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密闭环境中人体可能产生诸多心理、生理上改变,如电梯故障被困、地震后掩埋、空间站、载人飞船、潜艇作业等。这主要与密闭特殊环境有关,如通风较差使空气质量下降,缺少正常光照或仅有人工光照导致节律紊乱,活动量大大减少引起机体功能下降等。同时密闭环境作为特异性应激源会对心理造成极大影响,如感觉剥夺、睡眠障碍、情绪功能失调、认知功能受损、内分泌失调、代谢失调等[1],大大影响了工作效率和生活质量。本文综述了密闭环境影响脑功能的机制、模型建立、评价指标及治疗的潜在药物,以期为密闭环境中脑功能维持提供有效干预措施。
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对密闭环境引起的脑功能下降,以对症治疗为主,主要包括抗抑郁、抗焦虑药物和改善认知能力药物(表1)。除了常见的选择性5-羟色胺再摄取抑制剂(SSRIs)用作抗抑郁、抗焦虑外,天然药物在治疗抑郁症、改善认知方面也显示出广阔前景[22] ,如肉苁蓉、薰衣草、西番莲、藏红花、黑升麻、洋甘菊和荆芥等[23],赖氨酸和镁离子、维生素也具有镇静、保持清醒、治疗焦虑等疗效[24]。
表 1 已上市的改善认知障碍药物
种类 名称 胆碱酯酶抑制剂 加兰他敏、多奈哌齐 兴奋性氨基酸受体拮抗剂 盐酸美金刚 麦角碱类药物 二氢麦角碱、尼麦角林 神经营养剂 叶酸、维生素B12、B1 抗氧化剂 银杏叶片、维生素E、C 中药制剂 苁蓉总苷胶囊 除用药物改善脑功能增强认知外,还可通过调节合理的饮食结构来增强认知能力,如控制好脂肪和糖的摄入,对增强认知能力有很好的辅助作用。
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脑中5-HT的水平是决定抑郁情绪的关键因素,当5-HT水平较低时会导致抑郁、焦虑等负面情绪出现。几十年来,SSRIs一直作为抑郁、焦虑治疗的一线用药,常见的有氟西汀、帕罗西汀、舍曲林、氟伏沙明、西酞普兰等,通过选择性抑制中枢神经系统突触前神经元对5-羟色胺的再摄取,提高突触间隙5-羟色胺浓度而发挥抗抑郁作用以及缓解焦虑情绪的作用[25]。服用SSRIs后,缺乏5-HT自身受体的小鼠腹侧海马体中5-HT水平增加,焦虑样行为减少。SSRIs的出现是精神类疾病治疗的一大突破,相比于其他药物它的副作用得到了极大的改善。
虽然SSRIs对抑郁症状有改善,但治愈率较低,复发风险较高。此外,大多数抗抑郁药物会产生一些不良反应,如抗胆碱能作用、直立性低血压、心律失常和性功能障碍等[26];同时还可能存在起效延迟、耐受性、滥用(如苯二氮䓬类、普瑞巴林)等问题。密闭空间所致的焦虑、抑郁等情绪问题多数程度较轻,治疗药物选择原则为有效、毒性小、不良反应少、尽量减少药物戒断反应。
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哌醋甲酯是一种拟交感神经药物,在中枢神经系统中与儿茶酚胺竞争大脑前额叶皮层的结合位点,阻断多巴胺和去甲肾上腺素转运体,导致突触细胞外多巴胺和去甲肾上腺素水平升高而发挥改善注意力和认知能力的作用[27]。哌醋甲酯用于治疗注意缺陷障碍和发作性睡病已有数十年,近年也被用于增强认知和作为兴奋剂,但不规范使用会引起急性中毒和死亡[28]。所以应密切监控哌醋甲酯及其类似物用于治疗认知障碍。
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吡拉西坦及其类似物是大脑功能调节剂,可用于治疗认知障碍和中枢神经系统疾病[29],如认知/记忆下降、癫痫和癫痫发作、神经退行性疾病、中风、脑缺血、压力过大和焦虑[30]等。它与脑中目标受体结合后,可调节神经递质、神经激素和/或突触后信号的兴奋和/或抑制过程,影响信号传输,最终改善认知。吡拉西坦能增加大脑中氧气利用率,并增加细胞和线粒体膜对三羧酸循环中间物的通透性[31]。俄罗斯已批准苯吡拉西坦作为治疗脑血管病、抑郁症、冷漠、注意力和记忆力下降的处方药,建议宇航员在太空中可用于提升生理和认知能力。
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镁对人的情绪稳定具有重要作用,包括改善躁狂症、快速循环型双相情感障碍、慢性疲劳综合征等[32]。低镁血症会增加啮齿类动物抑郁行为,提升小鼠焦虑状态;而适量补充镁可降低焦虑相关行为[33]。镁与维生素B6联用可提高焦虑、抑郁等情绪问题的治疗效果[34]。镁对情绪调节作用可能基于镁能调节下丘脑-垂体-肾上腺轴,继而调节应激反应而改善焦虑状态。
