸浓度短时间内的急剧下降,甚至低于定量下限,这一发现超出本领域预期,虽然肝脏本身是叶酸的存储器,但在饮酒后这部分叶酸并不能及时进入血液循环中,即使预先或酒后补充叶酸,叶酸需要在肝脏中利用二氢叶酸还原酶转化为四氢叶酸,但是由于人类肝脏中该酶的活性很低,0.2mg以上的叶酸就会导致肝脏代谢能力饱和[Bailey,Steven,W,el.The extremely slow and variableactivity of dihydrofolate reductase in human liver and its implications forhigh folic acid intake.[J].Proceedings of the National Academy of Sciences ofthe United States of America,2009.],因此补充叶酸无法解决血清中叶酸浓度下降的问题,而本发明的5-甲基四氢叶酸或其组合物却能够解决因一次大量饮酒导致的急性血清叶酸浓度下降的问题。
基于上述发现,发明人进一步经实验证实了,服用5-甲基四氢叶酸或其组合物可以预防、改善、治疗人或动物急性酒精中毒后产生的各种不适状态,所述不适状态包括宿醉,头痛,酒后的负面精神状态。
此外,在我国叶酸作为孕妇补充剂,每天的剂量是0.4mg/天,而美国自1996年美国食品药品管理局强制要求粮食制品100g中必须添加140ug叶酸。如果以每人每天食用500g粮食制品计,补充的叶酸剂量是0.7mg/天。然而,这一剂量的全民补叶酸运动也并未减少因急性或慢性酒精中毒引发的上述各种疾病,例如美国脂肪肝发病率逐年持续增高,目前以达到15%以上。而且有文献[Christensen KE,Mikael LG,Leung KY,et al.High folicacid consumption leads to pseudo-MTHFR deficiency,altered lipid metabolism,and liver injury in mice.Am J Clin Nutr.2015;101(3):646-658.]表明高剂量的叶酸(folic acid)的摄入会导致肝脏损伤、促进肝脏细胞凋亡。5-甲基四氢叶酸虽然是叶酸代谢物的一种形式,但是二者具有本质的不同。
发明人发现,一定剂量的5-甲基四氢叶酸或其组合物可以预防、改善、治疗人或动物由慢性酒精中毒导致的各种疾病。现有的解酒保健品或药品往往关注于肝脏对酒精的代谢,而忽略了脑组织对饮酒产生的酒精同系物(甲醇、甲醛、甲酸盐)的代谢,本发明能够促进脑组织中有关物质的代谢与消除。
在本发明的一个实施例中,5-甲基四氢叶酸能够抑制慢性酒精中毒引起的大脑炎症因子(例如TNF-α,IL-1β)的表达,并且具有一定的量效关系,因此5-甲基四氢叶酸能够预防由慢性酒精中毒引起的头痛和偏头痛。
在本发明的一个实施例中,5-甲基四氢叶酸显示出可改善因长期饮酒(即慢性酒精中毒)导致的酒精性肝损伤活性,其显著降低血清中总胆固醇(TC)、甘油三酯(TG)、丙二醛(MDA)的水平并提高超氧化物歧化酶(SOD)水平,并且能够使肝脏质量,肝指数恢复到正常形态,肝脏病理学检查状况良好。此外5-甲基四氢叶酸能够维持肠屏障功能,降低肠道内毒素进入肝肠循环,这表明5-甲基四氢叶酸阻止酒精性脂肪肝恶化为肝炎等疾病,特别是预防及治疗酒精性脂肪肝、肝炎、肝纤维化。
在本发明的一个实施例中,5-甲基四氢叶酸显示出预防或治疗高血脂症引起的脂肪肝的活性,从而用于预防或治疗高血脂症。而本领域技术人员公知,高血脂症会引发一系列相关疾病,已有研究表明,其与脂肪肝、动脉粥样硬化、冠心病、脑梗塞、糖尿病、血管血栓、胰腺炎等的发病密切相关。
在本发明的一个实施例中,所述5-甲基四氢叶酸显示出改善因一次性大量饮酒(急性酒精中毒)后带来的不良精神状态、负面情绪、甚至是酒后抑郁的活性。
