抗神经退行性疾病的潜在替代药物: 植物药物

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A Potential Alternative against Neurodegenerative Diseases: Phytodrugs

Abstract

摘要

Neurodegenerative diseases (ND) primarily affect the neurons in the human brain secondary to oxidative stress and neuroinflammation. ND are more common and have a disproportionate impact on countries with longer life expectancies and represent the fourth highest source of overall disease burden in the high-income countries. A large majority of the medicinal plant compounds, such as polyphenols, alkaloids, and terpenes, have therapeutic properties. Polyphenols are the most common active compounds in herbs and vegetables consumed by man. The biological bioactivity of polyphenols against neurodegeneration is mainly due to its antioxidant, anti-inflammatory, and antiamyloidogenic effects. Multiple scientific studies support the use of herbal medicine in the treatment of ND; however, relevant aspects are still pending to explore such as metabolic analysis, pharmacokinetics, and brain bioavailability.

神经退行性疾病(ND)主要影响继发于氧化应激和神经炎症的人脑神经元。新城疫更为常见,对预期寿命较长的国家具有不成比例的影响,是高收入国家总体疾病负担的第四大来源。大多数药用植物化合物,如多酚、生物碱和萜类,具有治疗性能。多酚是人类食用的草本植物和蔬菜中最常见的活性成分。多酚对神经退行性疾病的生物活性主要是由于它的抗氧化、抗炎和抗淀粉样变性作用。多项科学研究支持使用草药治疗 ND; 然而,相关方面仍有待探索,如代谢分析、药代动力学和大脑生物利用度。

1. Introduction

1. 引言

Neurodegenerative diseases (ND) such as Alzheimer’s (AD) and Parkinson’s disease (PD) and multiple sclerosis (MS) primarily affect the neurons in the human brain and are characterized by deterioration of neurons or myelin sheath, sensory information transmission disruption, movement control, and more [1]. The greatest risk factor for ND is aging, which carries mitochondrial dysfunction, chronic immune-inflammatory response, and oxidative stress [23], the major causes of neuronal damage and death. Nowadays, ND are chronic and incurable conditions whose disabling effects may continue for years or even decades representing an enormous disease load, regarding human suffering and economic cost. The ND are more common and have a disproportionate impact on countries with longer life expectancies and represent the fourth highest source of overall disease burden in the high-income countries. According to the World Health Organization, 37 million people currently have dementia worldwide, and about 50% of them are being affected by AD and this number is expected to grow up to 115.4 million people by 2050 [4].

神经退行性疾病如阿尔茨海默氏症(AD)、帕金森氏症(PD)和多发性硬化症(MS)主要影响人脑的神经元,它们是神经元或髓鞘的拥有属性退化、感觉信息传输中断、运动控制等等。新城疫最大的危险因素是衰老,它携带线粒体功能障碍,慢性免疫炎症反应,和氧化应激,神经元损伤和死亡的主要原因。如今,新城疫是一种慢性的、不可治愈的疾病,其致残效应可能会持续数年甚至数十年,对人类的痛苦和经济成本构成巨大的疾病负担。新城疫更为常见,对预期寿命较长的国家具有不成比例的影响,是高收入国家总体疾病负担的第四大来源。根据世界卫生组织的数据,目前全世界有3700万人患有痴呆症,其中大约50% 患有 AD,预计到2050年这个数字将增加到1.154亿。

Recently, a great number of natural medicinal plants have been tested for their therapeutic properties, showing that the raw extracts or isolated pure compounds from them have more effective properties than the whole plant as an alternative for the treatment of ND. These properties are due mainly to the presence of polyphenols (Figure 1), alkaloids (Figure 2), and terpenes (Figure 3(d)), among others, that are micronutrients produced by plants as secondary metabolites [56]. There is substantial evidence (epidemiological studies, animal studies, and human clinical trials) that indicates that polyphenols reduce a wide range of pathologies associated with inflammation [79]. The main mechanisms of polyphenols include their well-characterized antioxidant effects [1011], inhibition of intracellular kinases activity [12], binding to cell surface receptors [13], and modifying cell membrane functions [14]. Also, recently the neuroprotective effects of polyphenols have been described in several models of ND and involve mainly signaling pathways mediators [15], modulation of enzymes in neurotransmission [1617], inhibition of neurotoxicity via ionotropic glutamate receptors [18], antiamyloidogenic [19], and anti-inflammatory effects [20]. This review focuses on the plant extracts or compounds isolated from plants that may hold potential in the treatment of the principal ND.

