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   大连医科大学学报  2022, Vol. 44 Issue (3): 239-243      DOI: 10.11724/jdmu.2022.03.10
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脑内脂质代谢在抑郁症发生发展中作用的研究进展
杨文山1,2, 王一晨1, 王元博1, 李夏1, 王超臣1, 胡园1    
1. 中国人民解放军总医院 医疗保障中心 药剂科,北京 100853;
2. 中国人民解放军陆军第82集团军医院 门诊部,河北 保定 071000
摘要:抑郁症是一种十分常见且严重的精神类疾病,通常表现为兴趣或愉悦感丧失,缺乏情绪反应,明显的精神运动迟缓或躁动以及食欲、体重和性欲的减退。大脑中富含脂质,脂质对于中枢神经系统的神经发生和突触形成等功能非常重要。脂肪酸、鞘脂、磷脂和胆固醇等脑内脂质代谢紊乱在不同程度上调节下丘脑-垂体-肾上腺轴(HPA轴)活性和脑内多巴胺、脑源性神经营养因子等的表达水平,进而影响抑郁的发生发展。本文重点总结脑内脂质代谢在抑郁症发生发展中的作用,同时归纳总结现有与脑内脂质代谢相关的抗抑郁药物,为临床抗抑郁药物的选择及其治疗方式提供综述基础。
关键词抑郁症    脂质代谢    中枢神经系统    抗抑郁药物    
Study progress on the role of brain lipid metabolism in the development of depression
YANG Wenshan1,2, WANG Yichen1, WANG Yuanbo1, LI Xia1, WANG Chaochen1, HU Yuan1    
1. Department of Pharmacy, Medical Supplier Center, Chinese PLA General Hospital, Beijing 100853, China;
2. Out-patient Department, the Army of Chinese PLA 82 Group Military Hospital, Baoding 071000, China
Abstract: Depression is a very common and serious mental illness, usually manifested by loss of interest or pleasure and lack of emotional response. The brain is rich in lipids, which play an important role in neurogenesis and synaptic formation of the central nervous system. The metabolism disorders of fatty acids, sphingolipids, phospholipids, cholesterol and other lipids are not only related to the activity of the HPA axis and the expression levels of dopamine and neurotrophic factors, but affect the occurrence and development of depression. We reviewed the role of brain lipid metabolism in the occurrence and development of depression, associated antidepressants.
Keywords: depression    lipid metabolism    central nervous system    antidepressants    

抑郁症是一种十分常见且严重的精神类疾病,通常表现为兴趣或愉悦感丧失,缺乏情绪反应,明显的精神运动迟缓或躁动以及食欲、体重和性欲的减退。目前,抑郁症在全球疾病负担中排名第四,预计到2030年将上升到全球第二位,并且在高收入国家中排名第一[1]。抑郁症目前在全世界范围内影响着约3亿人,并且人的一生中至少有一次遭受抑郁症的困扰[2]。与一般人群相比,抑郁症的自杀风险增加了数倍[1]。世界卫生组织估计,到2030年,抑郁症将成为全球残疾的主要原因[2]。抑郁症的发病机制复杂,主要包括下丘脑-垂体-肾上腺轴(HPA轴)的激活、神经内分泌和神经递质的改变、炎症和脑源性神经营养因子(BDNF)等。在人体,脂质参与复杂的生理功能,如能量储存,细胞运输和细胞膜的形成。大脑中富含脂质,脂质对于中枢神经系统的神经发生和突触形成等功能非常重要。近年来,脑内脂质代谢紊乱与抑郁症之间错综复杂的关系也深受广大学者的关注。本文重点对脑内脂质代谢紊乱与抑郁症发病之间的关系进行综述。

1 脑内脂质紊乱参与抑郁症发生发展的主要机制

中枢神经系统是继脂肪组织之后机体中脂质含量最高的部位(占大脑干重的50%~60%)。脑内的脂质主要包括脂肪酸(fatty acid)、鞘脂(sphingolipids)、磷脂(phospholipids)和胆固醇。脑内脂质代谢涉及脂质的合成、摄取、运输以及脂质分子的降解。正常的脂质代谢对于中枢神经系统髓鞘的形成、突触可塑性和受体功能至关重要。长期的饮食结构不合理直接影响脑脂质的组成,进而影响情绪和情绪行为。