在本发明的一个实施例中,所述5-甲基四氢叶酸显示出抑制脂多糖诱导的神经胶质细胞释放炎症因子的作用。更为意外的是,5-甲基四氢叶酸与姜黄素联合使用时,显示出抑制脂多糖诱导的神经胶质细胞释放炎症因子的协同作用,尤其是对TNF-α炎症因子。在联合使用时,二者的比例可以是3~1:1~3,例如是1:1。
本发明的药物或保健食品,每剂量中含有1mg-500mg的5-甲基四氢叶酸,在预防用药时,优选使用每剂量含有0.1mg-100mg的活性物质,在治疗用药时,优选使用每剂量含有5mg-200mg的活性物质。其具体的使用剂量取决于各种因素,例如患者的年龄、体重、给药时间和途径、病情等等,优选最佳治疗剂量为5-50mg/日,例如是10-50mg/日,预防剂量为1-10mg/日。
本发明中,所述药物或保健食品组合物,含有各种载体、赋形剂和/或辅助功能剂,例如水、油、苯甲醇、聚乙二醇、甘油三乙酸酯、明胶、卵磷脂、环糊精、乳二糖或淀粉等糖类,硬脂酸镁、滑石、硅胶或纤维素。所述辅助功能剂,例如是稳定剂、抗氧剂、缓冲剂、抑菌剂等等。在本发明的一个实施方式中,所述赋形剂或载体是微晶纤维素,或者微晶纤维素与交联羧甲基纤维素钠的组合,或者微粉硅胶。
附图说明
图1实验例4中正常大鼠组肝脏组织图。
图2实验例4中模型对照组大鼠肝脏组织图。
图3实验例4中阳性药组大鼠肝脏组织图。
图4实验例4中低剂量组大鼠肝脏组织图。
图5实验例4中中剂量组大鼠肝脏组织图。
图6实验例4中高剂量组大鼠肝脏组织图。
图7实验例6中MR1未给药的离子色谱图及内标离子色谱图。
图8实验例10中饮酒后各组大鼠尿液甲醛平均浓度与时间折线图。
图9实验例10中饮酒后各组大鼠尿液甲酸平均浓度与时间折线图。
图10实验例12中酒精喂养第八周各组大鼠的5小时尿液乳果糖的口服剂量分数(小肠渗透性指数)图。
图11实验例12中酒精喂养第八周各组大鼠尿中5小时三氯蔗糖的口服剂量分数(全肠[小肠+大肠]渗透性指数)图。
图12实验例12中酒精喂养第八周各组大鼠血清内毒素水平图。
具体实施方式
特别说明:
本发明中提出的血清叶酸,指是血清中的5-甲基四氢叶酸。
叶酸如无特别说明指是合成叶酸。
实施例1
100g的5-甲基四氢叶酸钙盐,与700g的微晶纤维素混合,干法制粒后,灌1000粒胶囊,制成每粒含100mg5-甲基四氢叶酸钙的胶囊制剂。
实施例2
100g的5-甲基四氢叶酸钙盐,加入200g的微粉硅胶,混匀,后于压片机压片成形,得到解酒含片。
实施例3
各个原料药的重量如下:5-甲基四氢叶酸钙40g,姜黄素40g,原料粉碎后与微晶纤维素和交联羧甲基纤维素钠,制成颗粒,干燥,灌胶囊,制得每粒含有5-甲基四氢叶酸钙20mg,姜黄素20mg的胶囊。
实施例4
各个原料药的重量如下:5-甲基四氢叶酸钙40g,还原性谷胱甘肽颗粒20g,姜黄素40g,原料粉碎后与微晶纤维素和交联羧甲基纤维素钠,制成颗粒,干燥,灌胶囊,制得每粒含有5-甲基四氢叶酸钙20mg,还原性谷胱甘肽颗粒10mg,姜黄素20mg的胶囊。
实验例1 5-甲基四氢叶酸对饮酒大鼠翻正反射消失和恢复的影响
取30只SD大鼠,SPF级,雄雌各半,随即分成5组,每组6只,分别为正常组,模型组,阳性药组(维和牌维甘片),5-甲基四氢叶酸给药组(中、高剂量组分别为4mg·Kg-1、8mg·Kg-1)。禁食12h后,给药组分别给予50mg·Kg-1维和牌维甘片、4mg·Kg-15-甲基四氢叶酸(金康和信产品)、8mg·Kg-15-甲基四氢叶酸(金康和信产品)。30min后模型组及给药组分别给予二锅头(批号:201603092,规格:2L,产地:北京顺鑫农业股份有限公司:)9ml·Kg-1,正常组服用等量的生理盐水。大鼠醉酒与否以翻正反射消失为指标,即用纱布盖住大鼠的头,将大鼠背向下轻轻放在动物笼中,1min内前爪翻回者,判定为未出现翻正发射消失;反之为翻正反射消失。记录给酒后大鼠翻正反射消失时间和恢复时间,实验结果见下表
注:n=6与模型组比较:*p<0.05,**p<0.01