最近,大量的天然药用植物已被测试其治疗性能,表明从他们的原始提取物或分离纯化合物具有更有效的性能比整个植物作为替代治疗 ND。这些特性主要是由于多酚(图1)、生物碱(图2)和萜烯(图3(d))等微量营养素的存在,这些营养素是由植物产生的次生代谢物[5,6]。有大量的证据(流行病学研究、动物研究和人体临床试验)表明,多酚可以减少与炎症有关的各种病理[7-9]。多酚类化合物的主要作用机制包括抗氧化作用[10,11]、抑制细胞内激酶活性[12]、与细胞表面受体结合[13]和修饰细胞膜功能[14]。此外,最近多酚的神经保护作用已在几种 ND 模型中被描述,主要涉及信号传导通路介质[15]、神经传导酶的调节[16,17]、通过热带谷氨酸受体[18]抑制神经毒性、抗淀粉样变性[19]和抗炎作用[20]。本文着重介绍了从植物中分离得到的可用于治疗主要 ND 的植物提取物或化合物。(a)
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(p)Figure 1 图1Representative polyphenol compounds. (a) Benzoic acids: 具代表性的多酚化合物(a)苯甲酸:-hydroxybenzoic acid R – 羟基苯甲酸 r1 = R3 = R4 = H, R = h,r2 = OH; protocatechuic acid R 原儿茶酸 r1 = R4 = H, R = h,r2 = R3 = OH; gallic acid R = OH; 没食子酸 r1 = R2 = R3 = OH, R = OH,r4 = H; and salicylic acid R = h; 和水杨酸 r1 = R2= R3 = H, R = h,r4 = OH. (b) Hydroxycinnamic acids: coumaric acid R = OH. (b)羟基肉桂酸: 香豆酸 r1 = R2 = H; caffeic acid R = h; 咖啡酸 r1 = OH, R = OH,r2 = H; ferulic acid R = h; 阿魏酸 r1 = OMe, R = OMe,r2 = H; and sinapic acid R = h; 芥子酸 r1 = R2= OMe. (c) Stilbenes: resveratrol R 二苯乙烯类: 白藜芦醇 r1 = H; oxyresveratrol R 羟基白藜芦醇 r1 = OH. (d) Hydroxycinnamoyl ester: chlorogenic acid. (e) Hydroxycinnamoyl derivatives: gingerol; (f) Chavicol R = OH. (d)羟基肉桂酰酯: 绿原酸. (e)羟基肉桂酰衍生物: 姜酚; (f) Chavicol r1 = H; eugenol R = h; 丁香酚 r1 = OMe; (g) curcumin; (h) magnolol; and (i) echinacoside. Flavonoid compounds. (j) Nobiletin; (k) Flavones: apigenin R = OMe; (g)姜黄素; (h)厚朴酚; (i)松果菊苷。黄酮类化合物。(j) Nobiletin; (k)黄酮: 芹菜素 r1 = R4 = H, R = h,r2 = R3 = R5 = OH; baicalein R1 = R2 = H, R = h,r3 = R4 = R5 = OH; chrysin R = OH; 白杨素 r1 = R2 = R4 = H, R = h,r3 = R5= OH; and luteolin R = OH; 木犀草素 r4 = H, R = h,r1 = OMe, R = OMe,r2 = R3 = R5= OH. (l) Flavonols: kaempferol R = OH。(1)黄酮醇: 山奈酚 r1 = R4 = H, R = h,r2 = R3 = R5 = OH; quercetin R4 = H, R = h,r1 = R2 = R3 = R5 = OH. (m) Flavanols (+)-catechin R = OH. (m)黄烷醇(+)-儿茶素 r1 = H; (+)-gallocatechin R = h; (+)-牛儿茶素 r1= OH. (n) Flavanones: hesperetin R4 = H, R = h,r1 = R3 = R5 = OH, R = OH,r2 = OMe; naringenin R1 = R4 = H, R = h,r2 = R3 = R5 = OH; pinocembrin R1 = R2 = R4 = H, R = h,r3 = R5 = OH. (o) Anthocyanins: aurantinidin R 花青素: 金黄色素 r1 = R2 = H, R = h,r3 = R4 = OH; cyanidin R2 = R4 = H, R = h,r1 = R3 = OH; pelargonidin R1 = R3 = R4 = H, R = h,r2 = OH; and peonidin R = OH; 和 peonidin r2 = R4 = H, R = h,r1= OMe, R = OMe,r3 = OH. (p) Flavonolignans: silydianin. = OH。(p)黄酮木脂素: 硅烷(a)
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(f)Figure 2 图2Some alkaloid compounds in plants. (a) Capsaicin; (b) protoberberines: jatrorrhizine R 植物中的一些生物碱化合物。(a)辣椒素; (b)原小檗碱: 药根碱 r1 = OH, palmatine R = OH,palmatine r1 = OMe; (c) vincamine; (d) piperine; (e) diallyl sulfide; and (f) sulphoraphane. = OMe; (c) vincamine; (d)胡椒碱; (e)二烯丙基硫醚; 及(f)磺酸盐(a)
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(d)Figure 3 图3Some miscellaneous antioxidant compounds from plants. (a) Coenzyme Q 从植物中提取的一些杂类抗氧化化合物6–10 6比10; (b) l-theanine; (c) ascorbic acid; and (d) lycopene. (b)茶氨酸; (c)抗坏血酸; 及(d)番茄红素

