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玛咖药理毒理研究进展

2021-07-20陈红映孙建辉于泽玥

世界中医药 2021年7期
关键词:多糖小鼠细胞

陈红映 孙建辉 于泽玥

摘要 玛咖(Lepidium meyenii Walper,Maca)为十字花科独行菜属一年生或两年生草本植物,源自南美洲,有悠久的食用历史。除了秘鲁当地人食用玛咖,全世界对玛咖的需求都在增长,玛咖在20世纪90年代初引入我国,并于2011年获批为新资源食品,现阶段我国云南、西藏等高海拔地区均成功引种玛咖。研究表明,玛咖对生殖系统具有调节性激素、改善性功能、抑制前列腺增生的作用;对消化系统具有促进胃肠运动、预防肝损伤的作用;对神经系统具有改善记忆力、抗抑郁、保护神经和镇痛的作用;对免疫系统具有增强细胞免疫和体液免疫的作用;对血液循环系统具有降低舒张压和收缩压的作用;还具有抗炎、抗疲劳、抗氧化、抗紫外辐射及抗骨质疏松等作用。相关毒理研究表明,玛咖无细胞毒性、体外肝毒性、急性毒性、长期毒性以及生殖毒性。现查阅近些年的玛咖药理毒理相关文献,对玛咖药理作用研究、毒理研究进行了归纳、梳理和总结,未发现玛咖具有不良反应,且具有多种药理作用及营养保健功能。希望能为玛咖今后的药用实验及临床研究提供帮助和参考。

关键词 玛咖;性激素;性功能;免疫力;抗疲劳;胃肠运动;毒理;研究进展

Abstract Lepidium meyenii Walper (Maca) is an annual or biennial herb of the genus Lepidopsis in the cruciferous family.It originates from South America and has a long history of consumption.In addition to the locals in Peru who consume maca,the interest and demand for Maca are growing all over the world.Maca was gradually introduced into China in the early 1990s and was approved as a new resource food in 2011.At this stage,maca has been successfully introduced in high-altitude regions such as Yunnan and Tibet.A large number of experimental studies have shown that Maca can regulate sex hormones,improve sexual function and inhibit prostatic hyperplasia of the reproductive system.It can promote gastrointestinal motility and protect against liver injury in digestive system.It has the effect of improving memory,anti-depression,protecting nerve and analgesia to nervous system.Maca can enhance cellular immunity and humoral immunity to the immune system.It can reduce diastolic blood pressure and systolic blood pressure in the blood circulation system.It also has the functions of anti-inflammatory,fatigue resistance,oxidation resistance,resistance to ultraviolet radiation and anti osteoporosis and other effects.Relevant toxicological studies showed that maca had no cytotoxicity,in vitro hepatotoxicity,acute toxicity,long-term toxicity or reproductive toxicity.In this paper,the pharmacological and toxicological studies of maca in recent years were reviewed,and the pharmacological and toxicological studies were summarized.It was found that maca had no toxic and side effects,as well as a variety of pharmacological and nutritional functions.It is hoped that this paper can provide help and reference for maca′s future medicinal experiment and clinical research.

Keywords Maca; Sex hormone; Sexual function; Immunity; Anti-fatigue; Gastrointestinal motility; Toxicology; Research Progress

中圖分类号:R285文献标识码:Adoi:10.3969/j.issn.1673-7202.2021.07.003

玛咖(Lepidium meyenii Walper,Maca)是属于十字花科的秘鲁土著植物,主要生长在海拔高于4 000米的高原地区[1]。玛咖在20世纪90年代初引入我国,并于2011年获批为新资源食品。玛咖传统上在秘鲁被当地人作为一种粮食作物种植,除了作为食品食用外,玛咖还被视为一种天然的壮阳药物。除了秘鲁当地人食用玛咖,全世界对玛咖的需求都在增长,现阶段我国云南、西藏等高海拔地区均成功引种玛咖。为了更好的探索和利用新资源食品——玛咖,我们对玛咖的药理作用及毒理相关文献进行综述,为玛咖应用提供参考。