1.1 脂肪酸参与抑郁发生发展的机制

大脑内的脂肪酸是维持神经细胞膜结构和功能完整性的关键。多不饱和脂肪酸作为细胞膜的成分、信号传递介质和信号传递介质的前体发挥着许多重要的生理作用。其中,ω-3多不饱和脂肪酸参与了中枢神经系统突触的形成和神经的发生[3]。ω-3多不饱和脂肪酸改善抑郁症状的机制与大脑海马中5羟色胺能神经传递有关[4]。增加脑内ω-3多不饱和脂肪酸的含量可以增加突触前神经元5羟色胺的释放[5-6],进而通过影响神经可塑性发挥其调节抑郁的作用[7]。饮食中ω-3多不饱和脂肪酸的摄入增加也能增加脑内的多巴胺能系统水平[5]。ω-3多不饱和脂肪酸的摄入减少可使腹侧纹状体和额叶皮层的D2多巴胺受体表达减少和伏隔核的D2受体表达增加[8]。另外,ω-3多不饱和脂肪酸水平或ω-6/ω-3脂肪酸平衡和多巴胺能之间的平衡关系也能影响抑郁的发生与发展[9]。BDNF与cAMP响应元件结合蛋白(CREB)是调节突触传递的重要神经营养因子。ω-3多不饱和脂肪酸能提高BDNF和CREB的表达水平来维持神经元功能和可塑性[10]。脑内ω-3多不饱和脂肪酸的减少可以减少脑内BDNF和CREB的表达进而影响抑郁的进程[11]。此外,ω-3多不饱和脂肪酸及其衍生物是炎症反应的调节剂,其可以降低大脑中促炎性细胞因子TNF-α,IL-6和IL-1β的表达[12]。有研究表明,在慢性应激的动物抑郁模型中,补充ω-3多不饱和脂肪酸可以改善神经胶质过度激活和BDNF下调,进而改善机体炎症反应,发挥对抑郁的保护作用[13]。ω-3多不饱和脂肪酸的缺乏还可以激活HPA轴,导致皮质神经元萎缩、血浆皮质酮水平升高和抑郁行为[14-15]

1.2 鞘脂参与抑郁发生发展的机制

在中枢神经系统中,神经鞘磷脂大量存在于神经纤维的髓鞘中。神经鞘磷脂在鞘磷脂酶的作用下分解为神经酰胺(ceramide)和磷酸胆碱。鞘磷脂酶家族中的酸性鞘磷脂酶在免疫和应激反应中起重要作用。研究表明氧化应激能够增加酸性磷酸酯酶的活性,而氧化应激的增强是抑郁症的重要发病机制之一[16]。酸性磷酸酯酶的激活可以增加IL-1β和IL-6的释放,进而促进抑郁的发生[17-18]。海马中酸性鞘磷脂酶活性的增高能够产生更多的神经酰胺,神经酰胺的增加则降低了神经发生、神经元成熟和神经元的存活,从而促进了抑郁的发生[19]。神经酰胺还可通过激活血清磷脂酶A2的活性导致神经元网络的失衡从而影响抑郁症的发生[20]。酸性鞘磷脂酶/神经酰胺通路(ASM-ceramide pathway)还可激活HPA轴影响抑郁的发生与发展。酸性鞘磷脂酶/神经酰胺通路的激活可能增加IL-1β,IL-6和TNF-α等炎性因子的活性进而影响抑郁的发生与发展[21]。氧化应激和炎症应激增加导致酸性鞘磷脂酶的过度激活可以增加神经酰胺的含量从而直接或间接致使HPA轴的失调,从而影响抑郁的发生发展[22-23]

1.3 胆固醇参与抑郁进程的机制

大脑是胆固醇含量最高的器官,含量占人体总胆固醇的25%。脑内胆固醇主要存在于神经元和神经胶质细胞中, 是中枢神经系统突触和树突形成所必需的。胆固醇含量减少可导致突触和树突棘变性,神经传递失败和突触可塑性降低。大脑突触膜胆固醇含量减低可减少5羟色胺受体数量而影响抑郁的进程[24-25]。Sun S等[26]在抑郁模型大鼠内侧前额叶皮层中预先注射5-HT1A受体拮抗剂WAY100635可以阻止胆固醇对抑郁行为反应的治疗作用。这表明胆固醇可能是通过在内侧前额叶皮层中调节大脑5-羟色胺系统发挥作用的。高胆固醇膳食导致抑郁行为可能与toll样受体4(toll-like receptor 4, TLR4)基因和蛋白质的脑内过表达有关。胆固醇及其相关分子的氧化衍生物作为肝X受体(LXR)的脑内内源性配体调节中脑多巴胺神经元的发育[27]。脑内胆固醇的分解产物羟基胆固醇在神经系统疾病中有重要意义,其涉及到突触可塑性或细胞信号的改变。24S-羟化酶(CYP46A1)的过表达会增加发育中脑中24S-羟基胆固醇水平,24S-羟基胆固醇作为LXR的配体与LXR结合而导致中脑多巴胺能神经发生的增加,并且可能影响突触的维持而参与抑郁的进程[25]