2. Etiology of Neurodegenerative Diseases

2. 神经退行性疾病的病因学

ND are incurable and disabling conditions secondary to progressive neuronal loss, which leads to chronic brain damage and neurodegeneration. The etiology of ND is still unknown, although several ND animal models showed associated damage with the blood-brain barrier, protein aggregation, toxin exposure, and mitochondrial dysfunction, which lead to oxidative stress and inflammation, and consequently neuronal death [21].

新城疫是不治之症,继发于渐进性神经元丢失,这会导致慢性脑损伤和神经退行性疾病。新城疫的病因仍然不清楚,虽然几个新城疫动物模型显示与血脑屏障,蛋白质聚集,毒素暴露和线粒体功能障碍相关的损害,导致氧化应激和炎症,从而神经元死亡[21]。

The blood-brain barrier controls the internal environment of the vertebrate CNS and represents the border between the capillary and the extracellular fluid of CNS neurons and glial cells; it also ensures specific brain homeostasis allowing adequate neuronal function [22]. Neurovascular changes normally occur as part of aging, but these are more evident in chronic ND [23]. About 20% of blood flow decreases in the aged brain, which associates with reduced protein synthesis [24]. Interestingly, this blood flow reduction is higher in the presence of any ND, which may lead to changes in intracellular pH and accumulation of interstitial lactate and glutamate [2325]. These changes are observed in specific brain regions in diseases such as AD, PD, MS among other CNS disorders [2528].

血脑屏障控制脊椎动物中枢神经系统的内部环境,代表中枢神经元和神经胶质细胞的毛细血管和细胞外液之间的边界,它还确保特定的脑内稳态,允许充分的神经元功能[22]。神经血管的变化通常发生在衰老的一部分,但这些是更明显的慢性新城疫[23]。大约20% 的血流量在老化的大脑中减少,这与蛋白质合成减少有关[24]。有趣的是,这种血流量的减少在任何新城疫的存在是更高的,这可能导致改变细胞内的 pH 值和间质乳酸盐和谷氨酸盐的积累[23,25]。这些变化是在特定的大脑区域观察到的疾病,如 AD,PD,MS 和其他中枢神经系统疾病[25-28]。

Abnormal protein aggregation of specific regions and neuronal populations is a common feature among ND. For example, the α-synuclein inclusions in dopaminergic neurons from the substantia nigra are the main histopathological marker in PD [29]. Also, insoluble aggregates of the amyloid beta-peptide (Aβ) and neurofibrils composed of Tau protein are found in AD [3031] and hyperphosphorylated Tau aggregation in demyelination areas in MS [32]. Finally, superoxide dismutase 1 (SOD1) aggregations are present in amyotrophic lateral sclerosis (ALS) [33]. The main relevance of protein aggregates is that they lead to mitochondrial dysfunction inducing apoptotic neuronal death.