1 药理作用

1.1 对生殖系统的作用

玛咖对生殖系统具有调节性激素、改善性功能、抑制前列腺增生的作用。

1.1.1 调节性激素

玛咖在秘鲁被广泛用做民间药物,并在欧洲和美洲用于治疗阳痿、更年期疾病和不孕。玛咖水提物可增加雄性大鼠精囊刺激时血清中的睾酮含量,睾酮增加可能与睾丸间质细胞产生睾酮的能力增强有关[2]。Yoshida等[3]发现玛咖水提物可增强雄性大鼠睾丸Leydig细胞的类固醇生成能力,从而减缓其随年龄增长而下降的趋势。玛咖的活性成分Lepidiline A可改善小鼠内源性性激素的平衡,提高果蝇的繁殖力;Lepidiline A靶向HSD17B1基因的机制来增强酶的活性,提高性激素的生物转化效率,将雌激素转化为17-雌二醇,将4-雄酮-3,7-二酮转化为睾酮,最终提高生殖能力[4]。促黄体生成素(Luteinizing Hormone,LH)能促进胆固醇在性腺细胞内转化为性激素。玛咖粉末能增加雌性大鼠血清中LH和促卵泡激素(Follicle-stimulating Hormone,FSH),且LH水平在玛咖3~30 g/kg范围内呈剂量依赖性增加[5]。玛咖还可以调节去卵巢大鼠内分泌激素,对FSH的调节作用较强[6]。Oshima等[7]研究发现玛咖提高了雌性小鼠孕酮水平和雄性小鼠睾酮水平,但它不直接影响血清雌二醇-17β水平和雌性胚胎着床率。

1.1.2 改善性功能

Zenico等[8]对50名有轻度勃起功能障碍的男性进行了双盲临床试验,随机使用玛咖提取物或安慰剂进行治疗,治疗前后分别采用国际勃起功能指数(International Index of Erectile Function,IIEF-5)调查问卷和满意度问卷(Satisfaction Profile,SAT-P)检测患者的治疗效果和主观性幸福感。试验发现玛咖能改善勃起功能障碍,还能提高患者的性幸福感。Melnikovova等[9]研究发现玛咖粉末给药12周后,能提高男性的精子活力和水平。玛咖粉还能提高男性自行车手计时赛的时间和性欲[10]。

玛咖可以改善雄性大鼠的性行为,Cicero等[11]研究发现单次给药和长期给药均可显著改善雄性大鼠的性行为参数,玛咖能缩短雄性大鼠爬高潜伏期(Mount Latency,ML)、插入潜伏期(Intromission Latency,IL)、射精潜伏期(Ejaculation Latency,EL)、射精后潜伏期(Postejaculatory Latency,PEL)和交配间隔(Intercopulatory Interval,ICI)。玛咖还能缩短雌性小鼠的怀孕潜伏期,增加产仔数[12]。玛咖和韭菜提取物对性功能有良好的协同作用,且明显提高了小鼠血清和阴茎中一氧化氮含量以及阴茎中的环鸟苷酸含量[13]。Clément等[14]发现玛咖能提高公牛精子的DNA碎片指数和精子活力。玛咖能增加种马的射精量和精子水平,提高精子活力和顶体完整性[15]。Aoki1等[16]研究发现玛咖能通过诱导顶体反应和增强精子活力来提高体外受精率。玛咖水提物口服能增加精子数量,而腹腔注射无效;玛咖水提物pH的降低增加了精子数量,而pH的升高会导致精子数量减少[17]。

1.1.3 抑制前列腺增生

前列腺增生是一种进行性雄激素依赖性疾病,其特征是5-还原酶作用失调,导致前列腺双氢睾酮水平升高,前列腺体积增大。Gonzales等[18]研究发现红玛咖能通过降低前列腺增生大鼠的锌水平来抑制前列腺增生。还有研究表明红玛咖通过Th2型免疫应答途径减少炎症从而抑制前列腺增生[19]。

1.2 对消化系统的作用

玛咖可以促进胃肠运动和保护肝损伤。

1.2.1 促进胃肠运动

胃肠运动障碍是胃肠道最常见的疾病之一。有研究認为玛咖地上部分能作为促进胃肠运动的功能性蔬菜食用[20]。因为玛咖地上部分营养成分和矿物质特别丰富多样,其中必需氨基酸占总氨基酸的41%~47%,维生素C、烟酸、钾和钙含量均高于常见蔬菜。且能通过提高小鼠血清胃动素(MTL)和胃泌素(GAS)水平,促进胃排空、小肠推进。

1.2.2 保肝作用

肝炎是一个人类公共卫生问题。而急性肝炎以强炎症为特征,可引起肝细胞死亡,导致肝衰竭。有研究表明玛咖能抑制急性肝炎引起的炎症。玛咖可以抑制刀豆素A诱导的急性肝炎小鼠的转移酶产生,并通过抑制核因子κB、IFN-γ/STAT1、IL-6/STAT3信号通道从而抑制炎症反应[21]。还有相关组织病理学研究表明玛咖多糖减轻了乙醇引起的炎症,且玛咖多糖在体外可以减轻乙醇对人肝癌细胞的损伤,还能抑制血清和肝组织中的三酰甘油(TG)水平[22]。玛咖多糖可降低酒精性肝损伤小鼠血清中的天冬氨酸转氨酶(AST),γ谷氨酰转肽酶(γGT),丙氨酸转氨酶(ALT),还能提高超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)和谷胱甘肽S-转移酶(GST)的含量。证明了玛咖多糖具有成为防止人类酒精性肝损伤的食品或药品的潜力。

