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胰高血糖素样肽介导运动抗抑郁作用的潜在机制

作者:刘佳彤 刘微娜 漆正堂 季浏 来源:首都体育学院学报 论文栏目:体育论文     更新时间:2019-07-12   浏览

原文标题:《胰高血糖素样肽介导运动抗抑郁作用的潜在机制》,作者:刘佳彤刘微娜漆正堂季浏,该学术论文发表于:首都体育学院学报,2017年5期 ,由论文网在线小编整理。

刘佳彤刘微娜漆正堂季浏

摘 要:胰高血糖素样肽-1(GLP-1)是机体在响应营养摄入时而释放的一类肠促胰岛素,主要由肠道末端L细胞分泌,是目前治疗糖尿病的重要靶点。近年来,研究发现:GLP-1受体不仅在肠、胰腺等外周组织中表达,而且在海马、下丘脑等脑组织中也大量表达,这暗示其可能在糖尿病的并发疾病——抑郁症中发挥作用;但GLP-1易被二肽基肽酶Ⅳ降解失活,难以发挥作用,而长期运动可增加GLP-1的表达和分泌。基于此,旨在探究运动介导GLP-1调控抑郁行为的可能机制,进而为运动的抗抑郁机制研究提供新的视角。通过对相关领域文献资料的梳理分析发现,GLP-1介导运动的抗抑郁作用涉及HPA轴激活、中枢单胺类神经递质、中枢营养因子及中枢炎症因子的水平4个维度。由此推论,GLP-1可能是运动发挥抗抑郁作用的重要介质,从而为抑郁症的能量代谢机制和治疗策略提供了新的靶点和阐释路径。

关键词:抑郁症;胰高血糖素样肽;运动;HPA轴;单胺类神经递质;神经营养因子;炎症

中图分类号:G 804.2 文章编号:1009-783X(2017)05-0474-07 文献标识码:A

Abstract: Glucagon-like peptide -1 (GLP-1), mainly secreted by L cells, is a kind of incretin hormone released by the body in response to nutritional intake and an important target for the treatment of diabetes. Recent studies have found that GLP-1 receptor is not only expressed in intestinal and pancreatic, but also in the hippocampus and hypothalamus, suggesting its role in depression accompany with diabetes. However, GLP-1 can be degradated by dipeptidyl peptidase Ⅳ, thus being difficult to work, while long term exercise can increase the expression and secretion of GLP-1. Therefore, the current study aimed to explore potential mechanisms of GLP-mediated antidepressant effects of exercise, and to provide a new perspective for exercise effects on depression. The available documents demonstrate that the activation of HPA axis, the expression of central monoamine neurotransmitters, neurotrophic factor and central inflammatory cytokines are involved in the antidepressant effects. To sum up, GLP-1 may be a mediator of exercise effects on depression, which suggests a novel target and pathway of energy metabolism and treatment strategy for depression.

Keywords: depression; glucagon-like peptide; exercises; HPA axis; monoamine neurotransmitters; neurotrophic factors; inflammation

研究已經充分证实,抑郁症患者存在HPA轴功能失调、单胺类功能异常、脑源性神经营养因子减少及中枢炎症反应增加。临床上,糖尿病患者罹患抑郁症现象正受到越来越多研究者的关注,反之亦然[1]。胰高血糖素样肽(glucagon-like peptide),包括胰高血糖素样肽-1(GLP-1)和2(GLP-2),是目前治疗糖尿病的重要靶点。最新研究表明,GLP-1、GLP-2或其受体激动剂、水解酶抑制剂具有抗抑郁、抗焦虑作用[2-3],但这种功能分子的作用机制目前尚未完全阐明。GLP-1是肠L细胞分泌的肠促胰岛素,其功能由GLP-1受体介导,可调节胰岛素信号通路,从而保护胰岛β细胞,促进胰岛素的分泌;GLP-1及其受体激动剂对2型糖尿病[4]、肥胖[5]、心血管疾病[6]、脂肪肝[7]有较好的疗效。而在中枢神经系统中,GLP-1也可通过血脑屏障与其脑内受体结合,参与神经系统的调节,从而发挥神经保护作用,对帕金森和阿尔兹海默症等疾病[8-9]有显著疗效。GLP及其受体激动剂的抗精神病作用逐步显现,其分子机制存在多种途径。基于此,本文旨在探究运动介导GLP-1调控抑郁行为的可能机制,进而为运动的抗抑郁机制提供新的视角。通过对相关领域文献资料的梳理分析发现,GLP-1介导运动的抗抑郁作用涉及HPA轴激活、中枢单胺类神经递质、中枢营养因子及中枢炎症因子的水平4个维度。本文将对此类研究进行综述,并基于HPA轴功能、单胺类神经递质、中枢神经营养因子、中枢炎症等4个方面阐释GLP在抑郁症中的作用机制,及其介导运动抗抑郁作用的潜在途径,如图1所示。