异常的蛋白质聚集的特定区域和神经元群体是一个共同的特点新城疫。例如,来自黑质的多巴胺能神经元中的 α- 突触核蛋白包涵体是 PD 的主要组织病理学标志物[29]。另外,在 AD [30,31]中发现 β 淀粉样蛋白(aβ)的不溶性聚集体和 Tau 蛋白组成的神经原纤维,在 MS [32]中发现脱髓鞘区出现过度磷酸化 Tau 蛋白聚集。最后,超氧化物歧化酶1(SOD1)聚合物出现在肌萎缩性嵴髓侧索硬化症(ALS)[33]中。蛋白质聚集体的主要相关性是,它们导致线粒体功能障碍诱导凋亡神经元死亡。

Redox state imbalance and chronic inflammation, a major cause of cell damage and death, characterize ND [34]. Reactive oxygen species (ROS) are key mediators of cell survival, proliferation, differentiation, and apoptosis [3536]. Excessive production of ROS by mitochondria and NADPH oxidase in oxidative stress is usually thought to be responsible for tissue damage associated with inflammation and ND [343638]. Moreover, many of the well-known inflammatory target proteins, including matrix metalloproteinase-9, cytosolic phospholipase A2, cyclooxygenase-2, inducible nitric oxide synthase (iNOS), and adhesion molecules, are associated with oxidative stress and induced by proinflammatory factors such as cytokines, peptides, and peroxidants agents [363940]. Several studies have shown that ROS act as a critical signaling molecule to trigger inflammatory responses in CNS through the activation of the redox-sensitive transcription factors, including nuclear factor-κB (NF-κB) and activator protein-1 [343639].

氧化还原状态不平衡和慢性炎症,细胞损伤和死亡的主要原因,特点 ND [34]。活性氧类(ROS)是细胞存活、增殖、分化和凋亡的关键介质[35,36]。氧化应激中线粒体和 NADPH 氧化酶过量产生活性氧,通常被认为是导致炎症和 ND 相关组织损伤的原因。此外,许多众所周知的炎症靶蛋白,包括基质金属蛋白酶9、胞质 A2磷脂酶、环氧化酶2、诱导性一氧化氮合酶(iNOS)和粘附分子,都与氧化应激有关,是由细胞因子、多肽和过氧化剂等促炎症因子诱导的。一些研究表明,ROS 是通过激活氧化还原敏感的转录因子,包括核因子 -κb (NF-κB)和激活蛋白 -1(34,36-39) ,触发中枢神经系统炎症反应的关键信号分子。

Mitochondrial damage leads to neuronal oxidative damage in ND pathogenesis. ROS and reactive nitrogen species, which are normal byproducts of mitochondrial respiratory chain activity, are mediated by mitochondrial antioxidants such as manganese superoxide dismutase and glutathione peroxidase. In addition to the ROS generation, mitochondria are also involved with life-sustaining functions including adenosine triphosphate synthesis by oxidative phosphorylation, apoptosis, calcium homeostasis, mitochondrial fission and fusion, lipid concentration of the mitochondrial membranes, and the mitochondrial permeability transition. Mitochondrial disease leading to neurodegeneration is likely, at least on some level, to involve all of these functions [41]. In ND several mitochondrial alterations are found like bioenergetics anomalies in the process of oxidative phosphorylation and ATP production, defects of mitochondrial dynamics, increase sensitivity to apoptosis, and accumulation of damaged mitochondria with unstable mitochondrial DNA [2].

