Article(id=1193548058832106480, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1193548058421064688, articleNumber=1001-2494(2025)05-0441-06, orderNo=null, doi=10.11669/cpj.2025.05.001, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1723478400000, receivedDateStr=2024-08-13, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1762493632276, onlineDateStr=2025-11-07, pubDate=1741363200000, pubDateStr=2025-03-08, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1762493632276, onlineIssueDateStr=2025-11-07, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1762493632276, creator=13701087609, updateTime=1762493632276, updator=13701087609, issue=Issue{id=1193548058421064688, tenantId=1146029695717560320, journalId=1190317699101192196, year='2025', volume='60', issue='5', pageStart='441', pageEnd='552', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1762493632178, creator=13701087609, updateTime=1762493856082, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1193548997664146365, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1193548058421064688, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1193548997664146366, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1193548058421064688, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=441, endPage=446, ext={EN=ArticleExt(id=1193548059050210290, articleId=1193548058832106480, tenantId=1146029695717560320, journalId=1190317699101192196, language=EN, title=Recent Advances in Research on the Effects of Aminobutyric Acid on Sleep, columnId=null, journalTitle=Chinese Pharmaceutical Journal, columnName=null, runingTitle=null, highlight=null, articleAbstract=

Sleep disorders are increasingly prevalent within the population, and optimal sleep is essential for overall health. The sleep-wake cycle is a multifaceted process influenced by a variety of factors, including several neurotransmitters such as acetylcholine, norepinephrine, serotonin, histamine, dopamine, orexin, and gamma-aminobutyric acid (GABA). The activity of these neurotransmitters is further modulated by numerous nutrients involved in their metabolic pathways. In recent years, GABA has garnered significant attention due to its critical role in sleep regulation. This review aims to examine the mechanisms through which GABA affects sleep, its clinical implications, as well as recent advancements in research and future directions in this field.

, correspAuthors=Dan YAO, authorNote=null, correspAuthorsNote=null, copyrightStatement=null, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Liuyan ZHU, Dan YAO), CN=ArticleExt(id=1193548425053565434, articleId=1193548058832106480, tenantId=1146029695717560320, journalId=1190317699101192196, language=CN, title=氨基丁酸对睡眠作用的研究新进展, columnId=1190352408384471863, journalTitle=中国药学杂志, columnName=综述, runingTitle=null, highlight=null, articleAbstract=

睡眠问题在人群中普遍存在,良好的睡眠对健康至关重要。睡眠-觉醒周期是一个复杂的、由多种因素共同作用的过程,涉及诸如乙酰胆碱、去甲肾上腺素、血清素、组胺、多巴胺、食欲素和氨基丁酸等多种神经递质,而这些递质又反过来受到参与其代谢途径的各类营养物质的调节。近年来,氨基丁酸作为一种神经递质,其与睡眠的关系引起了广泛关注。本综述旨在探讨氨基丁酸对睡眠的作用机制、临床效果以及研究的新进展和未来展望。

, correspAuthors=姚丹, authorNote=null, correspAuthorsNote=
* 姚丹,女,博士,副主任医师 研究方向:儿童语言发育、营养生长发育、免疫接种 Tel:(0571)87023391
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朱柳燕,女,硕士,主治医师 研究方向:儿童睡眠和营养生长发育、儿童早期发展指导

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朱柳燕,女,硕士,主治医师 研究方向:儿童睡眠和营养生长发育、儿童早期发展指导

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朱柳燕,女,硕士,主治医师 研究方向:儿童睡眠和营养生长发育、儿童早期发展指导

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氨基丁酸对睡眠作用的研究新进展
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朱柳燕 1, 2 , 姚丹 1, 2, *
中国药学杂志 | 综述 2025,60(5): 441-446
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中国药学杂志 | 综述 2025, 60(5): 441-446
氨基丁酸对睡眠作用的研究新进展
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朱柳燕1, 2, 姚丹1, 2, *
作者信息
  • 1 浙江大学医学院附属儿童医院儿保科, 杭州 310003
  • 2 国家儿童健康与疾病临床医学研究中心, 杭州 310003
  • 朱柳燕,女,硕士,主治医师 研究方向:儿童睡眠和营养生长发育、儿童早期发展指导

