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褪黑素改善认知作用研究进展

更新时间:2021-04-16 08:37点击:

  摘    要:
  
  对褪黑素改善认知作用的研究进展进行综述,为褪黑素的进一步开发利用提供科学依据。
  
  关键词:
  
  褪黑素 老年认知障碍 轻度认知障碍
  
  Research Progress on Melatonin Improving Cognitive Function
  
  MA Cong-cong WANG Zi-ping XU Ji-qu
  
  Oil Crops Research Institute of Chinese Academy of Agriculture Sciences/Hubei Key Laboratory of Lipid Chemistry and Nutrition/Key Laboratory of Oilseeds Processing,Ministry of Agriculture and Rural Affairs; School of Public Health,Wuhan University of Science and Technology;
  
  Abstract:
  
  This paper reviewed the cognitive effects of melatonin to provide scientific reference for the further development and utilization of melatonin.
  
  Keyword:
  
  melatonin; aging-induced cognitive impairment; mild cognitive impairment;
  
  研究表明,褪黑素有神经保护作用[1-3]。褪黑素是哺乳动物必需氨基酸-色氨酸的衍生物[4]。褪黑素在植物中广泛存在,植物中的褪黑激素水平似乎远远高于在动物血清中测得的浓度[5]。在哺乳动物海马中,褪黑素及其受体的异常水平与衰老相关的疾病老年痴呆症和帕金森氏病等有关[6]。并且,利用外源性褪黑素可以显著改善这些疾病的症状[7-8]。褪黑素改善认知作用与其物理化学结构相关。基于结构-活性关系的分析表明,褪黑素分子的吲哚部分由于其高的共振稳定性和对自由基反应的非常低的活化能垒而成为与氧化剂相互作用的反应中心[9-10]。甲氧基具有亲脂性和促氧化潜力,阻止褪黑素表现出前氧化活性,酰胺侧链N-C=O结构有利于新五元环的形成[11]。与经典的抗氧化剂不同,褪黑激素没有前氧化活性,并且褪黑激素与反应性物质相互作用产生的所有已知中间体也是自由基清除剂[9],该现象被定义为褪黑激素家族的自由基清除级联反应。由于这种级联作用,1个褪黑激素分子具有清除多达4个或更多反应性物质的潜力,这使得褪黑激素作为抗氧化剂非常有效。褪黑素可清除各种活性氧和氮[12],研究表明,褪黑素对于老年认知障碍、异氟烷诱导的认知障碍、轻微认知障碍和缺氧引起的认知障碍等的治疗和预防都与其抗氧化功能密切相关。老年认知障碍是神经衰老导致的神经变性和神经损伤。褪黑素及其代谢产物可作为自由基清除剂防止衰老,同时抑制自噬、调节胰岛素信号通路和炎症信号通路改善老年认知障碍。对于麻醉相关的神经毒性,褪黑素能够有效地预防和治疗异氟烷引起的脑损伤。同时,褪黑素对于轻度认知障碍(MCI)和缺氧引起的认知障碍也具有一定的治疗效果。
  
  1 老年认知障碍
  
  褪黑素及其代谢产物可作为自由基清除剂防止衰老。褪黑素合成中涉及的酶、代谢物和受体的水平在衰老过程中降低,从而导致老年人中褪黑激素的水平较低。胰岛素、类胰岛素生长因子1 (IGF1)和类胰岛素生长因子2 (IGF2)促进MAPK/ERK途径,激活蛋白激酶(AKT)[13]。AKT激活哺乳动物雷帕霉素靶标(m TOR)和自噬,褪黑素对自噬具有抑制作用[14]。哺乳动物褪黑激素受体MT1 (Mel1a)和MT2 (Mel1b)是G蛋白偶联受体,在激活过程中与G蛋白偶联[15]。MT1和MT2表达随着年龄的增长而降低[16]。随着年龄的增长,褪黑激素通过MT1抑制小鼠神经干细胞中CREB磷酸化[17-18]。衰老过程中,除胸腺外,胸外组织(肝脏、脾脏、肾脏和心脏)的MT1和MT2 mRNA水平显著降低[6]。在下丘脑中,与年龄相关的神经退行性疾病中MT2水平降低[19]。老年人中褪黑素代谢产物的分泌下降[20]。与褪黑素从生产到降解的途径相似,褪黑素受体随着年龄增加相关的功能显著下降,这种下降可能导致衰老过程中褪黑激素水平的降低。神经系统和非神经系统的正常和病理性衰老所涉及的机制也可能导致这种减少。β-淀粉样蛋白(Aβ)积聚和神经纤维缠结以及缩短和高度磷酸化的TAU蛋白是老年痴呆症的神经病理学特征。褪黑素治疗可恢复高脂饮食老年大鼠脑胰岛素信号传导障碍[21]。褪黑素阻止高脂诱导的海马Aβ积累和TAU磷酸化增加,改善海马神经炎症,减轻高脂大鼠氧化应激,并恢复海马中的CREB活动和BDNF水平以及神经元活动。烟酰胺单核苷酸和褪黑激素通过调节额叶皮层和海马中的线粒体功能和凋亡来减轻衰老引起的认知障碍,能够显著降低前额皮质和海马的ROS水平,提高其线粒体膜能力和ATP水平[22]。
  
