Research progress on the chemical composition and antidepressant mechanism of volatile oils of traditional Chinese medicine
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摘要:
抑郁症是一种由多种复杂原因引起的患者情绪低落和认知功能障碍的精神疾病。临床上抗抑郁药具有良好的短期疗效,但长期服用存在较多不良反应以及耐药性等问题。挥发油是以单萜和倍半萜为主的小分子化合物,大多具有芳香气味、易于透过血脑屏障和不良反应小的特点。中药挥发油通过调节神经单胺递质、下丘脑—垂体—肾上腺轴、脑源性神经营养因子、神经炎症和氧化应激、肠道菌群—肠—脑轴等机制,多途径多靶点发挥抗抑郁作用。本文总结中药挥发油抗抑郁主要化学成分、药理作用机制及临床应用,旨在为中药挥发油的进一步开发和临床应用提供参考。
Abstract:Depressive disorder is a mental illness characterized by poor mood and cognitive dysfunction caused by a range of complicated factors. Antidepressants have strong short-term efficacy in clinical application, yet with significant adverse effects and resistance in long-term use. Essential oils are small molecular compounds mainly composed of monoterpenes and sesquiterpenes, most of which are characterized by aromatic odors, easy permeability through the blood-brain barrier, and low toxic side effects. Volatile oil from traditional Chinese medicine can regulate neurotransmitter monoamine, hypothalamic-pituitary-adrenal axis, brain-derived neurotrophic factor, neuroinflammation and oxidative stress, and intestinal microbiota-gut-brain axis to exert an antidepressant effect through multiple pathways and targets. This review summarizes the main antidepressant chemical components of essential oil of traditional Chinese medicine, their pharmacological mechanisms and clinical application, aiming to provide some reference for further development and clinical application of essential oil of traditional Chinese medicine.
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Keywords:
- volatile oil /
- antidepressant /
- active ingredient /