通讯作者:

* 姚丹,女,博士,副主任医师 研究方向:儿童语言发育、营养生长发育、免疫接种 Tel:(0571)87023391
Recent Advances in Research on the Effects of Aminobutyric Acid on Sleep
Liuyan ZHU1, 2, Dan YAO1, 2, *
Affiliations
  • 1 Department of Pediatric Health Care, Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
  • 2 National Clinical Research Center for Child Health, Hangzhou 310003, China
出版时间: 2025-03-08 doi: 10.11669/cpj.2025.05.001
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睡眠问题在人群中普遍存在,良好的睡眠对健康至关重要。睡眠-觉醒周期是一个复杂的、由多种因素共同作用的过程,涉及诸如乙酰胆碱、去甲肾上腺素、血清素、组胺、多巴胺、食欲素和氨基丁酸等多种神经递质,而这些递质又反过来受到参与其代谢途径的各类营养物质的调节。近年来,氨基丁酸作为一种神经递质,其与睡眠的关系引起了广泛关注。本综述旨在探讨氨基丁酸对睡眠的作用机制、临床效果以及研究的新进展和未来展望。

氨基丁酸  /  睡眠问题  /  生物节律

Sleep disorders are increasingly prevalent within the population, and optimal sleep is essential for overall health. The sleep-wake cycle is a multifaceted process influenced by a variety of factors, including several neurotransmitters such as acetylcholine, norepinephrine, serotonin, histamine, dopamine, orexin, and gamma-aminobutyric acid (GABA). The activity of these neurotransmitters is further modulated by numerous nutrients involved in their metabolic pathways. In recent years, GABA has garnered significant attention due to its critical role in sleep regulation. This review aims to examine the mechanisms through which GABA affects sleep, its clinical implications, as well as recent advancements in research and future directions in this field.