1.4 磷脂参与抑郁发生发展的机制

近年来,越来越多的研究表明磷脂在抑郁症的发生发展过程中起着重要作用。许多学者在抑郁症患者和慢性应激(抑郁)模型大/小鼠海马内发现了磷脂代谢异常[28-29]。慢性应激在大脑中引起氧化应激反应,氧化应激反应会改变大脑的磷脂含量,从而引起抑郁行为[30]。磷脂酶A2(PLA2)从膜磷脂中释放出花生四烯酸(AA),AA在人体的细胞信号传导中起主要作用。研究表明AA参与了抑郁的生理和病理过程[31-32]。其中,前列腺素E2与抑郁症的发病十分密切。PGE2是在脑血管中合成的,可以介导外周血中促炎细胞因子作用于脑实质神经元网络进而导致抑郁的发生[33]。另外,PGE2-EP1信号可介导前额多巴胺能反应的减弱,从而导致由反复的社交失败压力引起的抑郁行为[34]。PGE2-EP1信号传导通过至少部分抵消多巴胺D1受体在额叶皮层中的抗抑郁作用,在慢性应激后诱发抑郁行为。除了PGE2,PGD2也参与了抑郁的发病进程。CRTH2(也称为DP2)是PGD2的受体,对于慢性皮质类固醇治疗引起的抑郁行为至关重要[35]。CRTH2的基因缺失或对其拮抗剂的全身治疗可改善抑郁症的行为。

综上所述,脑内的脂质不仅是中枢神经系统的重要组成成分,还具有维持中枢神经系统保持正常水平的功能。脑内脂质代谢的紊乱可能通过影响多巴胺能系统、HPA轴的活性、脑源性神经营养因子和炎性因子等参与抑郁的发病进程。

2 与脑内脂质代谢相关的抗抑郁药物

目前抑郁症的一线治疗用药主要包括选择性5-羟色胺再摄取抑制剂(selective serotonin reuptake inhibitors, SSRIs)、5-羟色胺和去甲肾上腺素再摄取抑制剂(serotonin-norepinephrine reuptake inhibitors, SNRIs)和三环类抗抑郁药(tricyclic antidepressants, TCAs)等。其中以氟西汀(fluoxetine)为代表的SSRI在临床上应用最为广泛。氟西汀和阿米替林(amitriptyline,TCA)可降低海马体中ASM活性和神经酰胺浓度,增加神经元增殖,成熟和存活,并改善应激性抑郁症小鼠模型的抑郁行为[21]。另外,氟西汀治疗增加了抑郁模型大鼠脑前额叶外皮的CB1受体密度[36]。帕罗西汀(paroxetine)和地昔帕明(desipramine,TCA)可通过神经鞘氨醇通路发挥抗抑郁作用[37]。地昔帕明还可导致海马和下丘脑中大麻素CB1受体的密度显著增加[38]。强心百乐明(tranylcypromine, 单胺氧化酶抑制剂)能够显著降低大鼠前额叶皮层、海马和下丘脑内的内源性大麻素AEA的含量,增加前额叶皮层的2-AG的含量,还可以显著增加前额叶皮层和海马中CB1受体的结合密度[36]

中医药是治疗复杂疾病的有效途径之一。逍遥散可以增加慢性温和不可预知应激(CUMS)模型大鼠海马分泌型磷脂酶(PLA2G5)表达水平,PLA2G5能催化脂蛋白和细胞膜上甘油磷脂分子的Ⅱ位酰基酯键水解形成脂肪酸和溶血磷脂进而广泛参与细胞内生物学途径,发挥其对慢性应激损伤模型大鼠的保护作用[39]。Ganança等[40]使用富含多不饱和脂肪酸的鱼油治疗抑郁症,结果发现血浆中的DHA可能是鱼油发挥抗抑郁作用的主要途径,并且抗抑郁作用可能取决于EPA转化为DHA的效率。越来越多的证据表明,饮食中缺乏ω-3多不饱和脂肪酸可能有助于情绪障碍的发展,补充ω-3多不饱和脂肪酸为抑郁症提供了一种新的治疗选择[41]

以上研究表明抗抑郁药物能够通过调节抑郁患者脑内脂质代谢发挥抗抑郁作用。因此,调节脑内脂质代谢紊乱可能是未来治疗抑郁症的新思路。

3 结语

迄今为止,抑郁症的治疗主要是基于单胺类神经递质假说,因此SSRI成为最广泛使用的药物。随着世界范围内抑郁症发病率的上升,目前常规一线抗抑郁药疗效有限且不良反应多,人们对新疗法的需求日益增加。近年来,研究者越来越关注脑内脂质代谢紊乱与抑郁之间的联系。深入研究脑内脂质代谢紊乱在抑郁的发生发展中的作用,将为发现抑郁症发病的新机制和药物治疗新靶点提供契机。

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文章信息

杨文山, 王一晨, 王元博, 李夏, 王超臣, 胡园
YANG Wenshan, WANG Yichen, WANG Yuanbo, LI Xia, WANG Chaochen, HU Yuan
脑内脂质代谢在抑郁症发生发展中作用的研究进展
Study progress on the role of brain lipid metabolism in the development of depression
大连医科大学学报, 2022, 44(3): 239-243.
Journal of Dalian Medical University, 2022, 44(3): 239-243.
通信作者
胡园,副研究员。E-mail:huyuan1980619@126.com.
基金项目
国家自然科学基金项目(81573876, 81973502)

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