- mechanism of action
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透明质酸(hyaluronic acid, HA)是由N-乙酰氨基葡萄糖(N-acetyl-glucosamine, GlcNAc)和D-葡萄糖醛酸(D-glucuronic acid, GlcUA)通过β-1,4糖苷键交替连接而成的高分子线性糖胺聚糖。HA在生理条件下荷高负电,具高极性、可高度水合等聚电解质特性[1]。当HA的主链基团或分子量增长至一定数值,HA因分子内和分子间形成的大量氢键而呈现线团状。因此,HA具有黏弹性和剪切稀化等流变学特征[2]。除了具有良好的理化性质,HA还具有生物相容和可降解性、分化簇44(cluster of differentiation 44, CD44)靶向性、炎症调节等独特的生物学特性。因此,HA是医药研发领域的重要原材料。
然而,HA的分子内和分子间氢键易受体液稀释、蛋白、盐等复杂成分的影响。因此,未化学改性的HA经注射后难以形成稳定的凝胶[3]。此外,人类基因组含有6种透明质酸酶(hyaluronidase, HAase)。HAase通过切割GlcNAc和GlcUA之间的β-1,4糖苷键降解HA[4]。大多数组织中的主要HAase为透明质酸氨基葡糖苷酶1(hyaluronoglucosaminidase 1, HYAL-1)和透明质酸氨基葡糖苷酶2(hyaluronoglucosaminidase 2, HYAL-2)。虽然,已有文献表明HAase对HA的特异性降解作用可被用于构建基于HA骨架的、病灶靶向的尺寸可变型或触发释药型药物传递系统[5]。但是,由于血清含有大量HYAL-1,静脉注射的HA可被HYAL-1快速清除。可见HA的医药应用受限于机体的生理复杂性。
化学改性可调控HA的理化性质、增强其功能性,从而拓展其医药应用范围。但化学改性在改变HA理化性质的同时,亦可能影响其生物学特性。本综述结合HA生物学性质的产生机制、以及其衍生化方法和表征手段总结并讨论化学改性对HA生物学性质的影响,为合理的HA化学改性研究提供参考。
1. HA的生物学特性
与在高尔基体内合成的其他蛋白聚糖和糖胺聚糖不同,HA是由真核生物质膜内表面上的透明质酸合成酶(hyaluronan synthase, HAS)催化合成[6]。HAS以尿苷二磷酸-葡糖醛酸和尿苷二磷酸-N-乙酰氨基葡萄糖为原料,在细胞质内膜连续合成HA,并通过跨膜通道将新生HA挤出至胞外基质[7]。HAS1和HAS2具中等活性,负责合成高分子量透明质酸(high molecular weight hyaluronic acid, HMWHA); HAS3蛋白则具有最高活性,负责合成低分子量透明质酸(low molecular weight hyaluronic acid, LMWHA)。HMWHA和LMWHA的分子量分别大于100 kD及介于10~100 kD;而小于25个双糖单元的HA则被称为透明质酸寡糖(hyaluronan oligosaccharides, oHA)[7]。不同分子量的HA表现出截然不同的生物学特性。
1.1 受体靶向性
CD44是由单一基因编码、不同亚型表达的受体蛋白。不同亚型CD44的N端均具有两个透明质酸结合结构域(hyaluronic acid binding domain, HABD)[8]:Link结构域和BX7B基序(B代表赖氨酸或精氨酸,X7代表任意非酸性氨基酸)[9]。HA的羧基与HABD的至少两个丙氨酸残基(Ala102,Ala103)相互作用,伯羟基则与HABD的至少一个酪氨酸残基(Tyr109)相互作用[10−11]。因此,“HA-CD44”特异性结合力随HA分子量的增大而增强。CD44识别HA所介导的胞吞作用也高度依赖HA的分子量,分子量小的HA更容易被细胞内化[12−13]。虽然CD44介导HA内吞的具体机制尚未被完全解析,但是现有研究已证明脂筏参与了该内吞过程:HA结合CD44并激活脂筏相关功能,从而驱动能量依赖性的细胞膜穴样内陷[14]。HA分子量造成的内化效率差异可能与膜内陷的难易程度相关[15]。