线粒体损伤在新城疫发病机制中导致神经元氧化损伤。活性氧和活性氮是线粒体呼吸链活动的正常副产品,是由线粒体抗氧化剂如超氧化物歧化酶和谷胱甘肽过氧化物酶介导的。除了产生活性氧外,线粒体还参与维持生命的功能,包括三磷酸腺苷合成、细胞凋亡、钙稳态、线粒体分裂和融合、线粒体膜脂质浓度和线粒体通透性转换。导致神经退行性疾病的线粒体疾病可能,至少在某种程度上,涉及所有这些功能。在 ND 中发现了一些线粒体改变,如氧化磷酸化和 ATP 产生过程中的生物能学异常,线粒体动力学缺陷,对细胞凋亡的敏感性增加,以及线粒体脱氧核糖核酸不稳定的受损线粒体积聚。

The proteins aggregation also plays an important role in mitochondrial dysfunction; for example, the accumulation of mitochondrial Aβ aggregates has been observed both in patients and in transgenic models of AD [4244]. Additionally, inhibition of mitochondrial complex I occurs in PD patients [45] and the two principal models used for the study of PD. Rotenone—a natural compound used as an insecticide, piscicide, and pesticide—and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)—a neurotoxin precursor of 1-methyl-4-phenylpyridinium (MPP+), which destroys dopaminergic neurons in the substantia nigra—both act by inhibiting mitochondrial complex I [21]. In ALS, mitochondrial SOD1 enzyme aggregates cause loss of mitochondrial function and induce cellular death by apoptosis [46]. This phenomenon is present in almost all ND and associated with inflammation, which is one of the points of therapeutic interest and study.

蛋白质聚集在线粒体功能障碍中也起重要作用,例如,在 AD 患者和转基因模型中都观察到线粒体 aβ 聚集体的积累。此外,线粒体复合物 i 的抑制发生在帕金森病患者[45]和两个主要模型用于帕金森病的研究。鱼藤酮是一种天然化合物,用作杀虫剂、杀鱼剂和杀虫剂; 1-甲基-4-苯基-1,2,3,6-四氢吡啶是 MPP+ 的神经毒素前体,能破坏黑质的多巴胺能神经元,两者都通过抑制线粒体复合体 i [21]发挥作用。在 ALS 中,线粒体 SOD1酶聚集体导致线粒体功能丧失,并通过凋亡诱导细胞死亡[46]。这种现象几乎存在于所有的新城疫和炎症,这是治疗的兴趣和研究的重点之一。

The CNS inflammation is dependent on inflammatory mediators produced mainly by glial cells, specifically microglia and CNS macrophages [47]. Microglial activation is crucial in the pathogenesis and the course of PD [48], AD [49], prion disease [50], and MS [51], among others. Uncontrolled microglia activation produces neuronal damage due to overproduction of proinflammatory mediators such as tumor necrosis factor α (TNFα) [52], and nitric oxide (NO), leading to the generation of oxidative stress and apoptotic cell death [485253].

中枢神经系统的炎症依赖于神经胶质细胞,特别是小胶质细胞和中枢巨噬细胞产生的炎症介质[47]。小胶质细胞激活在 PD [48]、 AD [49]、朊病毒病[50]和 MS [51]等发病机制和病程中至关重要。不受控制的小胶质细胞活化产生神经元损伤,这是由于过度产生促炎介质,如肿瘤坏死因子-α α (tnfα)和一氧化氮(NO) ,导致氧化应激和细胞凋亡的产生。

3. Main Therapeutic Effects of Plant Extracts

3. 植物提取物的主要治疗作用

The plant extracts have become interesting candidates as therapeutic agents due to their antioxidant, anti-inflammatory properties, and chemical characteristics derived as follows.

植物提取物由于具有抗氧化、抗炎和以下化学特性而成为有趣的治疗剂候选物。

(i) Direct Uptake of Free Radicals. Primarily polyphenols (Figure 1) and alkaloids (Figure 2) function as scavengers due to their multiple phenolic hydroxyl and nitrogen groups, respectively, which act as an electron donor to the aromatic ring. These systems are excellent nucleophiles that readily lose electrons and easily oxidize. Therefore, they can catch free radicals and react with ROS, such as superoxide, peroxyl, hydroxyl radicals, NO, nitrogen dioxide, peroxynitrite, and singlet oxygen [5456].

(i)直接摄取自由基。主要的多酚(图1)和生物碱(图2)作为清除剂的功能,由于它们的多酚羟基和氮基,分别作为一个电子供体的芳香环。这些体系是极好的亲核体,容易失去电子并且容易氧化。因此,它们能捕获自由基并与活性氧反应,如超氧化物、过氧化物、羟基自由基、一氧化氮、二氧化氮、过氧亚硝酸根和单线态氧[54-56]。

(ii) Chelation of the Divalent Cations in Fenton Reactions Involved. Many polyphenol compounds chelate iron cations due to multiple hydrophilic groups and are efficient scavengers because phenolic groups inhibit iron-mediated oxyradical formation like other iron chelators, such as desferrioxamine, 1,10-phenanthroline, and pyridoxal isonicotinoyl hydrazone [5758].