  2 对异氟烷诱导的认知障碍
  
  麻醉相关的神经毒性对发育中的大脑的影响,包括氧化应激,突触形成受损,甚至是长期的行为障碍[23-26]。褪黑素治疗可有效地恢复异氟烷致海马损伤大鼠海马结构和功能的损害。异氟烷暴露早期,引起线粒体形态改变。Bei Li等[27]证明,褪黑素能够预防和治疗异氟烷引起的海马损伤。γ-氨基丁酸(GABA)是大脑中的抑制神经递质。异氟烷能增强大脑的GABA受体的功能,从而起到麻醉作用[28],但是麻醉过程会对神经元以及突触内环境造成干扰,引起细胞凋亡,进而产生认知障碍。一些研究声称,异氟烷可以在血液中产生不同数量的三氟乙酸,从而诱导细胞毒性[29]。另有研究认为,麻醉会破坏体内氧化和抗氧化的平衡。氧化应激与保护机制之间的平衡是通过复杂的细胞生理学维持的,如果打破平衡,则会产生异常的氧化还原稳态,从而导致病理变化[30]。
  
  氧化应激在哺乳动物大脑发育中对麻醉剂引起的神经元变性起重要作用[31]。根据以前的研究,异氟烷可以显著增加ROS的积累[32]。某些酶(如SOD、GSH和MDA)可以对氧化剂和抗氧化剂产生响应。SOD和GSH可以减少源自氧的自由基对细胞的损害[33]。褪黑素显著降低了ROS和MDA的水平,并显著增加了SOD和GSH的活性。这表明褪黑素可以通过上调抗氧化酶的表达来清除活性氧,以保护海马。结合病理结果表明褪黑素可以明显减轻神经元细胞的病理损伤,我们证明褪黑素具有缓解异氟烷引起的海马氧化应激的能力。因此,结果表明减少ROS的积累可能是在异氟烷吸入过程中保护脆弱组织的有效方法。
  
  Nrf2在蛋白激酶C (PKC)中启动,它在氧化应激反应中起着关键作用[34-35]。在氧化应激条件下,Nrf2被PKC磷酸化,然后诱导HO-1和其他抗氧化酶(如SOD和GSH)的转录激活[35-37]。在我们的研究中,蛋白质印迹的结果表明褪黑激素可以激活PKCα/Nrf2信号传导途径发挥抗氧化作用。同时,褪黑素显著增加了核Nrf2表达并过表达HO-1。这些结果证明褪黑素不仅增加了Nrf2的表达,而且还促进了其在核部分的积累。Nrf2在Neh2结构域与Keap1结合后通过泛素-蛋白酶体途径降解[38],而PKC磷酸化Nrf2使Nrf2与Keap1分离,从而发挥生物学作用[39]。另有研究表明,PKCα使Nrf2磷酸化,导致Nrf2易位至细胞核[40]。总之,褪黑素可以激活PKCα/Nrf2信号通路,促进Nrf2的核转运,并诱导Nrf2下游的抗氧化酶HO-1的表达,从而减少异氟烷引起的氧化应激和随后的海马损伤。
  
  围手术期神经认知障碍指手术和麻醉后导致的认知障碍,尤其是老年患者更容易产生围手术期神经认知障碍[41]。围手术期神经认知障碍影响学习、记忆、注意力和语言理解能力等认知功能,增加患者死亡率[42]。Hui Yuan等[43]采用C57小鼠2%异氟烷吸入4 h造围手术期神经认知障碍。研究表明,褪黑素和雷帕霉素显著改善了异氟烷引起的认知障碍,并导致褪黑素水平以及海马中TNF-α、IL-1β、IL-6、p-m TOR的表达水平下降。但并未阐明褪黑素使m TOR失活的机制,可做进一步研究。高龄是术后认知功能障碍的重要独立危险因素。在年轻小鼠中,觉醒节律与异氟烷引起的记忆障碍有关。长期异氟醚麻醉可导致衰老小鼠的记忆缺陷和昼夜节律紊乱进一步加剧和延长[44]。褪黑激素已被认为是昼夜节律转变的有效疗法。在老年小鼠中,在麻醉前连续7d每天以10μmg/kg剂量的褪黑激素进行预处理。我们发现,褪黑激素可通过时钟基因重新同步来恢复运动活动和温度昼夜节律,从而预防异氟烷引起的认知障碍。所以,褪黑素可以通过昼夜节律性重新同步来预防异氟烷引起的认知障碍[45]。
  