不同分子量的HA靶向结合CD44后,可以通过不同信号通路对肿瘤起到不同的药理作用。HMWHA和oHA可抑制肿瘤生长和转移,LMWHA则加速肿瘤恶化。具体而言,HMWHA与细胞膜表面的CD44结合并导致CD44聚集,从而激活肿瘤抑制性Hippo通路以调节细胞增殖和凋亡。相反,LMWHA结合CD44并竞争性抑制“HMWHA-CD44”介导的部分缺陷1b蛋白(partitioning-defective 1b, PAR1b)募集,造成HMWHA对Hippo信号通路的激活作用被抑制。oHA则结合CD44并抑制PI3K/Akt细胞存活通路,减少磷酸化Akt对B细胞淋巴瘤-2相关死亡促进因子(B-cell lymphoma-2-associated death promoter, BAD)、叉头转录因子(forkhead transcription factor, FKHR)等的抑制作用,有效诱导肿瘤细胞凋亡[16]。
HA还可主动靶向透明质酸介导的运动受体(receptor for hyaluronan mediated motility, RHAMM)、Toll样受体2(Toll-like receptors 2, TLR2)、TLR4、淋巴管内皮透明质酸受体1(lymphatic vessel endothelial hyaluronan receptor 1, LYVE-1)、透明质酸内吞受体(hyaluronan receptor for endocytosis, HARE)和Layilin蛋白(LAYN)[9],参与多项细胞信号的传导。LYVE-1和HARE通过Link结构域结合HA[17−18]。缺乏Link结构域的RHAMM、TLR2和TLR4则通过两个规范BX7B基序与HA结合[19−21]。LAYN不仅不含Link结构域,而且含有两个可阻碍其结合HA的非规范BX7B基序。然而,LAYN仍能特异性结合HA,只是具体的结合机制尚不明晰[22−23]。
本文仅总结并讨论HA的化学改性对机制相对清晰且应用相对广泛的“HA-CD44”靶向性的影响。
1.2 炎症调节特性
HMWHA限制炎症细胞的趋化、吞噬作用以及炎症介质和裂解酶的自由运动,具抗炎特性,可促进伤口愈合[24];而LMWHA促进单核细胞转变为巨噬细胞,提高胰岛素样生长因子1(insulin-like growth factor 1, IGF-1)和白细胞介素-1β(interleukin-1β, IL-1β)的分泌水平,起促炎作用。基于HMWHA良好的黏弹性和炎症抑制能力,临床已使用关节腔注射型Hyalgan®(500~730 kD)治疗骨关节炎[25−26]。但需指出的是,HA基于分子量发生促炎、抗炎性质转变的机制尚不明确。
1.3 酶解特性
HYAL-1常见于血清、组织基质和溶酶体,可降解各种分子量的HA。HYAL-1的最适pH为3~4.5。因此,HYAL-1在溶酶体内活性最强,在pH大于4.5时其酶活力为最大效力的50%~80%。HYAL-2主要锚定于质膜表面富含CD44的脂筏区域。HYAL-2仅在低pH条件下具有酶活力,其最适pH为4[4]。HMWHA结合脂筏区域的CD44并激活Na+-H+交换蛋白,从而形成胞外局部酸性环境。随后,HYAL-2被激活并降解HMWHA至20 kD左右的分子片段。HA片段被CD44介导内吞,并于溶酶体内被HYAL-1降解为四糖。四糖最终被β-葡萄糖醛酸酶和β-N-乙酰葡萄糖胺酶降解为单糖[13,15]。
2. 不同修饰位点的化学改性和结构确证方法
HA富含羟基、羧基、酰胺基等官能团,可通过酰胺化、酯化、开环、交联等原理进行化学改性,从而制备功能化HA衍生物以扩大其应用范围[27]。HA不同修饰位点的化学改性结构式见图1。