以上结果表明,5-甲基四氢叶酸对急性酒精中毒的大鼠具有明显拮抗作用。其中,用量远低于阳性药物组的中、高剂量组的饮酒大鼠翻正反射恢复时间方面优于阳性药组,这显示了5-甲基四氢叶酸具有缩短醒酒时间的作用。
实验例2 5-甲基四氢叶酸对饮酒大鼠血浆中同型半胱氨酸(Hcy)影响
取30只SD大鼠,SPF级,雄雌各半,随即分成5组,每组6只,分别为正常组,模型组,阳性药组(维和牌维甘片),5-甲基四氢叶酸给药组(中、高剂量组分别为4mg·Kg-1、8mg·Kg-1)。禁食12h后,给药组分别给予50mg·Kg-1维和牌维甘片、4mg·Kg-15-甲基四氢叶酸(金康和信产品)、8mg·Kg-15-甲基四氢叶酸(金康和信产品)。30min后模型组及给药组分别给予二锅头(批号:201603092,规格:2L,产地:北京顺鑫农业股份有限公司)20ml·Kg-1,正常组服用等量的生理盐水。酒后6小时,眼眶取血,0.5%EDTA-Na抗凝(10ml/L),立即冰浴冷却,于30分钟内4℃离心(3500r/min)15分钟,收集血浆,-20℃保存。采用高压液相-荧光检测法测定Hcy血浆浓度。实验结果见下表。
注:n-6与模型组比较:*p<0.05,**p<0.01
结果表明,急性大量酒精会导致大鼠体内同型半胱氨酸升高,5-甲基四氢叶酸能够明显降低大鼠血清中Hcy的水平,并且具有量效关系。Hcy不仅仅会造成对神经系统的损害,还会造成缺血性心脏病和缺血性卒中,虽然随着酒精代谢这些指标会回复到正常水平,但是依然会产生不良状态,因此5-甲基四氢叶酸也能降低饮酒来带来的心血管疾病的风险。
实验例3 5-甲基四氢叶酸钙对四氯化碳诱导的肝损伤的保护作用
取30只SD大鼠,SPF级,雌雄各半,根据体重随机分为溶媒对照组(植物油)、模型对照组(1.5ml·kg-1,20%四氯化碳植物油溶液,每隔3天腹腔注射一次)、5-甲基四氢叶酸钙低剂量组(1mg·Kg-1)、5-甲基四氢叶酸钙中剂量组(2mg·Kg-1)、5-甲基四氢叶酸钙高剂量组(4mg·Kg-1)。采用20%四氯化碳植物油溶剂为诱导剂,每隔3天腹腔注射一次,共60天。造模成功后,给药组按上述设定的叶酸钙剂量每日灌胃一次,模型组及正常对照组每日灌胃纯净水,连续用药60天,第61天取血,检测血清ALT,AST水平。结果如下表
表3 5-甲基四氢叶酸钙对四氯化碳诱导的肝损伤的保护
注:1.动物数:各组n=6;2.*:各剂量组与溶媒对照组相比,P<0.05;#:各剂量组与模型对照组相比,P<0.05
实验例4一定剂量5-甲基四氢叶酸钙对酒精性肝损害预防脂肪肝的作用
取96只SD大鼠,SPF级,雌雄各半,实验开始时体重均数176~220g,根据体重随机分为溶媒对照组(纯化水,ig)、模型对照组(白酒,10ml·Kg-1)、阳性对照组(双环醇片,50mg·Kg-1,ig)、叶酸钙盐高剂量组(4mg·Kg-1)、叶酸钙盐中剂量组(2mg·Kg-1)、叶酸钙盐低剂量组(1mg·Kg-1),雌雄各半,每组16只。阴性对照使用纯化水,阳性药为双环醇片(产地:北京协和药厂,规格:25mg/片,批号:H20040467)。给药途径:全部为经口灌胃给药。给药剂量:以1mg·Kg-1、2mg·Kg-1、4mg·Kg-1为给药剂量。给药频率:每天给药1次,连续60天。二锅头(批号:201603092,规格:2L,产地:北京顺鑫农业股份有限公司)造模方法:将稀释的56度二锅头灌胃,每日2次,连续60天。
给药方法:造模当天按拟定剂量开始给药,连续60天,60天给药结束。同时在给药期间每间隔一周给各组大鼠称重,以监测其体重变化,给药期间大鼠体重增重的变化如表4所示。第61天解剖大鼠,取血清进行甘油三酯(TG)、胆固醇(TC)、丙二醛(MDA)、超氧化物歧化酶(SOD)和肝脏病理学检查。结果见表5。取大鼠脑组织,在冰台上分离海马组织,用纯净水制成质量分数为10%的匀浆,离心取上清液。采用ELISA法,以连续光谱酶标仪检测海马组织中炎症因子TNF-α、IL-1β的水平。结果见表6
注:1.动物数:各组n=16;2.各剂量组与正常对照组相比,*:P<0.05.