(ii)芬顿反应中二价阳离子的螯合作用。由于多亲水基团的存在,许多多酚类化合物能够螯合铁离子,并且能够有效地清除铁离子,因为酚类化合物能够像其他铁离子螯合剂一样抑制铁离子介导的氧自由基的形成,如去铁胺、邻二氮菲和吡哆醛异烟酰腙[57,58]。

(iii) Modulation of Enzymes Associated with Oxidative Stress. ND associate with molecular alterations in cell-signaling pathways that regulate cell proliferation and differentiation, such as the family of mitogen-activated protein kinases (MAPK). Abnormal activation or silencing of the MAPK pathway or its downstream transcription factors can result in uncontrolled cell growth leading to malignant transformation. Some plant compounds “switch on” or “turn off” the specific signaling molecule(s), depending on the nature of the signaling cascade they target, preventing abnormal cell proliferation and growth [5960].

(iii)调节与氧化应激有关的酶。ND 与调节细胞增殖和分化的细胞信号通路的分子改变有关,如丝裂原活化蛋白激酶(MAPK)家族。MAPK 通路或其下游转录因子的异常激活或沉默可导致细胞生长失控,导致恶性转化。一些植物化合物“打开”或“关闭”特定的信号分子,这取决于它们所针对的信号级联的性质,防止细胞异常增殖和生长[59,60]。

4. Antioxidant and Anti-Inflammatory Properties in Central Nervous System

4. 中枢神经系统的抗氧化和抗炎特性

Flavonoids, a type of polyphenolic compounds found in fruits, vegetables, red wine, and green tea, reduce the risk to developing ND [61]. In 2010, Vuong and colleagues showed that cranberry juice in neuronal cultures significantly increased the activity of antioxidant enzymes such as catalase and SOD1 and protected neurons against H2O2 induced cell death, possibly due to the activation of survival pathways dependent from p38 and blocking death pathway associated with MEK1/2 and ERK1/2 [62]. A comparative study of two extracts of Salvia species, S. hydrangea and S. macilenta, also showed strong antioxidant properties, also at high concentrations (≥50 μg/mL) they can inhibit DNA damage by free radicals. Moreover, these species not only showed no cytotoxic effect in cultured PC12 cells, a cell line derived from a pheochromocytoma obtained from rat adrenal medulla differentiated with neural growth factor, but also protected them from peroxide-induced cell death [63]. Similarly selaginellin, a compound extracted from the plant Saussurea pulvinata, showed a neuroprotective effect in a glutamate neurotoxicity model in PC12 cells by trapping ROS and regulating the expression of the klotho gene, which has an antiapoptotic role [64].

类黄酮,一种存在于水果、蔬菜、红酒和绿茶中的多酚类化合物,可以降低患 ND 的风险[61]。2010年,Vuong 和他的同事们发现,在神经细胞培养中蔓越莓汁能显著增加抗氧化酶的活性,如过氧化氢酶和 SOD1,并能保护神经元免受 H2O2诱导的细胞死亡,这可能是由于依赖 p38的生存通路的激活以及与 MEK1/2和 ERK1/2[62]相关的死亡通路的阻断。八仙花和大西洋鼠尾草两种鼠尾草提取物的比较研究也表明,两种鼠尾草提取物均具有较强的抗氧化性能,并且在高浓度(≥50μg/mL)时可抑制自由基对 DNA 的损伤。此外,这些物种不仅在培养的 PC12细胞中没有表现出细胞毒作用,而且还保护它们免受过氧化物引起的细胞死亡[63]。 PC12细胞系来源于一种分化了神经生长因子的大鼠肾上腺髓质嗜铬细胞瘤。类似地,从植物垫风毛菊中提取的化合物 selaginellin,通过捕获 ROS 和调节 klotho 基因的表达,在 PC12细胞的谷氨酸盐神经毒性模型中显示了神经保护作用,klotho 基因具有抗凋亡作用[64]。

Ginger, the root of Zingiber officinale, an important specie used in the Chinese, Ayurvedic, and Tibia-Unani traditional medicine, has anti-inflammatory [6567] and antioxidant [68] properties, among others. The hexane fraction of ginger extract and the methanol extract of Ficus religiosa sheet significantly decreased the production of NO, prostaglandin E2, IL-1β, IL-6, and TNFα through the inhibition of MAPK and NF-κB in BV2 microglial cell line stimulated with lipopolysaccharide (LPS) [6970].