2.1 羧基位点
酰胺化和酯化是最常见的HA羧基化学改性方式。例如,将疏水性抗肿瘤药紫杉醇(paclitaxel, PTX)的羟基与HA羧基偶联,形成两亲性高分子以提高PTX的水溶性和靶向性[28];酰肼类等双端氨基化合物可用作交联剂,基于酰胺反应促使HA形成分子内或分子间交联。Seprafilm®可吸收防粘连薄膜(隔膜)是由HA羧基和羧甲基纤维素发生酯化交联而成;Monovisc®则是由HA羧基和6-位伯羟基发生分子内酯化交联而形成的水凝胶,用于关节腔注射以缓解关节炎疼痛。此外,HA还能以四丁基铵盐的形式与烷基卤化物、甲苯磺酸酯等物质通过烷基化反应生成酯键[29]。
2.2 羟基位点
HA的6-位羟基通常与羧基类、烷基琥珀酸酐或甲基丙烯酸酐等酸酐类、酰氯等物质发生酯化反应。同时,HA的分子内交联反应同样可在6-位羟基上进行。例如,交联剂二乙烯基砜(divinyl sulfone, DVS)在室温下可与HA的6-位羟基快速反应以形成HA凝胶,且交联度可由HA的分子量和浓度、反应pH、HA/DVS质量比来控制[27]。Juvéderm® ULTRA是以1,4-丁二醇二缩水甘油醚(1,4-butanediol diglycidyl ether, BDDE)高度交联HA而形成的均质凝胶,适用于面部真皮组织中层至深层注射,以纠正中度鼻唇沟皱纹;Juvéderm® VOLIFT和Juvéderm® VOLUMA则利用BDDE交联长链和短链HA,适用于面部深层注射,因其平衡弹性和内聚力的范围更大而塑形效果更佳。
2.3 酰胺基位点
乙酰氨基经脱乙酰化可被还原为游离氨基,从而实现HA的相关衍生化。但基于硫酸肼的HA脱乙酰化反应通常需在55 ℃下进行,可使分子链严重断裂。因此,该法不属于HA的常见化学改性方式[29]。
2.4 链端开环醛基位点
HA主链糖环和末端糖环亦可经开环反应产生醛基。醛基常与伯胺类化合物生成亚胺键,亚胺键可被进一步还原为胺[30]。该法常用于构建交联凝胶。然而,开环反应可显著改变HA的骨架结构,使其主链刚性减弱而更易降解。
2.5 结构确证
红外和紫外吸收光谱法、波谱法是初步确证HA是否成功改性的主要手段。例如,HA的羧基被酰胺化后,红外光谱
1560 cm−1处可见更强的酰胺Ⅱ键特征峰[31]。1H NMR则最常用于表征HA的特征氢峰(羧基氢或6-位伯羟基氢)以确认修饰位点的结构变化。此外,高分辨率13C NMR可用于区分HA的碳原子级数(伯、仲、叔和季),从而明确解析相应碳位的原子取代情况和结构的精细变化。但是,蛋白质、多糖等大分子的结构解析常受限于严重的谱峰重叠。二维核磁共振谱可将重叠的一维谱峰展开呈现于二维平面,从而显著提高峰归属辨析的准确率[32]。分子量检测法亦在高分子结构确证中起重要的辅助作用。研究人员通常利用体积排阻色谱法分离不同分子量的HA衍生物,再以多角度激光散射仪为检测器准确测定其绝对重均分子量及分布。散射仪的散射光强度和角度变化均与HA衍生物的分子量相关。
3. 化学改性对HA生物学性质的影响
HA分子量的多分散性和改性位点的不可控性促使HA衍生物的精确结构表征和构效关系研究难度剧增[9,33]。同时,研究人员对相关领域关注不足。因此,HA衍生物构效关系的科学研究体系尚未形成。本文从受体靶向性、生物可降解性、促炎或抗炎特性、免疫原性四方面总结并讨论现有研究中的化学改性对HA生物学性质的影响和相应的研究手段。
3.1 CD44靶向性
HA的羧基及伯羟基在CD44和HABD的靶向结合过程中起关键作用。同时,已有研究指出HA至少需6个连续双糖单元才能与HABD结合[34]。因此,羧基及伯羟基位点的过度修饰可显著削弱CD44对HA的特异性识别能力[9−10]。