aminobutyric acid  /  sleep problem  /  biological rhythm
朱柳燕, 姚丹. 氨基丁酸对睡眠作用的研究新进展. 中国药学杂志, 2025 , 60 (5) : 441 -446 . DOI: 10.11669/cpj.2025.05.001
Liuyan ZHU, Dan YAO. Recent Advances in Research on the Effects of Aminobutyric Acid on Sleep[J]. Chinese Pharmaceutical Journal, 2025 , 60 (5) : 441 -446 . DOI: 10.11669/cpj.2025.05.001
睡眠对人体健康起着至关重要的作用,睡眠不足或质量欠佳会给身体多个系统带来不良影响。比如睡眠不足不仅会引发胰岛素抵抗,提高患糖尿病的风险,还会干扰生长激素、睾酮等激素的正常分泌,影响垂体-性腺轴的功能。此外,睡眠不足还会影响认知功能和情绪的调节,对机体长期身心健康造成潜在风险[1-2]。英国一项母婴队列研究[3]显示,约20%~30%的幼儿和学龄前儿童受到睡眠问题的影响,主要是入睡困难和夜醒。近期我国研究[4]显示,儿童睡眠问题总患病率为37.6%,从婴幼儿期的33.3%增加至学龄期的43.7%。因此,寻找安全有效的方法来改善睡眠问题,对成人和儿童都具有重要意义。睡眠是由昼夜节律和稳态机制控制[5],两者相互影响调节睡眠-觉醒周期。
研究表明,药理学在睡眠障碍治疗中作用重大,其针对多个神经递质系统和肽系统,如氨基丁酸(aminobutyric acid,GABA)能系统、5-羟色胺(血清素)能系统,以及组胺能和食欲素能系统,而这些系统中产生的神经递质又反过来受到参与其代谢途径的各类营养物质的调节[6-8]。其中,GABA是大脑中主要的抑制性递质[9], 对中枢神经系统至关重要。大脑中超过20%的神经元是GABA能神经元[10],在神经元放电模式和神经网络活动中起着关键作用,其补充在睡眠领域的研究逐渐成为热点。低水平的GABA与急慢性压力[11]、焦虑障碍[12]以及睡眠障碍[13]的病因和维持相关,而睡眠与压力、焦虑密切相关。GABA在临床研究中应用广泛,包括治疗失眠、高血压、压力,以及提高血清生长激素水平[14]。脑干外的多种GABA神经元群参与昼夜节律的控制和睡眠的稳态调节[15]。因此,深入研究GABA对改善睡眠作用具有重要意义。笔者主要综述氨基丁酸的生物学特性和对睡眠的影响,旨在为睡眠干预寻找新思路。
GABA是一种四碳非蛋白质原氨基酸,存在于多种生物中。起初在植物中被发现[16],之后在哺乳动物大脑[17]以及其他生物中被找到[18]。GABA除作为神经递质外,还天然存在于多种食物中,如茶、番茄、大豆、发芽大米和一些发酵食品中,并可从正常饮食中获取[19]
GABA在神经元中由谷氨酸脱羧酶1(glutamic acid decarboxylase 1,GAD1)合成,并通过囊状GABA转运体(vesicular GABA transporter,vGAT)储存在囊泡中[20]。当神经受到刺激时,GABA被释放到突触间隙中,并与嗜离子性或代谢性突触后受体结合[21]。GABA会通过 GABA 转运蛋白(GABA transporter,GAT) 从突触间隙移除,这种转运蛋白仅在果蝇的星形胶质细胞中表达。在神经胶质细胞内,GABA 依靠以 GABA 转氨酶(GABA transaminase,GABAT)为核心的 GABA 旁路进行代谢。由此产生的谷氨酸随后会被转化为谷氨酰胺,这一转化过程由谷氨酰胺合成酶完成,而谷氨酰胺会再被转移到神经元中重新合成 GABA[22]。 GABAT的缺失会致使 GABA 在大脑中积累,从而引起睡眠[23]。星形胶质细胞中 GAT 水平的降低同样会引起睡眠[24]