1.3 对神经系统的作用

玛咖可能通过作用于中枢神经系统产生改善记忆力、抗抑郁、神经保护和镇痛的作用。

1.3.1 改善记忆力

黄、红、黑3种不同颜色玛咖改善记忆力作用的强度也不同,其中改善记忆力较佳的品种为黑玛咖[23]。Rubio等[24]通过莫里斯水迷宫和跳台测试发现黑玛咖水提物和醇提物均能显著改善东莨菪碱所致的记忆障碍,且黑玛咖对乙酰胆碱酯酶活性有抑制作用,对单胺氧化酶活性无影响。还有研究发现玛咖能改善线粒体呼吸功能和上调自噬相关蛋白从而改善中年鼠的认知能力、运动协调能力和耐力[25]。

1.3.2 抗抑郁

抑郁症是一种精神疾病,不少妇女在绝经前后出现情绪障碍。有研究发现玛咖能减轻中国绝经后妇女的抑郁症状[26]。Rubio等[23]采用强迫游泳试验法研究黄、红、黑3种玛咖对去卵巢小鼠抑郁的影响,每次治疗结束后,切除子宫并称重。结果显示,3种玛咖在去卵巢小鼠强迫游泳试验中都能减少小鼠静止时间并能增加小鼠子宫重量。证明了黄、红、黑3种玛咖均表现出抗抑郁活性。玛咖石油醚提取物能降低小鼠尾悬吊试验的静止时间和小鼠血清中的皮质酮水平[27]。玛咖石油醚提取物还能升高去甲肾上腺素和多巴胺水平,抑制活性氧活性。且能通过激活去甲肾上腺素和多巴胺系统以及减弱小鼠大脑氧化应激,来达到抗抑郁的作用。

1.3.3 神经保护作用

玛咖酰胺是玛咖产生的非常重要的次生代谢产物,具有多种生物活性,尤其是在神经元系统中。蛋白质组学和脂质组学综合研究发现玛咖中的苄基十六烷酰胺能通过调节鞘脂代谢和线粒体功能来保护神经,且该研究证明了苄基十六烷酰胺的神经保护作用伴随着线粒体呼吸功能的改善[28]。

1.3.4 镇痛作用

Tenci等[29]研究发现玛咖可以减轻关节和神经性疼痛。玛咖能够减轻关节内注射单碘乙酸盐和坐骨神经的慢性压迫性损伤引起的机械性超敏反应和姿势不平衡。此外,玛咖还可以增加奥沙利铂和紫杉醇引起的痛阈值。玛咖是否是作用于中枢神经系统的药物还有待于我们进一步验证。常见中枢性镇痛药如吗啡、芬太尼等反复使用容易产生成瘾性,而玛咖作用食品安全性较大,可以深入研究其镇痛作用。

1.4 对免疫系统的作用

玛咖可通过增强细胞免疫和体液免疫来调节机体免疫系统。玛咖中的主要蛋白可显著增强RAW 264.7细胞的吞噬能力,促进一氧化氮(NO)、肿瘤坏死因子(TNF)和白细胞介素-6(IL-6)的分泌[30]。玛咖水提物能通过增加Th1的分泌和减少Th2细胞因子,增强小鼠细胞免疫和体液免疫,同时还能促进脾T淋巴细胞的增殖和转化,从而改善环磷酰胺诱导的免疫力低下脾虚症小鼠的症状[31]。玛咖多糖对CD4+T细胞具有免疫增强作用,且玛咖多糖的分子量和半乳糖胺可能是决定其生物活性的重要因素[32]。从玛咖中分离得到的由葡萄糖和阿拉伯糖组成的多糖能通过TLRS/核因子κB炎症信号通路,激活RAW264.7巨噬细胞和激发免疫刺激活性[33]。

1.5 对血液循环系统的作用

玛咖能降低男性收缩压和舒张压可能是因为玛咖中富含钾元素[34]。玛咖还可以降低绝经妇女的血压,Stojanovska等[26]采用随双盲对照的方法,对29例绝经后妇女以调查问卷形式进行研究,与安慰剂比较,玛咖能减轻抑郁症状并明显降低绝经后妇女的舒张压。