各组大鼠体重均逐渐增加,但各造模用药组与正常对照组从第二周体重有显著差异。喝酒的模型组与给药组之间差异不是很明显,但是可以看出高剂量组体重增加高于中、低剂量组,即本发明的5-甲基四氢叶酸给药与体重增加具有一定的剂量关系,说明5-甲基四氢叶酸缓解了饮酒导致的食欲不振或者其他因素导致的大鼠体重增长缓慢。
注:1.动物数:各组n=16;2.*:各剂量组与溶媒对照组相比,P<0.05;#:各剂量组与模型对照组相比,P<0.05
结果表明:模型组大鼠的各项指标均与对照组有显著性差异(P<0.05),受试物三个剂量组的TG、MDA及SOD与模型组相比均有显著性差异(P<0.05),5-甲基四氢叶酸钙在1mg/kg/day的低剂量下就与阳性药物组的TG和TC指标接近,在SOD和MDA指标方面优于阳性药物组,这足以显示5-甲基四氢叶酸对饮酒导致的肝损伤及脂肪肝具有非常优异的治疗或缓解效果。
注:1.动物数:各组n=16;2.*:各剂量组与正常对照组相比,P<0.05;#:各剂量组与模型对照组相比,P<0.05
结果表明:5-甲基四氢叶酸钙能够抑制慢性酒精诱导的大鼠脑中的炎症因子产生,个体之间差异较大,模型组的数据波动较大,因此有必要增加酒精服用时间,造成“酗酒”模型来观察酒精对大鼠大脑炎症诱导的影响。但是可以确定5-甲基四氢叶酸组能够明显抑制大鼠脑中炎症因子的表达,有一定量效关系的趋势。因此5-甲基四氢叶酸能够预防由酒精诱导的头痛、偏头痛。
病理学检查:
对照组:肝小叶结构清晰,肝细胞未见变性、坏死、增生,间质结缔组织未见增生;模型组组:肝脏间质结缔组织中度增生,肝细胞脂肪变性;低剂量组:肝细胞尚见少量残存的脂肪空泡,间质结缔组织增生不明显;阳性药组、中剂量组、高剂量组:未见间质结缔组织增生和肝细胞的脂肪变性。(见说明书附图1-6)
实验例5 5-甲基四氢叶酸钙对高血脂大鼠的影响
取50只SD大鼠,SPF级,雌雄各半,给予普通饲料喂养5周后,将大鼠随机分为普通饲料喂养组(n=9)和模型组(n=41),分别给予普通饲料喂养或83%普通饲料+15%猪油+2%胆固醇构成的高脂饲料喂养。7周后,随即处死对照组1只和模型组1只,进行肝组织切片检查肝细胞脂肪变形情况(见表7),以确认制备模型成功。将剩余的成模大鼠40只随机分为低剂量(1mg·Kg-1)对照组、中剂量(2mg·Kg-1)对照组、高剂量(4mg·Kg-1)对照组、阳性药对照组、模型组。
阳性药为双环醇片(产地:北京协和药厂,规格:25mg/片,批号:H20040467)
造模成功后按拟定剂量开始给药,连续60天,并继续给予高脂饲料喂养,60天给药结束后第61天解剖大鼠。摘取肝脏并称质量,计算肝指数,取肝右叶组织,制备冰冻切片,用苏丹III进行脂肪染色,依据NAFLD诊疗指南进行病理性评分。另取肝组织,匀浆后,检测血清液中、总胆固醇(TC)、甘油三酯(TG)、丙二醛(MDA)、超氧化物歧化酶(SOD)。结果见表8
注:*:各剂量组与模型组相比,P<0.05;**:各剂量组与模型组相比,P<0.01
以上数据表明了5-甲基四氢叶酸钙能够预防和治疗高血脂引起的脂肪肝,使肝脏恢复到正常形态,并且能够预防脂肪肝的病理状态向脂肪肝炎(NASH)转变。5-甲基四氢叶酸中、高剂量组的大鼠肝脏均表现为良性或正常的状态。
注:各剂量组与正常对照组相比,*:P<0.05.#:各剂量组与模型对照组相比,P<0.05
表8显示结果与实施例4的表5的结论相近。肝脏作为叶酸代谢的重要器官,肝损伤与叶酸代谢有复杂和直接的联系,我们发现5-甲基四氢叶酸能够预防脂肪肝由良性状态转为病理状态,并在一定剂量水平下,能产生治疗效果。