GABA能神经元主要位于基底前脑和下丘脑前部,通过在睡眠中释放高水平的GABA来抑制刺激唤醒功能的细胞,而GABA主要在下丘脑腹外侧视前核中起诱导睡眠的作用,通过与特定的受体结合,抑制神经元的兴奋性,参与调节睡眠-觉醒周期[25]。迄今为止,研究发现在突触后膜上GABA受体主要有3种亚型[25]:即GABAA、GABAB以及GABAC,每种受体有各自的激动剂和拮抗剂,大多数催眠药通过作用于GABA系统发挥作用,如苯二氮䓬类药物作用于GABAA受体。GABAA和GABAC都属于离子型受体,GABAA受体(GABAA receptors, GABAARs)在介导GABA的睡眠调节作用中尤为重要,其主要存在于海马、下丘脑和大脑皮层[26]。GABAARs含有的跟睡眠调节有关的亚基包括α亚基(α1-α5),β亚基(β1-β3),γ亚基(γ1-γ2),delta, epsilon和theta亚基[27]。研究发现,在失眠患者中,年龄的增加与GABAAR α1和GABAAR α2 mRNA水平的降低有关,导致睡眠质量差,睡眠时间缩短[28]。此外,研究表明,丘脑网状核神经元上的 GABAAR α3亚基缺失会促进小鼠睡眠期间的δ波活动。全身性敲除 GABAAR β1亚基的小鼠表现出异常的睡眠表型,伴有非快速眼动(non-rapid eye movement,NREM)睡眠中δ波增加和快速眼动(rapid eye movement,REM)睡眠中θ波降低[29-30]
有趣的是,GABAA受体上的变构位点允许对大脑相关区域神经元的抑制水平进行调节,这些位点也是抗焦虑和催眠药物的分子靶点[31]GABABR (gamma-amino butyric acid B receptor)基因的Ala20Val多态性与阻塞性睡眠呼吸暂停综合征(obstructive sleep apnea syndrome,OSAS)的睡眠相关变化有关,尽管它不影响疾病的发生,Gly489Ser多态性则与OSAS无明显关联,而Phe658Phe基因的C/C变异与OSAS的发生相关,并且与多导睡眠图记录的某些睡眠参数(如呼吸暂停觉醒指数和NREM的百分比)有联系,这表明GABAB R1基因可能参与了OSAS的发生及其症状表现[32]。GABA信号通路受损与失眠、嗜睡症等睡眠障碍有关[13],因此GABA信号通路是治疗睡眠障碍的重要药理靶点。
GABAB则为代谢型受体[27],属于G蛋白偶联受体,对靶向GABAA的靶向药物不敏感。含有ρ亚基的GABAA受体的亚类通常被称为GABAC或GAB A ρ 33,主要存在于视网膜和上丘的视层[34],它们与GABAA同属快速作用的五聚体配体门控Cl-离子通道家族。GABAB和GABAC受体拮抗剂对睡眠有不同影响,前者增加REM睡眠,后者抑制REM睡眠;GABA受体对睡眠的影响各异,GABAA受体激动剂通过减少REM睡眠、促进高频波睡眠以维持睡眠状态;GABAB激动剂如巴氯芬通过增强REM和NREM促进睡眠,而GABAC激动剂对REM睡眠无影响[35-36]。这些研究结果表明,各种脑部疾病中突触和突触外GABA的失调与睡眠障碍的发生都有关系。
随着研究[37]的深入,发现GABA受体是个Cl-通道,被激活后通道开放,增加细胞膜对Cl-的通透性,Cl-流入神经细胞致细胞膜超极化,抑制神经元细胞激动,实现镇静催眠效果。对GABA的研究表明,GABA能神经元和神经递质调节大脑回路主要通过以下途径:调节杏仁核在正常和病理状态下的应激和焦虑反应[38];调节皮质-延髓通路中的REM和NREM,特别是慢波睡眠[39];调节视交叉上核中的昼夜节律[40]。Li等[41]总结出GABA改善睡眠的作用机制为通过脑肠轴(涉及迷走神经系统、神经内分泌途径和免疫途径3个方面)、脑组织透性以及体内代谢物来调节睡眠,进一步指出肠-脑轴是肠道和大脑间复杂的双向信息交流系统,胃肠道是摄入的GABA体内吸收的重要部位,GABA 通过肠-脑轴作用于中枢神经系统以改善睡眠。一项针对果蝇睡眠的研究发现[42],睡眠缺失会损害果蝇的肠道干细胞功能和肠道稳态,GABA通路可能在调节睡眠-肠道通路中起作用。Stahl等[43]发现GABA信号传递受到兴奋性氨基酸转运蛋白2(excitatory amino acid transporter 2,Eaat2)的调节,该转运蛋白将牛磺酸转运到包裹胶质细胞中。牛磺酸是一种GABAA受体激动剂,在哺乳动物清醒期间会积累,而Eaat2的缺失会导致果蝇睡眠增加。最新研究指出,从口服补充剂、益生菌、富含GABA的发酵食品或强化食品中获得的口服GABA可能通过复杂的外周机制对大脑产生影响,主要涉及肠神经系统和肠-脑轴[44]