1.6 抗炎作用

在高海拔地区红玛咖喷雾治疗可加速小鼠创面闭合,降低创面表皮增生程度,减少创面炎症细胞数量,从而促进皮肤伤口愈合[35]。

1.7 抗氧化作用

Wang等[36]从玛咖中分离的一种新多糖能清除DPPH自由基、ABTS自由基、超氧自由基和羟基自由基,提高Fe2+螯合能力,抑制脂質过氧化力,还能通过破坏自由基链提高还原能力。玛咖多糖还可以通过维持细胞活力,降低活性氧(ROS)、丙二醛(MDA)、乳酸脱氢酶(LDH)水平,增强超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)和过氧化氢酶(CAT)活性来保护RAW264.7细胞免受H2O2诱导的氧化损伤。玛咖挥发油、脂类和多糖均具有清除DPPH自由基的活性。其中玛咖挥发油对DPPH的清除作用最强,黑玛咖挥发油、脂类和多糖均比黄、红玛咖的抗氧化能力强[37]。且玛咖多糖的抗氧化能力呈剂量依赖性[22]。

1.8 抗疲劳作用

玛咖多糖具有抗疲劳的作用。持续给予玛咖多糖45 d后,可降低游泳后小鼠血清尿素氮含量,且能明显延长小鼠游泳时间[38]。还有相关研究表明玛咖多糖能延长小鼠力竭游泳时间的同时增加了小鼠血清中的肝糖原水平,降低了血乳酸(BLA)、血液尿素氮(BUN)、乳酸脱氢酶(LDH)的水平,且呈剂量依赖性[39]。

1.9 抗紫外辐射作用

Gonzales-Castaeda等[40]研究发现玛咖通过抗氧化和抑制脂质过氧化来达到抗中波紫外线(UVB)辐射作用。长波紫外线(UVR)照射大鼠可引起皮肤表皮厚度增加,而玛咖提取物可以通过减小受UVR照射的大鼠皮肤表皮厚度,来保护大鼠的皮肤免受紫外线照射。且经煮沸处理后的玛咖水提物比没有煮沸处理的玛咖提取物效果更好。玛咖叶可防止UVB辐射引起的晒伤细胞、表皮增生、白细胞浸润及其他病变的发展[41]。

1.10 抗骨质疏松作用

玛咖能增加股骨的钙含量和预防雌激素缺乏性骨丢失[42]。且玛咖中的N-(3-methoxybenzyl)-(9Z,12Z,15Z)-octadecatrienamide成分能通过抑制Tyr216处的糖原合成酶激酶-3(GSK-3β)的磷酸化和维持β-连环蛋白(β-catenin)的表达来激活Wnt/β-catenin信号通路,增加骨形成,来达到预防骨质疏松的目的[43]。Leiva-Revilla等[44]研究发现红玛咖可通过提高去卵巢大鼠的干扰素-γ(IFN-γ)水平来治疗骨质疏松症等。

2 毒理研究

玛咖作为一种新资源食品,有着悠久的种植和食用历史,安全性较高,相关毒理研究也表明玛咖无不良反应。

2.1 细胞毒性研究

Valentová等[45]用不同浓度玛咖醇提物和水提物体外分别培养大鼠肝细胞24、48和72 h,发现玛咖醇提物和水提物没有细胞毒性和体外肝毒性,还有轻微的细胞保护作用。

2.2 急性毒性研究

玛咖水提物剂量为17 g/kg时对大鼠无急性毒性,大鼠1 g/kg剂量连续给药84 d无不良反应,且无肝毒性[46]。玛咖醇提物剂量为2 g/kg时对小鼠无急性毒性[47]。Meissner等[48]研究发现玛咖对大鼠和小鼠的半数致死量(LD50)>2 g/kg。

2.3 長期毒性研究

小鼠以200 mg/kg、500 mg/kg、1 000 mg/kg剂量的玛咖醇提物连续给药45 d后,均未见毒性反应,且血液学指标、生化指标、脏器系数均无明显变化,对小鼠脏器的组织病理学评价也无明显变化[47]。

2.4 生殖毒性研究

D′Arrigo等[49]研究发现玛咖水提物不影响小鼠着床前胚胎的正常发育及生存能力,相反,玛咖水提物有利于小鼠胚胎的发育。

3 小结

玛咖作为一种新资源食品被广泛应用和研究,相关毒理研究表明玛咖安全性较高,且具有调节性激素、改善性功能、抑制前列腺增生、促进胃肠运动、预防肝损伤、改善记忆力、抗抑郁、保护神经、镇痛、调节免疫、降血压、抗炎、抗疲劳、抗氧化、抗紫外辐射、抗骨质疏松等作用。然而,现阶段针对玛咖作用机制的研究较少,临床研究更为缺乏,且多为调查问卷形式。因此,以后的研究中,我们应更多的研究玛咖药理作用机制,并进行可信度较高的临床研究。

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(2021-03-05收稿 責任编辑:徐颖)

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