实验例6人体饮酒的血浆中叶酸浓度
3名成人,在完全理解本实验方案的基础上,自愿参加该研究,3人基本状况如表9所述。
JK001胶囊:合成叶酸,来源:郑州裕和食品添加剂有限公司,纯度99.8%,分子量:441.4,换算因子:1,取42g合成叶酸与微晶纤维素混合均匀后,装入1000粒的胶囊中,制成JK001胶囊(含有42mg叶酸);JK002胶囊:5-甲基四氢叶酸钙,来源:连云港金康和信药业有限公司,纯度99.9%,分子量497.5,换算因子:0.8872,取47.34g的5-甲基四氢叶酸钙与微晶纤维素混合均匀后,装入1000粒胶囊中,制成JK002胶囊(含有42mg叶酸,换算量);
JK003胶囊:微晶纤维素,装入1000粒胶囊中制成JK003胶囊。
上述胶囊的型号规格一致,无法从外表分辨。
早上空腹情况下,上述三名自愿者在分阶段饮酒400ml(半小时内)之后,立即服用胶囊,之后24h期间正常饮食、饮水。
表9自愿者基本情况
采血方式:静脉采血,采血时间:喝酒前30min,给药前0min,药后0.25,0.5,1,2,4,6,8,24h。收集到的血样在5000rpm,4℃条件下离心5min,得到的血浆转移至1.5mL离心管中,然后置于-20℃冰箱保存。采用表9的分析检测条件测试血样中叶酸浓度。
表10分析检测条件
结果见表。
表11不同采血点的血药浓度
注:线性范围:5~10000ng/mL,LLOQ:5ng/mL,BLOQ:低于定量下限
结果表明:大量饮酒会导致血清叶酸的短时间急剧下降,下降至定量下限的水平,超出了我们的预期,肝脏本身作为叶酸的存储器,储存大约5-20mg的叶酸,但是饮酒后这部分叶酸并未立即进入血液循环中,5-甲基四氢叶酸能够解决短时间大量饮酒导致的血清叶酸下降的问题,合成叶酸则无法解决该问题。
结合上述动物实验数据,5-甲基四氢叶酸钙对酒精性肝损伤模型具有较好的保护作用,说明体内叶酸缺乏必然影响其保护功能,本实验数据与动物实验数据作用相吻合,可以相互印证和相互补充。
实验例7醒酒胶囊对宿醉症状的影响
为了证明本发明对酒后的宿醉导致的各种不良反应的影响,以实施例3中制备的胶囊作为样品,将实验志愿者10人,年龄20-40岁,男性,随机分成2组,一组使用样品,一组使用阴性样品。饮酒前2组服用解酒样品或阴性样品,之后完成规定的饮酒量,第二天早晨8:00前,填写调查问卷,询问是否出现过渡口渴、恶心、困倦、发汗、厌食、认知模糊、偏头疼等症状。结果见表。
表12人体宿醉反应试验结果
注:主要为主观评价,认为出现对应症状即统计
结果表明:本发明的组合物具有改善酒后不良的生理反应,特别是对恶心、困倦效果明显,能够显著维持喝酒人的精神状态,改善酒后情绪,减轻睡意。
实验例8酒后小鼠悬尾实验及游泳实验
清洁级昆明种雄性小鼠,体重18-22g。实验环境23℃,湿度50%。小鼠自由摄食和饮水,实验前适应5天。小鼠随即分成5组:模型组,正常组,5-甲基四氢叶酸钙高、中、低剂量组(16mg·Kg-1、8mg·Kg-1、4mg·Kg-1),每组10只,模型组进行灌胃给予二锅头(批号:201603092,规格:2L,产地:北京顺鑫农业股份有限公司)18ml·Kg-1,叶酸钙(连云港金康和信药业有限公司)高、中、低剂量组同样给予二锅头的叶酸钙溶液。24h后进行测试,小鼠悬尾试验主要是通过固定小鼠尾部使其头向下悬挂,小鼠在环境中处于拼命挣扎逃跑,又无法逃脱的状态,一段时间后,记录该环境下的小鼠产生绝望的不动状态过程的不动时间,以观察给药后的治疗效果。倒挂小鼠的头部距离箱底10cm,一次悬挂2只小鼠,中间用隔板隔开以避免碰撞。悬挂小鼠10分钟,统计后5分钟悬挂小鼠的累积不动时间。结果如下。