1 胰高血糖素样肽及其受体

GLP-1是肠L细胞以营养依赖性方式分泌的一种具有葡萄糖依赖性促胰岛素分泌功能的肠促胰岛素,是胰高血糖素原基因的编码产物之一;该基因在胰腺α细胞、肠L细胞及下丘脑、脑干等处的神经元中都有表达,具有促进胰岛素分泌、保护胰岛β细胞、抑制胰高血糖素分泌、抑制胃排空、降低食欲等药理作用,临床可用于2型糖尿病和肥胖症的治疗。GLP-2是一个有33个氨基酸的肽,在肠道和中枢神经中均有表达,在肠内主要起保护肠道的作用。GLP-1受体(glucagon-like peptide-1 receptor,GLP-1R)是由463个氨基酸组成的7次跨膜螺旋G蛋白偶联受体,在胰岛、心脏、肠、迷走神经、下丘脑、垂体、海马及大脑皮层表达[10],主要功能是促进胰岛素的分泌,刺激β细胞的增生。GLP-2受体不仅在不同胃肠细胞[11-12],而且在中枢神经系统,包括下丘脑背内侧核的特定区域、杏仁核、丘脑、小脑、海马和大脑皮层中也有表达[13-14]。人体内具有生物活性的GLP主要是GLP-1(7-36)酰胺、GLP-1(7-37)和GLP-2(1-33),天然GLP-1和GLP-2均被二肽基肽酶Ⅳ迅速水解失活(半衰期小于5 min),不具有临床使用价值。GLP-1受体激动剂(GLP-1RA)是GLP-1类似物,不易被二肽基肽酶Ⅳ降解,可以额外增加外源性GLP-1浓度,具有与GLP-1 相似的生物学活性。研究表明GLP-1RA可通过降低体脂、控制血糖治疗糖尿病[15],也用于治疗儿童性肥胖[5],通过延缓胃排空与抑制食欲等作用对肥胖症患者达到减重的效果[16]。GLP-1RA对于心血管疾病、神经退行性疾病也有一定的作用[17-19]。但是,近年来一系列研究显示,GLP-1、GLP-2或GLP-1RA在不同的抑郁动物模型中表现出显著的抗抑郁作用[3,20-23]。

2 GLP及其受体激动剂对焦虑、抑郁行为的影响

抑郁症常伴有焦虑症状,焦虑是抑郁症患者表现的一种情绪反应。研究表明,GLP-1可作为一种神经递质在神经元中表达。GLP-1与情绪有关,可能是通过多巴胺、5-羟色胺等产生作用。GLP-1R在杏仁核、中缝背核和海马等区域中被发现,主要是调节情绪和情感,与能量调节联系不大[22]。动物研究表明,GLP-1对焦虑行为的作用相互矛盾。一些临床前的研究发现,中枢直接注射GLP-1能增加啮齿类动物的焦虑行为[24-25];另一些研究则表明,长期外周注射GLP-1类似物没有改变其在FST(强迫游泳实验)中的焦虑行为[23,26]。但Sharma等的大量研究表明,急性外周注射GLP-1类似物降低了大鼠在EPM(高架十字迷宫实验)中的焦虑行为[2-3,27]。Anderberg等的研究也发现,急性注射GLP-1类似物增加了大鼠在EPM、黑白箱实验中的焦虑行为[22]。Komsuoglu等的研究也表明,长期注射GLP-1對糖尿病大鼠产生抗焦虑作用[28]。GLP-1对焦虑行为产生的影响不同可能是由于注射途径(中枢和外周)、给药方式(慢性、急性),及鼠种和动物所处生理状态不同所产生的结果。对于抑郁行为,目前的研究趋于一致,即GLP-1类似物能够产生明显的抗抑郁效果。Sharma等的研究表明,长期使用利拉鲁肽治疗能够逆转雌性精神病大鼠的抑郁行为,大鼠在FST中的不动时间明显缩短,游动时间增长[3]。Komsuoglu等的研究表明,艾塞那肽(EX4)对T2DM小鼠有抗抑郁作用,同样能够降低T2DM大鼠在FST中的不动时间[28]。Anderberg等[22]和Isacson等[29]的研究都表明,长期注射EX4能够降低大鼠在FST中的不动时间,缓解了抑郁样行为。一些研究表明,热量限制可以降低焦虑和抑郁,EX4导致厌食可能是其发挥抗抑郁作用的途径之一[30]。近几年对GLP-2的研究表明,GLP-2同样产生了抗焦虑和抗抑郁的效果。Takashi 等发现,GLP-2明显增加了促肾上腺皮质激素(ATCH)处理的小鼠在开场实验中处于中心区域的时间和在EPM实验中进臂的次数[31],从而降低小鼠的焦虑行为。短期注射GLP-2能够降低小鼠在FST和悬尾实验中的不动时间[20],进一步研究表明,GLP-2能够降低由FST诱导的血浆皮质酮的增加[21]。以上研究表明,GLP-1及其受体激动剂及GLP-2在改善抑郁行为中发挥积极作用。

