中医药治疗疲劳的研究进展

2022-05-22 01:37杨星哲李峰毛萌王若冲张翼飞徐一菲李杰宋丹丹于佳慧
世界中医药 2022年5期
关键词:抗氧化活性作用机制

杨星哲 李峰 毛萌 王若冲 张翼飞 徐一菲 李杰 宋丹丹 于佳慧

摘要 疲劳已成为影响人们生命质量的重要因素。疲劳发病机制复杂,常规治疗缺乏有效方案,部分药物有成瘾性和不良反应。中药抗疲劳药物具有安全有效、多种功效协同作用的独特优势。肝脾肾功能失调是疲劳发生发展的重要病机,中药处方多以疏肝健脾补肾为主。现通过对疲劳的病机、处方用药、抗疲劳作用机制进行全面系统地总结,为中医药抗疲劳提供依据。

关键词 作用机制;中药抗疲劳;肝脾肾功能失调;疏肝健脾补肾;神经免疫炎症;能量代谢;抗氧化活性

Research Progress on Anti-fatigue Effect of Chinese Medicine

YANG Xingzhe,LI Feng,MAO Meng,WANG Ruochong,ZHANG Yifei,XU Yifei,LI Jie,SONG Dandan,YU Jiahui

(School of Traditional Chinese Medicine,Beijing University of Chinese Medicine,Beijing 100029,China)

Abstract Fatigue has become an important factor affecting people′s quality of life.With high incidence,fatigue can be regarded as an independent disease and is a symptom of a variety of chronic diseases.Since many clinical drugs have common side effects,effective prevention and treatment of fatigue has become an urgent problem to be solved.As the pathogenesis of fatigue is complex,western medicines lack an effective and complete program and have the risk of addiction and side effects.Chinese medicines for resisting fatigue boast the unique advantages of safety,effectiveness and synergistic effect.It is of great significance to explore the safe and effective Chinese medicines for treating fatigue.Liver,spleen and kidney dysfunction is an important pathogenesis of fatigue,and most of Chinese prescriptions for treating fatigue are mainly soothing liver,invigorating spleen and tonifying kidney.The mechanism of improving fatigue by Chinese medicines includes reducing the accumulation of metabolites,improving neuroimmune inflammatory reaction,and regulating immune function,energy metabolism,HPA axis function and synthesis and release of neurotransmitters in the brain,with antioxidant activity.This article systematically and comprehensively summarized and analyzed the core pathogenesis of fatigue,anti-fatigue Chinese medicine prescriptions,and the mechanism of anti-fatigue by Chinese medicine,so as to provide a basis for comprehensive and in-depth discussion on the anti-fatigue mechanism of Chinese medicines and the effective prevention and treatment.

Keywords Mechanism; Anti-fatigue by Chinese medicine; Liver,spleen and kidney dysfunction; Soothing liver,invigorating spleen and tonifying kidney; Neuroimmune inflammation; Energy metabolism; Antioxidant activity

中圖分类号:R228文献标识码:Adoi:10.3969/j.issn.1673-7202.2022.05.026

Chaudhuri 和Behan[1]将疲劳定义为开展或维持随意活动过程中出现障碍的表现。随着生活节奏的加快,疲劳已成为影响人们生命质量的重要因素。调查报告发现,有1/2以上的人群感到疲劳,其中超过1/3的人群明确指出疲劳严重降低生命质量和工作效率[2]。疲劳既可作为一种症状伴随其他疾病出现,如恶性肿瘤、多发性硬化综合征、缺铁性贫血、中风、帕金森病等,又可作为独立的疾病,同时还是抗惊厥药、止痛药、抗抑郁药等常见的不良反应[3]。世界卫生组织在报告中将疲劳列为21世纪危害人类健康的主要因素之一,医学界对疲劳的关注度逐年升高。因此,疲劳的有效防治成为亟待解决的问题。

中药抗疲劳药物作用研究

疲劳的发病机制复杂,包括能量损耗、免疫功能下降、递质分泌失常、下丘脑-垂体-肾上腺轴功能失调等[4]。临床常规治疗缺乏综合有效方案,以药物治疗和营养补充类制剂为主。药物治疗通常用以兴奋大脑皮质,提高中枢神经系统功能活动,部分药物具有一定的成瘾性和不良反应[5-6]。研究发现,中药抗疲劳药物具有不含违禁成分、天然安全和多种功效协同作用的独特优势[7-12]。

2 肝脾肾功能失调

中医学中,“疲劳”一词最早可见于《金匮要略》,记为“夫尊荣人骨弱肌肤盛,重因疲劳汗出”。疲劳属于中医“虚劳”的范畴。病因病机与脏腑功能失调密切相关,主要涉及脾、肝、肾的功能失调,尤其与脾失健运密切相关。中医理论认为脾为后天之本,气血生化之源,在体合肉,主四肢。脾气健运,则水谷精微化生充沛,气血调和,肌肉丰满,肢体健壮;若脾失健运,水谷精微化生乏源,气血失运,肢体倦怠乏力,导致疲劳产生。《素问·至真要大论》云:“诸湿肿满,皆属于脾。”脾失健运可导致其升清降浊功能受损,水液停聚为湿,导致头脑不清,昏沉倦怠,肢体重着。肝为罢极之本,主疏泄,主藏血,主筋。因各方面压力等引起的生活节律失常,易致肝失疏泄,出现肌肉酸软,躯体疲劳感。肾为先天之本,气血化生之根源,主骨生髓。若肾气虚损,则形体失充,出现躯体疲劳感、腰酸膝软无力等。