生姜是姜的根,这是一种重要的物种,广泛用于中药、印度草药和 Tibia-Unani 传统药物中,具有抗炎和抗氧化等特性。正己烷提取物和无花果甲醇提取物通过抑制脂多糖(LPS)刺激的 BV2小胶质细胞 MAPK 和 NF-κB 的表达,显著降低 NO、前列腺素E2、 il-1β、 IL-6和 tnfα 的产生。

Similarly, the ethanol extract of Knema laurina exerted anti-inflammatory and neuroprotective effects in a BV2 microglial cell culture line, in HT-22 hippocampal neurons and in organotypic hippocampal cultures. Knema laurinareduced microglial production of NO and IL-6 through the inhibition of ERK1/2 and IKKβ phosphorylation, and the subsequent translocation NF-κβ in microglial cells [71].

类似地,Knema 月桂醇提取物在 BV2小胶质细胞培养系、 HT-22海马神经元和器官型海马培养中均有抗炎和神经保护作用。Knema lauria 通过抑制 ERK1/2和 ikkβ 磷酸化,减少小胶质细胞产生 NO 和 IL-6,并抑制 nf-κb 转位[71]。

It is clear that aging is a critical factor for developing ND and facilitates the microglial promoted proinflammatory environment [7274] and oxidative stress [75]. Therefore, studying potential drugs that prevent or retard age-related changes has become crucial. Natural antioxidants such as some cocoa derivatives have shown to contain higher flavonoids levels [76]. For example, acticoa, a cocoa-derived polyphenol extract, administered daily orally at 24 mg/kg dose in Wistar rats 15 to 27 months old, improved cognitive performance, increased life expectancy, and preserved free dopamine levels in urine [77]. Another extract with high antioxidant activity is silymarin, a standardized mixture of flavonolignans (Figure 1(p)) extracted from the Silybum marianum fruits and seeds [78]. The treatment with 400 mg/kg/day of silymarin during three days increased reduced glutathione (GSH) and SOD activity in the brain of aged rats [79]. Vincamine (Figure 2(c)), a monoterpenoid indole alkaloid purified from the Vinca minor plant, has antioxidant activity similar to vitamin E. This compound increased cerebral blood flow, glucose, and oxygen utilization in neural tissue and promoted the rise of dopamine, serotonin, and noradrenaline levels [80]. Also, the treatment of rats with vincamine during 14 days at a daily dose of 15 mg/kg reduced about 50% the brain iron levels, which suggests a beneficial effect in reducing the oxidative stress associated with the iron deposition in ND [81]. Moreover, paeonol, a compound extracted from thePaeonia suffruticosa cortex or Paeonia lactiflora root, has been ascribed to anti-inflammatory and antioxidant properties. Paeonol effects were tested in a model of neurotoxicity induced with D-galactose injected subcutaneously in aged mice. Paeonol prevented memory loss in this model since it increased acetylcholine and GSH levels and decreased the activity of acetylcholinesterase (AChE) and SOD1 in the hippocampus and cortex, positioning it as a potential drug useful in age-related ND [15]. Also, Magnolia officinalis compounds, magnolol (Figure 1(h)) and their isomer honokiol, were tested in a senescence-accelerated prone mice; this compound prevented learning and memory deterioration, as well as acetylcholine deficiency by preserving forebrain cholinergic neurons [1882].