此外,GABA通过离子型GABA-Rdl受体抑制PAM-DANs(dopaminergic neurons)活性,并与多巴胺信号协同参与睡眠调控过程[45]。GABAergic的ER3d 细胞在驱动觉醒方面具有重要作用,且可能在特定生理情境下参与调节睡眠觉醒转换,而不影响基础睡眠量[46]。有意思的是,Bruni等[47]表明多数草药通过GABAA受体(主要通过与GABA或苯二氮䓬位点结合)发挥作用,如缬草根、木兰属、中国五味子等植物含有促进睡眠的GABAA受体激动剂;少数草药与GABAB或GABAC受体相互作用,如西番莲提取物可能含有这两种受体亚型的拮抗剂。一些草药提取物对GABA信号有间接影响,如缬草根提取物可能抑制GABA的酶促破坏,增加其可用性;柠檬香蜂草提取物可降低海马神经元中GABAT的水平。
动物研究发现肝脏是脑外GABA的主要代谢场所,并且大鼠的肝脏对GABA的摄取能力很强[48]。在大鼠和小鼠全身给药后,GABA主要分布到肝脏、肾脏和肌肉[49]。在小鼠的膀胱、胃肠壁、脑垂体、脊柱、肋骨和气管软骨中检测到大量的GABA。意味着肝肾功能正常的人群摄入一定剂量的GABA还是安全的。动物实验[50]表明,使用5 000 mg·kg-1剂量的天然GABA对大鼠进行的半数致死量测试未导致任何死亡。这表明其具有良好的安全性。
既往有研究指出,摄入GABA后出现的一些不良反应包括腹部不适、头痛、嗜睡和喉咙短暂灼烧感;但这些影响都为轻度至中度[51-52]。2021年的一例报道[53]显示,加拿大一名23岁男性口服500 mg GABA长达247 d。该患者出现焦虑、平衡障碍、抑郁、多汗、失眠、情绪波动、感觉异常、自残想法、异常思维和戒断综合征。但该患者同时还服用了5-羟基色氨酸、B族复合维生素缓释片和Hair Force,因此GABA在这些不良影响中的作用尚不确定。国外的一项数据显示,在摄入量高达18 g·d-1并持续4 d的情况下,以及在摄入量为120 g·d-1并持续12周的更长时间研究中,均未发现与GABA相关的严重不良事件。不过,GABA可能会导致一过性的血压轻中度下降(<10%的变化)。从一定程度上来说,此项调查结果反映了GABA具有一定的安全性[14]。Yoon等[54]发现低剂量天然GABA(75 mg)在改善失眠患者睡眠质量和功效方面与高剂量(300 mg)同样有效,可降低睡眠潜伏期,增加N3睡眠,降低唤醒指数,对睡眠起始性失眠有效,但对睡眠维持性失眠无效,低剂量天然GABA无不良影响,这可能反映出副作用与剂量成正比。
回顾上述的临床和动物研究并未发现任何与摄入GABA相关的严重不良事件。总之,目前关于睡眠问题中GABA的最佳补充剂量和疗程尚无定论,其对睡眠的作用机制需深入研究。虽然GABA的安全性有一定验证,但其安全有效剂量仍需进一步大数据的全面研究。
Mo等[55]发现,富含GABA酸奶不仅可提高小鼠睡眠发生率(中剂量能延长其睡眠时长,但对缩短潜伏期无作用),还能增加失眠小鼠脑内GABA含量,但对其血液中这些物质无显著影响。一项涉及166名睡眠时间短的受试者的队列研究[13]显示,通过磁共振波谱测量,睡眠时间短的受试者大脑中GABA水平较低,与工作记忆受损有关。这暗示了体内GABA浓度不足可能与睡眠问题相关联。
一项针对GABA和核桃肽单独或联合使用对小鼠睡眠作用的影响研究[56]指出,与对照组相比,GABA和核桃肽的联合使用显著延长了小鼠的睡眠时间,且增加GABA剂量会使小鼠睡眠时长呈剂量依赖性增加;并且单独使用GABA、核桃肽或两者联合使用均显著增加了小鼠大脑中GABA和乙酰胆碱的含量,降低了5-羟色胺的含量,作用机制可能与调节脑组织中的神经递质有关,表明其可作为睡眠障碍患者的非药物管理形式添加到食品中。Yamatsu 等[57]研究表明,持续1周睡前30 min摄入100 mg的GABA胶囊(与对照组相比)改善了醒来后的感觉评分,睡眠潜伏期缩短,干预后NREM总睡眠时间增加,给药30 min后血液GABA水平从244 nmol·L-1升高到329 nmol·L-1,60 min后降至290 nmol·L-1,表明GABA吸收和代谢快,这可能解释了其在睡眠早期有效的原因,但给药60 min后血液中GABA水平仍高于给药前,说明GABA在整个睡眠过程中均有效。