目前最常用于表征HA衍生物CD44靶向性的策略是荧光标记技术。例如,使用FITC标记的HA衍生物和CD44蛋白共孵育,荧光定量“HA-CD44”结合物以量化HA衍生物与受体的靶向结合力[10];或将荧光探针标记的HA衍生物与过表达CD44受体的细胞共孵育,以荧光显微镜、流式细胞仪等定性或定量胞内荧光强度,从而间接评价其对CD44的靶向性。此外,分子对接研究和结合能计算法可用于HA衍生物与天然HA的CD44靶向性质差异的深入分析。有研究者采用SwissDock和AutoDock对接软件模拟CD44对HA的识别作用[35],通过比较对接能量值分析HA化学改性对结合能的影响。
Oh等[36]将己二酸二酰肼(adipic dihydrazide, ADH)与HA羧基进行偶联,合成修饰率分别为14%、22%、45%、70%的HA-ADH偶联物。结果表明,当羧基的取代度超过25%,HA衍生物的CD44主动靶向作用显著减弱。Kwon等[11]则将降冰片烯(norbornenes, Nor)或甲基丙烯酸酯(methacrylates, Me)以酰胺键或酯键形式修饰于HA的羧基或6-位伯羟基,相关位点的取代度约为10%、20%、40%。结果表明,无论是何种修饰方式和位点,CD44与HA的结合效率都随疏水基团增多而下降;且在羧基位点修饰Nor的衍生物组的结合效率下降最为显著。此外,相比于同取代度的6-位伯羟基Nor衍生化HA,6-位伯羟基Me衍生化HA因Me的疏水性更强而具有更为紧密的疏水核心,表面暴露更多羧基,从而具有更强的CD44靶向结合能力。
3.2 生物可降解性
研究者常使用HAase生物降解实验定量分析HA衍生物的酶解抗性:即在生理条件下将HA衍生物与HAase共孵育,随后通过表征HA衍生物基本理化性质或特性参数的方式,对比评价HA衍生物的酶解抗性。目前最常用的表征手段为凝胶渗透色谱法和重量/黏度测量法,其通过测定HA衍生物在酶解前后的重均分子量大小和分布、重量、黏度等的变化来判断酶解程度[37]。
以HA为骨架的抗肿瘤药物递送系统可被肿瘤组织高表达的HYAL-1和HYAL-2降解,存在药物在胞外过早泄漏的风险。同时,胞内HYAL-1和胞膜HYAL-2对于HA的降解作用具CD44依赖性。因此,HA靶向CD44的关键结合位点(羧酸、6-位伯羟基)亦与HAase的降解活性紧密相关[10]。此外,HA化学改性所引入的基团可造成空间位阻,从而限制HAase结合HA。综上,HA羧基或6-位伯羟基的化学改性可能使HA衍生物获得HAase酶解抗性。Schanté等[38]将HA与不同大小的氨基酸通过酰胺化反应结合,获得各种HA-氨基酸衍生物(HA-amino acid derivatives, HA-aa)。与天然HA相比,HA-aa的HAase抗性显著增强;且小分子氨基酸(丙氨酸、精氨酸)改性的HA-aa相较于大分子氨基酸(苯丙氨酸、酪氨酸)改性的HA-aa酶解抗性低,证明改性基团位阻是影响HA衍生物抗酶解性的重要因素。然而,HA的过度改性,如对羧基进行全化学修饰,可导致HA衍生物不能被HAase降解。因此,HA衍生物的设计与制备需平衡其功能性和基于生物代谢的安全性。
3.3 促炎或抗炎特性
酶联免疫吸附测定法(enzyme-linked immunosorbent assay, ELISA)常用于HA衍生物的促炎或抗炎特性研究。该法首先收集巨噬细胞与HA衍生物共孵育后的培养基,而后利用ELISA测定培养基内促炎细胞因子(TNF-α、IL-6、IL-1β)和抗炎细胞因子(IL-10、IL-4)的浓度。体内抗炎实验是通过对小动物注射完全弗氏佐剂建立慢性炎症模型,而后对模型给以HA衍生物,最后以ELISA检测炎症相关因子的同时观测炎症组织的病理变化,综合评价HA衍生物的促炎或抗炎特性[39]。
现阶段HA及其衍生物促炎或抗炎特性的研究尚未深入到分子机制层面,仍仅是聚焦于HA及其衍生物的炎症调节功效:如联用HA与其他抗炎或促炎物质,实现炎症调节作用的增效;或利用HMWHA修饰具有机体炎症刺激特性的载体或物质,以减弱其炎症刺激性。目前亦缺乏相关研究深入探讨和揭示HA改性对其促炎/抗炎特性的影响和相关分子机制。
3.4 免疫原性