3 GLP-1及其受体激动剂对HPA轴功能的调节机制

促肾上腺皮质激素释放因子(CRF)和血管加压素(AVP)是下丘脑-垂体-肾上腺轴(HPA轴)的调节肽,促肾上腺皮质激素释放激素(CRH)、ATCH和糖皮质激素(GC,主要指皮质醇)是HPA轴的重要的基础调节激素。GLP-1参与应激反应的HPA轴的调节,可直接作用于CRF和AVP,进而通过调节基础激素发挥作用[32]。研究表明,中枢注射GLP-1能激活HPA轴,进而增加ACTH[25,33]、AVP[34]和血浆皮质酮[35]的水平。CRF是GLP-1影响HPA轴的重要介质,外周注射非特异性CRF受体拮抗剂Astressin能减弱GLP-1诱导ACTH和血浆皮质酮升高[25]。此外,EX4能有效激活皮质酮和ACTH,并且此前注射过Astressin,这种效果就会被减弱,EX4也可以增加GC的水平[36],表明GLP-1通过增加CRH活性来激活HPA轴反应。有证据表明,GLP-1通过交互作用激活HPA轴。在短期内,GLP-1R激动剂相当有效地激活HPA轴,引起下丘脑CRF升高,促进垂体ACTH的分泌。GLP-1R激动剂有助于恢复糖尿病患者的代谢水平,不只是因为减少食物的摄取,也源于脂肪组织保持相对高的脂解活性,这些作用一部分可能是通过中枢CRF介导的[37]。比较直接的证据是,GLP-1R基因沉默能降低HPA轴对急慢性应激的反应,并阻止慢性应激导致的体重流失。这表明,慢性应激诱导抑郁行为很可能是GLP-1介导的[38],但是神经内分泌研究已证实,HPA轴过度激活与抑郁行为有关。换言之,HPA轴过度激活是抑郁症的重要表现之一[39]。难以解释的是,GLP-1对HPA轴的激活应该是不利于抗抑郁作用的。另有研究表明,中枢GLP-1通过CRH这一关键介质诱导HPA轴反应,而在这一过程中可能存在GLP-1诱导的HPA轴的下调机制[40]。HPA轴的正常活动还有赖于负反馈调节抑制,内源性GC与GC受体(GR)结合,对下丘脑的CRH和垂体的ACTH的分泌产生负反馈抑制作用;因此,GLP-1可能通过增加GC水平促进GC的负反馈抑制作用,从而降低抑郁行为。另外,GLP-1可能通过作用于CRF来调节和纠正HPA轴功能紊乱,进而发挥抗抑郁作用。

4 GLP-1及其受体激动剂对中枢单胺类神经递质的调节机制

单胺类神经递质系统功能紊乱是抑郁症发病最重要的假说,5-羟色胺(5-HT)、多巴胺(DA)等神经递质释放异常与抑郁症的发病率密切相关。5-HTR(5-HT受体)在抑郁症的发病机制和抗抑郁剂的药理机制中发挥着极为重要的作用,急性中枢注射GLP-1RA能增加杏仁核5-HT的转运和5-HT受体基因的表达[22]。而在5-HT系统中的5-HT1AR(受体亚型,在海马中密度最高)在抑郁症发病机制及抗抑郁治疗中发挥着重要的作用。5-HT1AR被激活后,降低腺苷酸环化酶(AC)活性、cAMP(环磷酸腺苷)表达水平,进而影响PKA(蛋白激酶A)的活性,使核转录因子CREB发生磷酸化,而活化的CREB与靶基因调节区cAMP反应元件结合,进而调节下游信号通路神经营养因子基因的表达。5-HT1AR介导的信号通路异常是抑郁发生的重要机理,GLP-1可能通过调节 5-HT1AR介导的cAMP-PKA-CREB信号通路发挥抗抑郁作用。多巴胺也与抑郁密切相关[41]。中脑多巴胺神经元的抑制或激活能立即诱导或减轻慢性应激有关的多种抑郁行为和症状。采用光遗传学技术募集多巴胺神经元,显著改变了与抑郁有关的神经元基因表达[42],而GLP-1R激动剂-EX4,可以减弱可卡因诱导的小鼠纹状体多巴胺释放[43]。此外,EX4还有抗精神病样的作用[44],能降低由安非他命导致中枢DA水平增加所诱导的神经活动[45]。这表明EX4可能降低中枢多巴胺的水平,其抗抑郁作用可能与降低多巴胺转运有关。