注:n=10*与模型组相比p<0.05,**与模型组相比p<0.01
将小鼠放入长50cm,宽40cm,高40cm的塑料游泳箱中,从小鼠放入水中后计时10分钟,记录后5分钟内小鼠仅有微小肢体运动而不挣扎,记录漂浮状态的累积不动时间。
注:n=10*与模型组相比p<0.05,**与模型组相比p<0.01
结果表明,本发明的应用能够明显改善小鼠饮酒后的精神状态,改善小鼠抑郁的表现。
实验例9 5-甲基四氢叶酸与姜黄素对LPS诱导的星形胶质细胞炎症反应的抑制作用
无菌条件下取出1~2d昆明小鼠的大脑皮质,剥除残余脑膜及血管后用遇冷的PBS液清洗3次,吹打制成单细胞悬液,离心后弃去上清液,沉淀用AST基本培养液(含10%FBS的高糖DMEM)重新悬浮。接种于L-多聚赖氨酸(0.1mg/ml)包被的培养瓶中,置于CO2培养箱中培养,24h后换液去除组织碎片及未贴避细胞。以后每3d换液1次直到细胞达到80%的融合,然后置于恒温摇床,37℃、180r/min离心18h,去除上层的少突胶质细胞和小胶质细胞。然后用胰酶消化传代培养。将第二代AST接种于6孔板中,实验分为:空白组PBS液;对照组:LPS(1μg·ml-1)、LPS(1μg·ml-1)联合姜黄素(10μg·ml-1)、LPS(1μg·ml-1)联合5-甲基四氢叶酸钙(10μg·ml-1);实验组:LPS(1μg·ml-1)联合姜黄素(5μg·ml-1)联合5-甲基四氢叶酸钙(5μg·ml-1)。作用24h后收集培养上清液,ELISA法检测细胞因子IL-6、IL-1β和TNF-α,结果见表15。
注:n=6各剂量组与正常对照组相比,*:P<0.05.#:各剂量组与模型对照组相比,P<0.05
结果表明:5-甲基四氢叶酸与姜黄素均具有抑制脂多糖诱导的神经胶质细胞释放炎症因子的作用,特别是对肿瘤坏死因子TNF-α具有明显得效果,二者联合使用竟然使TNF-α的水平降低至正常对照组以下,说明姜黄素与5-甲基四氢叶酸具有协同起效的作用。该组合物抑制酒精诱导的人体神经系统炎症的发生,起到预防头痛发生的作用。
实验例10饮酒及5-甲基四氢叶酸对SD大鼠尿液中甲酸盐的影响
为了研究5-甲基四氢叶酸和乙醇对大鼠的甲醇代谢的影响,将SD大鼠,SPF级,雌性,禁食过夜分为4组:(1)乙醇组,分别在1小时,2小时,3小时灌胃给药1g/kg剂量的乙醇,n=7;(2)对照组,分别在1小时,2小时,3小时灌胃给药1.6g/kg剂量的葡萄糖(与酒精热量相当),n=5;(3)5-甲基四氢叶酸组,分别在0小时灌胃给药4mg/kg剂量的5-甲基四氢叶酸钙,之后分别在1小时,2小时,3小时灌胃给药1.6g/kg剂量的葡萄糖(与酒精热量相当),n=5;(4)5-甲基四氢叶酸酒精组,分别在0小时灌胃给药4mg/kg剂量的5-甲基四氢叶酸钙,之后分别在1小时,2小时,3小时灌胃给药1g/kg剂量的乙醇,n=5。
酒精使用食品级,甲醇含量小于5mg/L。从0至24小时收集尿液,尿液收集至装有0.1mL的硫基乙醇的试管中,-70℃保存。尿液样品分三份,分别采用气相色谱法检测尿液中乙醇和甲醇含量(见表16),采用荧光法检测尿液中甲酸盐的含量,采用HPLC-DNPH衍生物法检测尿液中甲醛含量(见表17)。