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藏红花中主要生物活性化合物包括番红花醛、番红花苷和苦红花苷[35],具有抗氧化、抗肿瘤、记忆增强、神经保护、心脏保护、抗焦虑和抑郁、调节情绪等药理作用[36]。其抗抑郁作用与氟西汀、丙咪嗪和西酞普兰等相当,主要来源于藏红花柱头中的抗氧化成分藏红花苷[37]。藏红花是治疗轻度焦虑和抑郁的有效药物。
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薰衣草被广泛应用于植物疗法和芳香疗法,以治疗中枢神经系统紊乱,如焦虑,压力和睡眠障碍。薰衣草精油的抗躁动和抗抑郁作用可能部分归因于两种主要萜类成分——芳樟醇和乙酸芳樟醇。这两种萜类成分可通过抑制电压门控钙通道、降低5-羟色胺受体活性、增加副交感神经张力、对NMDA受体的调节作用以及对5-羟色胺转运蛋白的抑制而产生抗焦虑作用[38],薰衣草精油还能保护SH-SY5Y细胞免受过氧化氢引起的神经毒性[39]。吸入给药的薰衣草精油通过嗅球途径调节杏仁核和海马中与情绪和记忆相关的边缘输入。
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西番莲曾被用作抗焦虑剂、抗躁动药物等。西番莲提取物中含有神经保护次生代谢物,可减轻癫痫小鼠癫痫发作的严重程度、改善认知功能障碍和抗氧化应激,改善脑功能,提高学习和记忆能力[40]。一项双盲安慰剂对照研究比较了奥沙西泮和西番莲在符合一般焦虑症标准的患者中的疗效差异[41]。结果显示两种抗焦虑药在治疗一般焦虑症方面没有差异。西番莲组受试者认知损伤表现低于阳性药组,但阳性药受试者症状缓解更快。西番莲作为一种药食同源的药物可用于治疗轻度焦虑和抑郁。
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贯叶连翘又名圣约翰草,主要成分为金丝桃素和贯叶金丝桃素,它能以非竞争性协同方式影响多种神经递质,具有促智作用,被认为是一种抗抑郁和抗焦虑剂。与其他抗抑郁药类似,贯叶连翘可抑制再摄取单胺类神经递质(5-羟色胺、去甲肾上腺素和多巴胺),增加海马、下丘脑、杏仁核和前额叶皮质等脑区细胞外空间中5-羟色胺和其他单胺类物质的浓度[31]。上述区域中5-羟色胺上调可减少影响记忆的负面因素。贯叶连翘对健康啮齿动物的认知能力有积极影响,对应激受损啮齿动物的影响更大。因此,贯叶连翘除用于治疗抑郁症外,也可用于改善认知障碍[27]。
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丹参中主要含有姜黄素、咖啡酸、丹酚酸、香豆素、紫草酸、黄酮类化合物(木犀草素、芹菜素、槲皮素)熊果酸等大量活性成分,对记忆、注意力和学习在内的认知能力有明显提升,可用于预防神经退行性疾病(如阿尔茨海默病)[42]。丹参精油提取物和丹参叶提取物对空间记忆的改善有显著作用。两种提取物的组合使用可以提高长期记忆。丹参的慢性作用机制可能与蛋白激酶的调节有关,蛋白激酶参与记忆和学习过程,它涉及到许多神经元功能的形成,尤其是神经递质代谢、神经元信号转导(离子和通道活性)、突触可塑性等。为了确定丹参在神经元功能中的作用,具体的通路还有待阐明,丹参改善认知等的相关作用机制还需进一步研究调查。研究发现,使用丹参提取物后小鼠在Morris水迷宫中实现任务和执行任务的能力得到提升[43],事实表明丹参是一种潜在的避免记忆丧失或提高认知能力的药物。
此外,我们要重点关注饮食对认知能力的影响。血糖生成指数低的食物能提高注意力、记忆和认知能力,而摄入大量富含单糖的食物则易导致注意力难以集中[44]。大脑需要连续不断的氨基酸来合成神经递质,特别是血清素和儿茶酚胺。低水平血清素与学习、推理、记忆能力下降有关。膳食脂肪含量和类型也会影响智力。高饱和脂肪的摄入会导致认知能力下降,而多不饱和脂肪酸(如二十二碳六烯酸)的摄入能预防认知能力下降。补充Omega-3和姜黄素已被证明对健康老年人和疾病状态认知功能下降有积极的改善作用,可提高记忆能力并降低认知功能退化。维生素B1、B6、B9、B12和D,叶酸、胆碱、铁、碘能发挥神经保护作用,改善脑功能。与此同时,抗氧化剂(如维生素C、E、A、锌、硒、叶黄素和玉米黄质等)在防治与氧化应激有关的精神退化和提高认知能力方面具有重要作用。合理的、充分的营养是优化大脑功能和防止认知衰退的必要条件[45]。
Effect of the insulated environment on brain function and its therapeutical drugs