Kim等[58]在戊巴比妥钠睡眠实验中发现GABA可显著缩短小鼠的睡眠潜伏期,同时延长小鼠睡眠持续时间。最新研究[59]指出,昼夜节律紊乱导致小鼠入睡潜伏期延长,GABA干预(150 mg·kg-1)可显著延长小鼠睡眠时间,但对小鼠睡眠潜伏期无显著性差异,可能的机制是GABA干预可能通过增强时钟基因(ClockPer1、Per2、Per3、Cry1、Cry2、Rev-erba/β、DbpCiart)昼夜节律振幅,降低前额叶皮层细胞外信号调节激酶(extracellular signal-regulated kinase,ERK)表达,降低丝裂原活化蛋白激酶激酶(mitogen-activated protein kinase kinase,MEK)、ERK1/2磷酸化水平,改善昼夜节律紊乱,从而提高小鼠睡眠质量。有研究表明100 mg的GABA显著缩短了入睡潜伏期和NREM睡眠潜伏期,从而使患者能够更快、更容易地入睡[60]。一项为期4周的研究考察了生物合成的GABA的摄入对健康老年参与者睡眠的影响。通过使用阻塞性睡眠呼吸暂停睡眠量表,他们发现,经过4周的治疗,GABA组在睡眠起始和维持、早晨困倦以及疲劳恢复得分方面有所改善[61]。Byun等[62]进行的一项为期4周的40例失眠患者的干预研究结果显示,睡前1 h摄入300 mg的GABA片剂(与对照片剂相比)在干预后减少了睡眠潜伏期。在GABA组中,N2 睡眠时间和失眠严重程度指数降低,匹兹堡睡眠质量指数(pittsburgh sleep quality index,PSQI)总分、PSQI睡眠质量、PSQI 睡眠潜伏期和 PSQI总睡眠时间得分(治疗前与治疗后相比)也有所降低。但这研究未能表明摄入GABA对睡眠的其他指标(如睡眠效率、REM睡眠时间、觉醒频率等)是否有有益影响。此外,Byun等[62]注意到有2例出现轻度腹部不适和头痛症状,有3例出现轻度嗜睡情况,但无严重的不良反应。
另有研究指出长期摄入GABA可能有益于诱导睡眠,而非维持睡眠。GABA主要影响睡眠起始和NREM的Ⅰ期[63]。Yi等[64]报道,酸枣仁汤可以用于改善患者的失眠状况,并在睡眠紊乱大鼠中被发现其作用机制是介导GABAARs而非GABABRs的表达。Wang等[65]发现红枣改善睡眠作用与其富含GABA活性成分有关。
随着对GABA的深入研究,发现许多发酵食品富含GABA,用于发酵食品生产的乳酸菌和酵母具有产生GABA的特性。在发酵产品中已经鉴定出许多产生GABA的微生物。例如,短乳杆菌J1是一种从发酵牛奶中分离出的乳酸菌菌株[66]。已有研究发现鼠李糖乳杆菌的菌株,如JB-1菌株(L.rhamnosus,JB-1)已被证明能增加小鼠大脑皮层的GABA能活性[67]。使用一种涉及短乳杆菌BJ20(Lactobacillus brevis,BJ20)的特定LAB发酵工艺,可以使海带中含有的谷氨酸被生物转化为GABA[68]
在一项研究藜麦酸奶饮料有益特性的实验中,鼠李糖乳杆菌SP1和植物乳杆菌T6B10将饮料中的GABA水平提高到了211 mg·kg-1[69]。有证据表明,在人类和动物中,口服GABA补充剂可以到达大脑并发挥生物效应,包括改善情绪和中枢神经系统的活动。高血浆GABA浓度也被证明可以增加大脑中GABA的浓度[70]
此外,有趣的是雌激素、锌或维生素缺乏,以及水杨酸和食品添加剂过量等因素,都可能抑制身体产生GABA的能力[71]。由此可以推测如果人体缺乏维生素或者锌都会影响睡眠。在高压力人群中,200 mL富含GABA的乌龙茶中,GABA质量低至2.01mg就能显示出减轻压力的效果[72]。对于睡眠质量差的人群,摄入100mg生物合成的GABA 1周可能会改善睡眠质量[60]。Kanehira等[73]研究了富含GABA的饮料对职业疲劳的影响,结果显示摄入含GABA的饮料,特别是含50 mg GABA的饮料,可能有助于减少心理和身体疲劳,并提高解决任务的能力。最新研究[74]指出,开菲尔(kefir,一种来自高加索山脉的传统发酵乳饮料,通过向牛奶中添加开菲尔粒制成)能提高小鼠肠道微生物群产生GABA的能力。在行为方面,饮用开菲尔改善了奖励学习和依赖恐惧的情境记忆。但Tnok等[75]发现在橙汁中添加800 mg GABA对空间注意力和视觉工作记忆没有积极作用。
以上研究表明,机体摄取含有能产生GABA的益生菌的食物可能有助于睡眠、减轻身体疲劳,但具体效果还需进一步研究。