甲酸盐检测方法如下,将0.1mL的尿液与0.1ml的10mmol/L的NAD+,0.1mL的磷酸钾缓冲液(pH7.4,20mmol/L)和50μL的甲酸脱氢酶混合,然后加入0.1mL的心肌黄酶(4U/mL),50μL的刃天青溶液(0.2mg/ml)和0.5ml的磷酸盐缓冲液(pH 6.00,200mmol/L)。混合液在37℃孵育5分钟,之后浸入沸水中3分钟,之后冷却至室温,混合物在使用荧光光度法测定甲酸盐的含量,发射波长590nm,吸收波长565nm。
甲醛含量检测方法如下,取0.1ml的尿液,过滤膜,加入0.05ml 2,4-二硝基苯肼(DNPH,0.1g/L)和0.25ml三氟乙酸,将样品涡旋30S,离心,上清液60℃水浴,通过HPLC分析,检测波长355nm,柱温35℃,流动相为65%乙腈。
表16饮酒及5-甲基四氢叶酸对大鼠尿液中乙醇及甲醇含量的影响
结果表明,大鼠饮用乙醇后,显示8小时左右的尿液乙醇含量最高,之后快速下降,而令人意外的是大鼠饮用乙醇后,血液中甲醇含量也快速积累,与乙醇上升的趋势一致,然而甲醇的消除速度比乙醇慢很多。显示内源性甲醇的代谢受到了乙醇的抑制,而导致血液甲醇浓度的上升。5-甲基四氢叶酸令人意外的可以降低尿液中甲醇的浓度。
表17饮酒及5-甲基四氢叶酸对大鼠尿液中甲醛及甲酸盐含量的影响
结果表明5-甲基四氢叶酸的摄入能够显著降低大鼠尿液中甲醛及甲酸盐的浓度,促进甲醇的代谢产物的消除。
实验例11饮酒及5-甲基四氢叶酸对大鼠大脑甲醛及甲酸盐浓度的影响
根据实验例10结果表明,饮酒后24小时,大鼠体内酒精基本代谢完毕。考察该时间大鼠脑组织中甲醛和甲酸盐的浓度,以及5羟色胺和多巴胺的浓度。将SD大鼠,SPF级,雌性,禁食过夜分为4组:(1)乙醇组,分别在1小时,2小时,3小时灌胃给药1g/kg剂量的乙醇,n=5;(2)对照组,分别在1小时,2小时,3小时灌胃给药1.6g/kg剂量的葡萄糖(与酒精热量相当),n=5;(3)5-甲基四氢叶酸组,分别在0小时灌胃给药4mg/kg剂量的5-甲基四氢叶酸钙,之后分别在1小时,2小时,3小时灌胃给药1.6g/kg剂量的葡萄糖(与酒精热量相当),n=5;(4)5-甲基四氢叶酸酒精组,分别在0小时灌胃给药4mg/kg剂量的5-甲基四氢叶酸钙,之后分别在1小时,2小时,3小时灌胃给药1g/kg剂量的乙醇,n=5。
酒精使用食品级,甲醇含量小于5mg/L。饮酒后24小时(根据实验例10结果表明24小时后,大鼠尿液乙醇浓度接近与零),摘眼球取血,脊椎脱臼处死,取动物脑组织,-80℃冰箱冷冻储存。气相色谱法检测大鼠血液甲醇和乙醇浓度,HPLC检测脑组织甲醛浓度,取0.1g脑组织,加入0.5ml SDN裂解液组织匀浆,随后加入0.5ml三氟乙酸,保持4℃下对样品进行离心,取0.4ml上清液,加入0.1ml DNPH(1g/L),混匀后60℃水浴孵育30min,4℃下离心,取上清液,检测甲醛,使用荧光光度法检测脑中甲酸盐的浓度,使用5-羟色胺、多巴胺酶联免疫吸附试剂检测脑中神经递质,检测步骤严格按照说明书进行。
结果如下:
表18饮酒24小时后大鼠脑组织甲醛、甲酸盐、5-羟色胺、多巴胺含量
注:n=5各剂量组与正常对照组相比,*:P<0.05.#;各剂量组与乙醇对照组相比,P<0.05
结果表明:5-甲基四氢叶酸能够促进脑组织中甲醛和甲酸盐的代谢,降低甲醛和甲酸盐的浓度,从而预防和治疗宿醉。此外,饮酒后大鼠脑组织中5-羟色胺水平下降,而5-甲基四氢叶酸能够改善5-羟色胺的分泌。
实验例12 5-甲基四氢叶酸对慢性酒精介导的肠道影响