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摘要: 长期密闭环境(如地震后掩埋、电梯故障被困等)可通过影响神经可塑性和神经递质来影响情绪,而不良情绪又会干扰和影响正常认知。药物可干预焦虑、抑郁等密闭环境引发的情绪问题、增强认知,对抗密闭环境对脑功能的影响。在有效药物筛选过程中,需首先建立密闭环境脑功能障碍动物模型,采用Morris水迷宫、Barnes迷宫等来评价认知、学习记忆能力和情绪。其中藏红花、薰衣草、西番莲、镁离子等显示出抗焦虑、抗抑郁的优良效果;哌醋甲酯及其类似物、吡拉西坦、贯叶连翘、丹参等能增强认知的药物可用于对抗密闭环境所致的注意力不集中、记忆力衰退等认知障碍,适用于密闭环境所致的轻症情绪问题。阐明密闭环境作用机制、寻找更多有效药物可为长期密闭环境导致脑功能下降提供更有效的解决方案。Abstract: The long-term insulated environment (such as burial after earthquakes, trapped elevators, etc.) can affect emotion by affecting neural plasticity and neurotransmitters, while the bad emotions can further affect normal cognition. Drugs can intervene the emotional problems induced by the insulated environment, such as anxiety and depression, and enhance cognitive ability, the negative influence on brain function induced by the insulated environment can be prevented or alleviated. First, the animal model of brain dysfunction in the insulated environment should be established. The cognitive, learning and memory ability can be evaluated by Morris water maze, Barnes maze, etc. The therapeutic drugs mainly include anti-depression/antianxiety drugs and cognition-improving drugs. Saffron, lavender, passion flower and magnesium ion, have shown good anti-anxiety and anti-depression effects and are suitable for the treatment of emotional problems caused by the insulated environment. Methylphenidate and its analogues, piracetam, hypericum perforatum, and salvia officinalis that can enhance cognition can also be used to prevent and treat cognitive disorders such as inattention and memory decline caused by the insulated environment. Elucidating the mechanism of closed environment and finding more effective drugs can provide a more effective solution to the decline of brain function caused by long-term closed environment..
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Key words:
- insulated environment /
- cognition ability /
- anxiety /
- depression
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表 1 已上市的改善认知障碍药物
种类 名称 胆碱酯酶抑制剂 加兰他敏、多奈哌齐 兴奋性氨基酸受体拮抗剂 盐酸美金刚 麦角碱类药物 二氢麦角碱、尼麦角林 神经营养剂 叶酸、维生素B12、B1 抗氧化剂 银杏叶片、维生素E、C 中药制剂 苁蓉总苷胶囊 -
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