5 GLP-1及其受体激动剂对中枢神经营养因子的调节机制

目前,抑郁症的5-HT假说仍有争议,因为抑郁症患者有近1/3不能从SSRI治療中得到缓解[46],因此,有学者提出,神经退行性变化也是抑郁症的发病机制之一,抗抑郁治疗应从增加神经发生着手[47-48]。GLP-1是一种具有神经保护特性的生长因子,并且有证据表明GLP-1R激动剂EX4有神经营养和神经保护的作用[49-50];因此,治疗抑郁可能从GLP-1R减少神经退行性病变和增加神经发生出发。GLP-1受体激动剂和葡萄糖依赖性促胰岛素激素(GIP)受体激动剂可通过血脑屏障[51-52],减轻神经元氧化应激,抑制细胞凋亡,促进神经细胞增殖和神经细胞长出新的突起[53-55],BDNF(脑源性神经营养因子)是目前抗抑郁研究中较为关键的一个神经营养因子,GLP-1和GLP-1R双重激动剂DA-JC能增加黑质中的BDNF表达,表明了GLP-1对神经元和突触的保护作用[56]。而神经生长因子的活化,能激活AKT并参与神经保护作用。AKT是激活细胞修复通路的关键激酶,能促进细胞增殖和能量利用。GLP-1和BDNF等生长因子激活AKT[57-58],能通过ERK1/2通路来发挥DA-JC的神经保护作用[55]。DA-JC还能增加生长因子信号传导分子Bcl-2的表达,减少凋亡信号分子Bax蛋白表达[56]。这些研究表明,GLP-1受体的激活调节这些关键信号分子的表达,可能通过BDNF/AKT/Bcl-2/BAX机制减少细胞凋亡,促进细胞增殖,进而增加神经发生产生抗抑郁作用。

6 GLP-1及其受体激动剂对中枢炎症的调节机制

许多研究表明抑郁症与中枢慢性炎症相关,抗炎是抑郁症治疗的一种重要策略;基于GLP-1的抗炎作用,GLP-1及其受体激动剂广泛用于慢性炎症有关的疾病,例如1/2型糖尿病、动脉粥样硬化、神经退行性疾病等[59-61]。神经胶质细胞对于中枢神经系统的炎症发挥关键作用,并且GLP-1R在星形胶质细胞和小胶质细胞中被观察到。GLP-1对表达其受体的细胞具有普遍的抗凋亡特性和保护作用,其机制可能与GLP-1受体介导的凋亡信号通路的失活及保护信号通路的激活有关[62]。促炎细胞因子,如白细胞介素-1β(IL-1β)、γ-干扰素(IFN-γ)和肿瘤坏死因子-ɑ(TNF-ɑ)是星形胶质细胞炎症的主要激活物。GLP-1类似物利拉鲁肽能抑制TNF-ɑ、IL-6、IL-1β的表达[63],并通过抑制小胶质细胞的活性,明显降低阿尔兹海默症小鼠的炎症反应[64]。星形胶质细胞中的NF-κB(核转录因子)是中枢神经系统中重要的炎性调节因子,TNF-ɑ、IL等在内的多种信号能够活化NF-κB途径,抑制此信号转导通路对组织再生有很好的效果。GLP-1R激动剂EX4能抑制炎症基因如NF-kB的表达[65]。在星形胶质细胞中,GLP-1能预防脂多糖(LPS)诱导IL-1β的表达,从而减轻炎症反应[66]。二肽基肽酶Ⅳ抑制剂维格列汀能减少GLP-1、2的水解,显著降低血浆TNF-ɑ浓度[67]。这些结果表明,GLP-1类似物、GLP-1R激动剂或者维持GLP-1水平均能抑制炎性细胞因子。上述研究发现提示,GLP-1的抗抑郁作用很可能与抗炎作用有关,但更多的直接证据尚有待于实验研究进一步证实。