取96只SD大鼠,SPF级,雌雄各半,实验开始时体重均数176~220g,根据体重随机分为溶媒对照组(葡萄糖,10g·Kg-1)、模型对照组(白酒,6g·Kg-1)、5-甲基四氢叶酸钙组(叶源酸,4mg·Kg-1,葡萄糖,10g·Kg-1),雌雄各半,每组16只。在实验过程中,每只大鼠每天灌胃给予大鼠酒精或等热量的葡萄糖,每天逐渐增加剂量,当剂量达到酒精6g·Kg-1时定义该天为造模第一天。在第2周、8周测量大鼠肠通透性,测量之后分别随机处死5只大鼠,取血和肝组织。
8周后,剩余各组大鼠分别接受酒精性脂肪肝炎患者的粪便菌群移植,于第10周处死,取血和肝组织。
使用口服糖测试来评估肠通透性,大鼠禁食8小时后,给予2.0ml的糖溶液,给药剂量为乳果糖107mg/kg、甘露糖醇30mg/kg、三氯蔗糖15mg/kg、蔗糖570mg/kg。将大鼠单独圈养在代谢笼中,收集尿液,尿液中糖浓度通过气相色谱法测定。血液样品通过Kinetic-QLC内毒素试剂盒分析血清样品中的内毒素。
肠道通透性检测结果见图10、图11。结果表明,酒精在6g/kg的剂量下会破坏大鼠的肠道屏障功能,慢性酒精喂养的条件下的大鼠在第八周时尿乳果糖(小肠通透性指数)明显高于葡萄糖喂养的大鼠。用酒精喂养的大鼠的尿中的三氯蔗糖(全肠通透性指数)也增加,在第八周时差异明显。
血液内毒素检测结果见图12。在处死的血液获得的血清中检测内毒素,在整个研究中,用葡萄糖喂养的大鼠血清内毒素值一直很低,而饮酒会导致血清中内毒素水平的升高,乙醇组在第八周血清内毒素与第二张相比水平上升了约3倍。
处死大鼠的肝脏最早可在2周内检测到脂肪变性,未见酒精性脂肪肝炎(炎症细胞浸润,斑点坏死和肝细胞坏死),在第八周的处死大鼠中可见脂肪肝炎的典型特征,但是依然较少。已经确定的是内毒素是促进严重肝损伤,促进肝炎发展的重要因素,肠腔中细菌产生的内毒素渗透到肝门脉循环中,然后到达肝脏。
将酒精性脂肪肝炎的患者的粪便收集60g,用300mL生理盐水混匀过滤,菌液保存在厌氧袋中4℃保存待用。第八周后所有组的剩余大鼠,经乙醚麻醉,菌液(2mL)通过导管缓慢注入结肠中,隔天继续按照相同剂量继续给药饲养。第10周,所有大鼠处死,肝脏组织用H&E染色,组织切片进行疾病评估,每只大鼠至少研究三个不同的切片,以合理评估肝脏的病变情况。为了合理评估肝脏的脂肪变性,坏死,炎症和纤维化,对不同程度进行了分级,脂肪肝细胞的比例,分别是<50%,50-75%和>75%对应脂肪变性的严重程度。环死灶也进行量化为坏死灶的数量/mm2,同样的对密集的炎性浸润也进行分级。酒精性脂肪性肝炎(ASH)定义为肝脏中存在炎性细胞浸润,斑点坏死和干细胞坏死。
结果如下
表19不同组移植肠道细菌后肝炎和干细胞损伤的指标
结果支持肠道内毒素渗入参与肝坏死和炎症的发生,这与前人的结论一致,酒精和内毒素协同作用对肝脏发挥破坏作用,通过口服非吸收性的抗生素或乳酸菌能够减轻大鼠酒精引起的肝损伤,实验也证明了内毒素血症的发生也先于脂肪肝炎的发生。
使用来自患有重症酒精性脂肪肝炎的人的肠道微生物移植来使常规大鼠人源化来诱导大鼠的肝损伤,结果发现5-甲基四氢叶酸能够改善酒精介入下的肠屏障的生理功能,预防由于有害作用的细菌引起的肝损伤。
Claims (3)
1.一种用于抑制由LPS诱导的神经系统炎症的药物组合物,其包括有效量的5-甲基四氢叶酸和姜黄素, 所述5-甲基四氢叶酸与姜黄素的质量比为1:1。
2.权利要求1的药物组合物在制备抑制由LPS诱导的神经系统炎症的药物中的用途。
3.一种用于改善由LPS诱导的神经系统炎症的保健食品组合物,其包括有效量的5-甲基四氢叶酸和姜黄素, 所述5-甲基四氢叶酸与姜黄素的质量比为1:1。
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