  褪黑素通过海马褪黑素受体2-c AMP反应元件结合信号传导减弱老年大鼠中异氟烷引起的认知障碍[46]。褪黑素减弱了异氟烷诱导的老年大鼠血浆/海马褪黑激素水平下降和认知障碍[47]。褪黑激素2受体(MT)在昼夜节律紊乱、阿尔茨海默氏病(AD)和其他神经系统疾病中起关键作用。c AMP反应元件结合(CREB)是记忆形成的重要转录因子。MT拮抗剂4P-PDOT阻止了褪黑素对异氟烷诱导的海马MT表达下降和下游CREB磷酸化的保护作用。而4P-PDOT阻止了褪黑素对异氟烷引起的记忆障碍的衰减作用。所以,海马MT-CREB信号传导可能是麻醉药引起的认知障碍的潜在治疗靶点。NR2B-CREB信号通路在该过程中也起着关键作用[48]。但有研究表明,选择不同的时间点麻醉大鼠,异氟烷在白天或晚上均未显著改变褪黑激素水平,地氟醚麻醉则会在白天改变褪黑激素水平[49]。
  
  褪黑素的预先用药减轻了异氟烷麻醉引起的老年大鼠海马中Aβ生成和胆碱能功能障碍[50]。全身麻醉药在发育中的大鼠大脑的许多区域引起广泛的凋亡神经变性。线粒体依赖性凋亡途径的激活在麻醉诱导的发育性神经细胞凋亡的早期阶段很重要。褪黑素可通过改善线粒体体内稳态并稳定线粒体内膜来抑制凋亡型神经元损害。褪黑激素诱导的神经保护作用至少部分是通过抑制线粒体依赖性细胞凋亡途径介导的,因为褪黑激素引起抗凋亡蛋白bcl-X的上调,麻醉诱导的细胞色素c释放减少进入细胞质并减少麻醉诱导的caspase-3活化,这是DNA酶活化和凋亡小体形成的重要步骤[51]。
  
  3 轻度认知障碍
  
  一些MCI患者似乎随着时间的推移保持稳定或恢复正常,但在5年内进展为AD的比例超过一半[52]。MCI患者睡眠周期紊乱,褪黑素分泌时间提前[53]。MCI老年人在补充含有褪黑激素和色氨酸的DHA磷脂油性乳剂12周后,在认知功能方面有了显著改善[52,54]。De Butte M等[55]采用大鼠颈动脉结扎模型模拟MCI模型,褪黑激素治疗可减轻动脉结扎导致的CA1海马神经元的衰减,并增强视觉记忆。
  
  4 缺氧引起的认知障碍
  
  全球范围内每年死亡的360万个新生儿中几乎有1/4是窒息死亡[56]。褪黑素减轻了新生儿缺氧缺血性脑病的氧化应激,减少了病儿癫痫发作和白质异常[57]。新生仔猪低温缺氧模型表明褪黑素增加了全脑磁共振波谱的核苷酸三磷酸/可交换磷酸盐池的水平。与单独的体温降低相比,体温降低加褪黑素组的TUNEL阳性细胞核减少,丘脑中的caspase 3裂解减少。尽管在灰色或白色物质中小胶质细胞总数没有减少,但是缺氧缺血后48 h皮质中典型的细胞毒性小胶质细胞活化标记CD86的表达减少了[58]。所以,褪黑素治疗能安全有效地改善新生儿脑病。
  
  5 展望
  
  褪黑素能够对衰老、麻醉剂、MCI和缺氧等认知障碍有预防和治疗作用。褪黑素能够减轻氧化应激,减少氧化应激引起的细胞损伤。同时降低细胞炎症,降低脑组织炎症因子表达。另外,通过调节胰岛素信号通路和抗凋亡作用起到神经保护作用。褪黑素作为神经保护剂未来的研究可能重点关注以下几个方面:(1)褪黑素抗氧化机理相关的信号通路以及抗氧化酶基因表达;(2)褪黑素抗炎作用相关机制研究;(3)褪黑素作用于胰岛素信号通路机制研究;(4)褪黑素抗神经细胞凋亡作用信号通路研究。关于褪黑激素治疗,仍有许多问题亟待解决。对于这些问题的研究将为褪黑素在医学、食品、保健等领域的未来提供重要的依据。
  
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