除了富含GABA的食物和菌群,临床上也存在一些经过体内代谢产物为GABA的类似物或衍生物的药物,这些药物对睡眠可能存在潜在影响。Bruni等[76]发现,苯二氮䓬类药物如氯硝西泮,可通过作用于 GABAA受体促进睡眠,增强含有GABA的神经元的抑制性输入,从而抑制上行唤醒通路。但因其存在认知损害、反弹失眠和依赖的风险,故在使用中受到限制。加巴喷丁(gabapentin)是GABA的环状衍生物,主要是通过与电压门控钙通道的α2-δ亚基结合来调节神经递质释放。有研究指出,服用加巴喷丁可能会出现嗜睡等不良反应,尤其是在用药初期或者剂量调整阶段,故在临床实践中不常作为一线睡眠药物使用。早期就有研究[77]发现,氨己烯酸(vigabatrin)是一种不可逆性的GABAT抑制剂,通过抑制GABA的代谢来提高脑内GABA浓度。有报道称服用氨己烯酸可能会对睡眠行为有影响,如出梦游等异常睡眠行为,但这种情况相对较少见。
此外,最新研究[78]指出,目前正在研发的GABAkines(GABAA受体的正变构调节剂)能够增强GABA对受体的作用,进而调节神经系统的兴奋性。其中,神经活性类固醇类药物,如Allopregnanolone,展现出抗焦虑、镇静和抗惊厥等作用;小分子类新药KRM-Ⅱ-81则在焦虑、抑郁、急性和慢性疼痛、癫痫和创伤性脑损伤的动物模型中显示出疗效,且不良反应较少,目前这两种药物均处于开发阶段。
但值得一提的是,虽然新型 GABAkines 在安全性方面相对传统药物更有保障,但仍面临挑战。例如,尽管一些药物在动物模型中表现出良好的效果且不良反应较少,但在临床试验中,仍出现了一些不可忽视的安全问题。此外,由于不同个体对药物的反应存在差异,部分患者可能对某些GABAkines更为敏感,更容易出现不良反应,这也增加了用药安全性的不确定性。
本文详细阐述了GABA对睡眠的作用机制、临床效果以及安全性等研究新进展。然而,当前研究仍存在一些局限性。虽然现有研究表明GABA在改善睡眠方面具有一定潜力,但在样本量方面,多数研究样本相对较小,这可能导致结果的代表性不足,无法全面反映GABA在群体中的真实作用。研究对象多样性也存在欠缺,例如,现有研究多集中在特定年龄段或特定睡眠问题的成人,缺乏对不同年龄、不同睡眠障碍类型儿童的广泛研究。研究方法上,部分研究依赖于主观评估工具,如睡眠问卷,客观性指标相对较少,影响了结果的准确性。
在未来研究方向上,首先,应开展大规模、长期的研究。大规模研究能够涵盖更广泛的群体,提高结果的可靠性和普遍性。纵向随访的长期研究则有助于观察GABA对睡眠的长期影响,以及潜在的不良反应。其次,需进一步明确最佳应用方式,包括合适的剂量、疗程以及给药途径等。同时,要综合考虑个体差异,如基因多态性、年龄、性别以及基础健康状况等因素对GABA效果的影响。最后,安全性评估应贯穿研究始终,确保GABA在睡眠应用中的安全性,为其作为改善睡眠的辅助手段提供更充分的科学依据,保障人群的健康福祉。
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doi: 10.11669/cpj.2025.05.001
  • 接收时间:2024-08-13
  • 首发时间:2025-11-07
  • 出版时间:2025-03-08
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    1 浙江大学医学院附属儿童医院儿保科, 杭州 310003
    2 国家儿童健康与疾病临床医学研究中心, 杭州 310003

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* 姚丹,女,博士,副主任医师 研究方向:儿童语言发育、营养生长发育、免疫接种 Tel:(0571)87023391
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2种不同金属材料的力学参数

Family
属数
Number of
genus
种数
Number of
species
占总种数比例
Percentage of
total species (%)

Genus
种数
Number of
species
占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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