化学改性是否会改变HA的免疫原性亦是研究者应当关注的关键问题。免疫原性评价试验通常涉及细胞免疫和体液免疫的激活检测。淋巴细胞的增殖与分化是机体激活细胞免疫的重要过程。在HA衍生物被重复注入小鼠体内之后,取小鼠脾细胞进行体外培养,再采用Alamar Blue法测定T细胞和B细胞的增殖活力、及流式细胞术检测T、B、NK细胞亚群及比例,以综合表征HA衍生物激活机体细胞免疫的效力。体液免疫激活效力的评价通常采用ELISA测定血清免疫球蛋白IgG、IgM、IgA的浓度[40]。
化学改性造成的HA自然构象变化可能影响其免疫原性,刺激机体产生免疫应答,诱发强烈炎症反应从而造成机体损伤;激活的机体免疫亦可加速人体对HA递送系统的清除,从而限制其药效发挥[41]。但已报道的相关研究一般仅利用生物相容性HA对具免疫原性的生物活性物质进行理化修饰,以提高其体内应用的安全性;尚缺乏相关研究探讨和揭示HA改性对其免疫原性的影响和相关机制。
4. 总结与展望
综上所述,化学改性虽可调控HA的理化性质、增强HA的功能性,但亦可影响其生物学特性。HA功能化的相关研究目前仍较少关注HA衍生物生物学性质的科学表征、及衍生化影响HA生物学性质的具体规律和机制,而相关研究结果将对HA衍生物在医药领域应用的安全性和有效性起关键指导作用。
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表 1 挥发油中主要的单萜类化合物
序 号 成 分 植物来源 分子式 CAS号 作用机制 参考文献 1 芳樟醇 薰衣草 C10H18O 78-70-6 增加PKA和CREB磷酸化 [5,9] 2 柠檬烯 甜橙,薰衣草,佛手柑 C10H16 138-86-3 降低单胺递质水平,下调BDNF [10] 3 薄荷醇 薄荷 C10H20O 2216-51-5 作用于GABA,5-HT,多巴胺能系统 [11] 4 香叶醇 天竺葵,柠檬草 C10H18O 106-24-1 影响PI3K/Akt和PKA信号通路 [12] 5 紫苏醛 紫苏 C10H14O 18031-40-8 增加单胺神经递质,上调BDNF/TrkB表达 [13] 6 β-罗勒烯 罗勒 C10H16 13877-91-3 影响PI3K/Akt和PKA信号通路 [12] 7 桉油精 柠檬草,迷迭香 C10H18O 470-82-6 影响GABA/BZ受体 [14−15] 8 α-蒎烯 松针,薰衣草,柑橘 C10H16 7785-70-8 上调钙结合蛋白,作用于GABA能神经元 [16] 9 樟脑 鼠尾草,薰衣草 C10H16O 464-48-2 作用于多巴胺能,去甲肾上腺素能系统 [17−18] 10 麝香草酚 牛至,百里香 C10H14O 89-83-8 上调中枢神经递质水平和抑制NLRP3表达 [19−20] PKA:蛋白激酶A;CREB:环磷腺苷效应元件结合蛋白;GABA:γ-氨基丁酸;PI3K:磷酸肌醇3-激酶;Akt:蛋白激酶B;TRKB:原肌球蛋白受体激酶B;BZ:苯二氮䓬类;NLRP3:NOD样受体热蛋白结构域相关蛋白3 表 2 挥发油中主要的倍半萜化合物
序 号 成 分 植物来源 分子式 CAS号 作用机制 参考文献 1 β-石竹烯 峨参,迷迭香 C15H24 87-44-5 上调 5-HT1A,增加5-HT含量 [21,24] 2 广藿香醇 广藿香 C15H26O 5986-55-0 提高脑内多巴胺水平 [25] 3 α-kessyl alcohol 缬草 C15H26O2 3321-65-1 尚不明确 [26] 4 β-榄香烯 红椿, 天女玉兰 C15H24 515-13-9 增加5-HT含量,增加脑组织中BDNF和5-HT1A表达 [23,27] 5 δ-杜松烯 丁香蒲桃,刺果峨参 C15H24 483-76-1 尚不明确 [26] 5-HT1A:5-羟色胺受体1A;BDNF:脑源性神经营养因子 表 3 具有抗抑郁作用的中药挥发油