7 GLP-1与运动的抗抑郁作用

大量研究表明,运动是治疗抑郁症的一种有效手段,规律的体育运动可以有效降低抑郁症状的发生[68];Conn等的荟萃分析发现,无论是抑郁还是非抑郁成年人,运动对其抑郁行为都有一定的缓解作用[69]。在动物研究中,也发现运动能够改善动物的抑郁行为。本课题组前期研究发现,游泳运动能够明显改善抑郁症模型大鼠的抑郁行为[70],另有研究表明,自主跑轮运动可以改善抑郁模型大鼠的抑郁样行为[71]。基于前文分析,运动的抗抑郁作用可能牵涉GLP-1对神经系统的多种作用途径。一方面,大量研究表明运动增加GLP-1表达和分泌。健康人运动后,血清GLP-1 的浓度明显增加[72-74],进食30 min后进行运动使GLP-1浓度明显增加[75];长期的广场舞运动可增加机体空腹基线水平内源性GLP-1的分泌量[76];长期的有氧运动、补充谷氨酰胺能够抑制炎症因子NF-κB的基因表达,升高GLP-1[77]。另一方面,运动对HPA轴活性、单胺类神经递质释放、神经营养因子表达以及中枢炎症等都有积极调节作用。Kim等研究发现,跑台运动可以降低大鼠海马CRF mRNA表达和血清ACTH水平下降,改善HPA轴的异常活动[78];Zheng等研究发现,运动能够逆转慢性应激所导致的大鼠皮质酮升高和GR的降低,从而使HPA轴对应激产生适应性反应[79]。运动可通过反复激活HPA轴,产生HPA轴的适应性,从而改善抑郁行为,而GLP-1是HPA轴应激反应的关键性介质,运动可能通过GLP-1R/CRH/GC这一正向通路和负反馈调节机制发挥作用。研究发现,小鼠在悬尾实验中的抑郁行为不是由于运动障碍和肌肉松弛,而是由于5-HT转运活性变化和5-HT释放减少[80]。抑郁行为伴随着5-HT和DA释放减少,运动能够增加大脑海马5-HT[81]、纹状体DA[82]等神经递质的释放。运动还能上调海马GLP-1的表达,通过5-HT1AR介导的cAMP/PKA/CREB信号通路发挥抗抑郁作用。同样,运动能够增加海马BDNF水平[79,83],GLP-1同样能够增加BDNF的表达,这种增加机制可能是通过CREB来调节,也可能通过GLP-1介导的BDNF/AKT/Bcl-2/BAX途径实现细胞的存活、生长、分化。运动能够调节IL-1、IL-6和TNF-ɑ等炎症因子的水平[84],使GLP-1表达增加,促使GLP-1抑制NF-κB,降低这些炎症因子的水平发挥抗抑郁作用[85]。

8 结束语

综合来看,GLP-1可能通过HPA轴激活、中枢单胺类神经递质、中枢营养因子及中枢炎症因子的水平等4个维度从多种途径介导了运动的抗抑郁作用(如图1所示)。抑郁症一直被认为是一种精神卫生问题,甚至被形象的称之為“精神感冒”。随着对抑郁症研究的不断深入发现,96%左右的抑郁症都是代谢性抑郁症,因而有学者提出“抑郁症实际上是一种代谢性疾病”。作为代谢性疾病的治疗靶点,GLP-1在抑郁症中的作用也就凸显而出。运动调控GLP-1通过作用于下游信号分子减轻中枢的炎症反应、减少神经毒害性代谢产物、增加脑源性神经营养因子的表达,从而作用于脑组织发挥抗抑郁作用。由此推论,GLP-1可能是运动发挥抗抑郁作用的重要介质。GLP及其受体激动剂的抗抑郁作用不仅为运动抗抑郁作用提出了一条新的阐释路径,也为抑郁症的能量代谢机制和治疗策略提供了新的靶点。目前临床上常用抗抑郁药,如三环类抗抑郁药(TCAs)、单胺氧化酶抑制剂(MAOIs)、选择性5-HT 再摄取抑制剂(SSRIs)等,均有毒副作用,都可能产生肝、肾毒性,并会增加患糖尿病的风险;因此,未来靶向GLP-1等代谢分子的药物研发及运动干预手段将有望改变抑郁症的治疗方向。

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