3 疏肝健脾补肾方

孙淑英等[13]研究发现,疏肝健脾膏可明显降低亚健康疲劳患者的疲劳程度。马彦波等[14]应用健脾益肾汤治疗亚健康所导致的疲劳状态,研究发现该方可明显提高疲劳治疗总有效率,明显改善脑力疲劳及躯体疲劳症状。李涛和糟玉琴[15]在临床上采用八珍汤及二仙汤进行化裁的健脾溫肾疏肝药物治疗更年期女性慢性疲劳综合征患者,发现疲劳缓解效果明显。

4 中药抗疲劳作用机制

4. 降低代谢产物的积累 血乳酸(Blood Lactic Acid,BLA)、乳酸脱氢酶(Lactate Dehydrogenase,LDH)、血尿素氮(Blood Urea Nitrogen,BUN)是研究躯体疲劳的常见指标[16]。肌酸激酶(Creatine Kinase,CK),谷丙转氨酶(Glutamic-pyruvic Transaminase,GPT)和谷草转氨酶(Glutamic-oxaloacetic Transaminase,GOT)是躯体疲劳造成组织损伤和对力竭运动的特征性反应的重要标志。运动至疲劳的过程中,代谢产物丙二醛(Malondialdehyde,MDA)是研究疲劳的重点观察指标[17]。剧烈的体育活动可导致肝糖原水平降低,造成肝功能障碍。GPT和GOT升高是肝细胞损伤的预测指标[18]。

研究表明,人参可加速自由基的清除,增加糖原储存,减少乳酸堆积,增强LDH活性,为肌肉活动及时提供能量,达到显著抗疲劳效果,同时提高机体运动能力[19-20]。中药九香虫提取物可通过降低血清乳酸和尿素氮的含量,达到良好的抗疲劳作用[21]。牛占忠等[22]研究发现补肾疏肝汤通过降低慢性疲劳模型大鼠血清中BLA、LDH、CK及BUN的含量,同时提高血红蛋白、肝糖原和肌糖原水平,产生抗疲劳作用。为了探索抗疲劳药物和食物的新来源,Zhu等[23]通过对小鼠进行游泳试验研究了大麻叶水提取物(Hemp Leaf Water Extract,HLWE)的抗疲劳活性。HLWE组小鼠的血乳酸浓度为0.76 mmol/L,比对照组低24.8%;谷胱甘肽过氧化物酶活性比对照组增加了296.2%,结果表明大麻叶水提取物通过减少乳酸积累、提高防御性抗氧化酶的活性表现出抗疲劳活性。Miao等[24]采用代谢组学方法结合气相色谱和质谱联用模式识别技术,通过负重强迫小鼠游泳造模,研究当归补血汤抗疲劳的潜在机制。研究发现当归补血汤通过调节血液生化指标和内源性代谢产物对模型小鼠的疲劳发挥作用。

4.2 调节免疫 研究发现多种补益类中药可通过提高机体免疫改善疲劳[25]。人参、党参、黄芪、枸杞子、灵芝、大枣等通过促进血液白细胞数量提升抗疲劳;人参、白术、当归、夏枯草、牛黄、茯苓等通过促进单核巨噬细胞系统功能提升抗疲劳;人参、丹参、灵芝、首乌、苦参、淫羊藿等通过促进T细胞数量增加和淋巴细胞转化提升抗疲劳[26]。多种中药复方通过提高机体免疫、改善神经炎症反应,具有抗疲劳作用。如参芪扶正注射液抑制炎症介质产生,改善T细胞的功能障碍,从而改善癌因性疲劳[27];柴胡桂枝汤通过抑制慢性疲劳综合征肝郁脾虚证患者的白细胞介素-1β(IL-1β)和干扰素-γ(IFN-γ)等细胞因子水平,从而缓解患者疲劳症状[28]。中药马齿苋的水提物可抑制疲劳模型小鼠核苷酸结合寡聚化结构域样受体蛋白3(Nucleotide-binding Oligomerization Domain-like Receptor Protein 3,NLRP3)炎症小体的活性起到抗疲劳效果[29];培元还五汤联合针刺四神聪、百会穴,以及培元通络汤、四逆温胆汤等方剂,可通过下调血清IL-1β、IL-6和肿瘤坏死因子-α(TNF-α)等炎症介质水平,改善临床上缺血性脑卒中后疲劳症状[30-31]。