植 物 挥发油的主要成分 动物模型 行为学测试 给药方式 作用机制 薰衣草 芳樟醇、乙酸芳樟醇、月桂烯、4-松油[15] CUMS大鼠 SPT
FST吸入 抑制电压依赖性钙通道,激活PKA和MAPK等激酶,激活转录因子CREB,改善神经可塑性[9,48] 紫苏 紫苏醛、1,4-桉叶醇、乙醛、缩二乙醇、D-柠檬烯、桉树醇[61] CUMS大鼠 SPT
FST吸入 增加海马区和大脑皮层中的5-HT、DA、
NE递质水平,并上调BDNF/TrkB通路[13]CUMS小鼠 SPT
TST
FST吸入 逆转CUMS小鼠海马5-HT和5-HIAA的变化,降低IL-6、IL-1β、TNF-α水平[55] 佛手 柠檬烯、芳樟醇、乙酸芳樟酯[15] CUMS大鼠 SPT
OFT灌胃 调节脑内神经递质、抑制 HPA轴亢进、促进BDNF产生、抗氧化应激、抗炎[43] 肉桂 反式肉桂醛、β-姜黄酮、邻肉桂醛二乙缩醛和邻甲氧基肉桂醛[31] CUMS大鼠 SPT
OFT灌胃 抗氧化,抑制NF-κB/NLRP3激活和降低
环氧合酶-2[54]藏红花 苯乙醇、2-(2-羟基丙氧基)-1-丙醇、2-
(3-氧-2-戊基环戊基)乙酸甲酯、1,3,3-
三甲基-2-(2-甲基-环丙基)-环己烯、
番红花醛[46]CUMS小鼠 OFT
SPT
TST
FST吸入 调节MAPK-CREB1-BDNF信号通路[46]
降低TNF-α、IFN-γ及IL-1β、IL-6、IL-12、IL-17a水平[57]荆芥 薄荷酮、胡薄荷酮[56] CUMS小鼠 SPT
FST
TST灌胃 抑制NLRP3炎症小体和小胶质细胞激活,抑制神经炎症;显著下调海马部位ASC、Caspase-1蛋白表达,抑制细胞焦亡[56] 大蒜 二烯丙基二硫、二烯丙基二硫醚和二烯丙基三硫醚[60] CUMS大鼠 OFT
SPT灌胃 调节SCFAs浓度,影响肠屏障功能和肠道
微生物[60]石菖蒲 α-细辛醚、β-细辛醚、甲基丁香酚、
榄香素[62]CUMS大鼠 OFT 灌胃 降低血清中促炎因子含量,增加中脑及纹状体中5-HT、5-HIAA和DA的含量[62,63] 薄荷 L-薄荷醇、左旋薄荷酮[64] CUMS小鼠 FST
OFT
SLT灌胃 升高海马体中NE和5-HT浓度,抑制IL-1β、IL-6和TNF-α表达[64] 积雪草 石竹烯、法呢醇、榄香烯、长叶烯[65] 利血平抑郁大鼠模型 ESCT 灌胃 降低单胺氧化酶活性,抑制血清CORT升高,增强单胺类神经递质功能[65] 苍艾 丁子香酚、1,8-桉叶素、广藿香醇、乙酰丁香酚、芳樟醇、乙酸芳樟醇、β-石竹烯、萜品烯-4-醇、α-松油醇[66] CUMS大鼠 TST
FST
SPT吸入 调节DA和5-HT代谢,抑制色氨酸降解以及抑制小胶质细胞炎症[66,67] 沉香 柏木脑、α-布藜烯、α-柏木烯、
广藿香萜醇[68]CUMS小鼠 TST
FST吸入
腹腔注射调控5-HT、GABAA、Glu神经递质水平以及其受体及转运体蛋白GluR1、VGluT1表达[69]
降低HPA轴下游ACTH和CORT浓度[41]牛至 麝香草酚、γ-萜品烯、冰片醇、
半胱氨酸、香芹酚[70]CUMS大鼠 SPT
FST腹腔注射 抑制单胺神经递质再摄取和降解[70] 迷迭香 树脑、樟脑、α-蒎烯、莰烯、α-松油醇[71] dl -4-氯苯丙氨酸诱导失眠模型 OFT 灌胃 上调5-HT1A受体表达,增加5-HT,GA,
DA水平[24]广藿香 广藿香醇、δ-愈创木烯、α-古芸烯、
β-石竹烯、β-广藿香[72]CUMS大鼠和CMS小鼠 SPT
FST
TST腹腔注射 抑制NLRP3炎症小体和小胶质细胞活化[58] CUMS:慢性不可预知温和应激;SPT:糖水偏好试验;FST:强迫游泳试验;TST:悬尾实验;OFT:旷场试验;ESCT:电刺激角膜试验 -
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