4.3 调节能量代谢 能量代谢异常是疲劳发生发展的重要机制[32]。ATP、糖原和脂肪是机体重要的能量物质。线粒体以ATP的形式产生细胞能量,在能量代谢中具有重要作用[33]。多种中药通过增加糖原存储或通过促进脂质代谢来延迟糖原的消耗,调节线粒体功能,从而产生抗疲劳作用。研究表明,巴戟天叶提取物可上调骨骼肌ACADM和FAT/CD36基因表达,促进脂质分解代谢、线粒体脂肪酸转运和细胞摄取,从而提高运动耐力[34]。槲寄生水提取物具有通过增加血浆游离脂肪酸水平和减少糖原消耗来增强小鼠抗疲劳的能力[35-36]。黄芪和西洋参可通过增强线粒体生物发生和修复线粒体功能障碍产生抗疲劳作用[37-38]。当碳水化合物和脂类分解代谢产生的能量不足时,氨基酸脱氨作用产生NH 3和CO 2供能。如五味子可调节三羧酸循环、丙氨酸、天冬氨酸和谷氨酸代谢[39],当归补血汤可调节苯丙氨酸、酪氨酸和色氨酸代谢及三羧酸循环等产生抗疲劳作用[40]。

4.4 抗氧化活性 机体在运动过程中会产生活性氧(Reactive Oxygen Species,ROS)等自由基[41],泛醇补充剂通过增加小鼠脂质利用来改善运动诱发的疲劳[42]。超氧化物歧化酶(Superoxide Dismutase,SOD),谷胱甘肽过氧化物酶(Glutathione Peroxidase,GSH-Px)和过氧化氢酶(Catalase,CAT)可清除肌肉细胞中的ROS等。SOD催化ROS产生过氧化氢(H 2O 2)和氧气(O 2)后,CAT和GSH-Px催化H 2O 2分解为H 2O和O 2[43]。当ROS与抗氧化剂系统失去平衡时,ROS积累引起氧化应激反应,产生脂质过氧化产物(如MDA)损害人体。大量研究证明,具有抗氧化活性的中药可通过改善抗氧化防御系统的活性,清除ROS,降低MDA含量,促进抗氧化系统与ROS之间的平衡,抑制脂质过氧化进而消除疲劳[44-45]。如木瓜可通过降低BLA、BUN和MDA的含量,并增加SOD、CAT、GSH-Px等抗氧化酶的活性产生抗疲劳作用[46];五味子可通过调节Nrf2蛋白和Bcl-2蛋白的表达,提升抗氧化和抗凋亡调节因子,并激活p38MAPK-PGC-1α通路,来增加小鼠的运动耐力和抗疲劳能力[47]。

4.5 调节HPA轴 在长期的心理压力和身体疲劳中,不受控制的慢性压力会激活下丘脑-垂体-肾上腺轴(Hypothalamic-Pituitary-Adrenal Axis,HPA轴),过度释放皮质酮和肾上腺素,导致慢性疼痛、免疫抑制和慢性疲劳。HPA轴失调常发生在慢性疲劳综合征中。淫羊藿是用于治疗慢性疲劳综合征(Chronic Fatigue Syndrome,CFS)的中药之一,通过上调去甲肾上腺素的表达,改善HPA轴失调,从而治疗CFS[48]。

4.6 调节大脑神经递质 疲劳的发生发展还与多巴胺(Dopamine,DA)、5-羟色胺(5-hydroxytryptamine,5-HT)、去甲肾上腺素的合成和释放密切相关[49]。研究表明,高浓度5-HT可引起中枢疲劳[50]。5-HT/DA被认为是中枢疲劳的评估指标[51]。色氨酸羟化酶2(Tryptophan Hydroxylase 2,TPH2)是5-HT合成中的限速酶[52]。1B型5-羟色胺能(5-HT1B)抑制5-HT的局部合成和释放[53]。石菖蒲抑制运动诱导的5-HT合成和TPH2蛋白表达增加,阻止运动诱导的尾状壳核5-HT1B蛋白表达降低,达到与咖啡因一样显著的抗疲劳效果[53-54]。

5 小结

中医學对疲劳的病因病机及治疗方药研究历史悠久,且具有明确的疗效,其中以脏腑辨证尤为重要。肝脾肾功能失调是疲劳发生发展的重要病机。治疗疲劳有效的中医临床方剂,以疏肝健脾补肾为主。中医药改善疲劳的机制包括降低代谢产物的积累;调节免疫功能,改善神经免疫炎症反应;调节能量代谢;具有抗氧化活性;调节HPA轴功能;调节大脑神经递质合成和释放等。见图1。

最新研究表明,疲劳的发生发展还与肠道菌群有关。中药常见成分如多糖和多酚类物质等,具有调节肠道菌群功能[55-56]。其作用机制不仅限于吸收后直接调节体内靶标的作用,还包括调节肠道菌群的作用。从肠道菌群的角度探讨中医药抗疲劳的机制是对现有机制研究模型的补充,也是未来的研究方向。同时,以药食同源中药为主要原料的抗疲劳保健品具有较好的研究前景。

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(2021-02-21收稿 本文編辑:孙昊)

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