很明显,衰老是发展新城疫的关键因素,促进了小胶质细胞促进的炎症环境[72-74]和氧化应激[75]。因此,研究预防或延缓衰老相关变化的潜在药物已变得至关重要。天然抗氧化剂,例如一些可可衍生物,含有更高的类黄酮水平[76]。例如,在15至27个月大的 Wistar 大鼠中,每天口服24毫克/千克剂量的可可衍生多酚提取物—— acticoa,改善了认知能力,延长了预期寿命,并保持了尿液中的游离多巴胺水平[77]。另一种具有高抗氧化活性的提取物是水飞蓟素,一种从乳蓟果实和种子中提取的黄酮橄榄素的标准化混合物。水飞蓟素400mg/kg/d 连续3天可增加老龄大鼠脑内 GSH 和 SOD 活性[79]。长春胺(图2(c)) ,一个从 Vinca 小植物纯化的单萜吲哚生物碱,具有类似维生素 e 的抗氧化活性。这种化合物增加了神经组织中的脑血流量、葡萄糖和氧气利用率,并促进了多巴胺、血清素和去甲肾上腺素水平的上升[80]。此外,每日剂量为15毫克/千克的长春胺处理大鼠14天后,大脑铁水平降低了约50% ,这表明在降低 ND 铁沉积相关的氧化应激方面有一个有益的作用[81]。此外,丹皮酚,一种从牡丹或芍药中提取的化合物,被认为具有抗炎和抗氧化的特性。采用 d- 半乳糖致衰老小鼠皮下注射模型,观察丹皮酚的神经毒性作用。丹皮酚能够提高乙酰胆碱和谷胱甘肽水平,降低海马和皮质的乙酰胆碱酯酶(AChE)和 SOD1活性,从而可以预防该模型的记忆丧失,使其成为治疗年龄相关性 ND 的潜在药物[15]。此外,厚朴化合物,厚朴酚(图1(h))和它们的同分异构体和厚朴酚,在一个快速老化的老鼠身上进行了测试; 这种化合物通过保存前脑胆碱能神经元,防止学习和记忆衰退,以及乙酰胆碱缺乏症[18,82]。

6. Plant Compounds Used for Alzheimer’s Disease

6. 用于治疗老年痴呆症的植物化合物

AD manifests as a progressive cognitive and behavioral disorder and is characterized by an immediate loss of memory secondary to neuronal loss in the limbic and association cortices. This neuronal death results from oxidative stress, neuroinflammation, and abnormal protein deposition [83], leading to a therapeutic opportunity for medicinal plants, which improve AD course principally by modulating A aggregation, AChE activity, oxidative stress, and inflammatory response [84].

AD 表现为一种进行性的认知和行为障碍,拥有属性是由于边缘系统和联想皮层神经元的丢失而引起的记忆的立即丧失。这种神经元的死亡是由氧化应激、神经炎症和异常蛋白质沉积引起的,这为药用植物的治疗提供了机会,主要通过调节 a 聚集、乙酰胆碱酯酶活性、氧化应激和炎症反应来改善 AD 进程。

Cryptotanshinone is an active component of Salvia miltiorrhiza with anti-inflammatory, antioxidant, and antiapoptotic properties [8586]. This compound crossed the blood brain barrier and decreased cognitive deficits in male IRC mice with scopolamine-induced cognitive impairments [87]. This compound also provided beneficial effects in patients with ischemia and cerebral infarct [88]. Additionally, cryptotanshinone reduced the Aβ aggregation in brain tissue and improved spatial learning and memory in APP/PS1 transgenic mice by promoting amyloid precursor protein metabolism via α-secretase pathway [89]. Silymarin also showed antiamyloid properties in vitro, and its chronic administration (half a year) significantly reduced the Aβ plaque burden associated with microglial activation, Aβ oligomer formation, and hyperactivity and disturbed behavior in APP transgenic mice [90]. The protective effect of silymarin on Aβ accumulation is attributable to the blockade of its aggregation, not to β-secretase inhibition [89]. The use of Centella asiaticain a dementia model in PSAPP mice improved memory retention in rodents [9192] and decreased amyloid deposition and the spontaneously Aβ plaque formation [93]. Likewise, the grape seed polyphenolic extract from Vitis viniferaattenuated the cognitive impairment observed in aging AD transgenic mice and decreased Aβ plaques deposition in the brains [94]. Nobiletin (Figure 1(j)), a flavonoid purified from Citrus depressa plant, prevents memory loss in APP695 transgenic mice and Aβ treated rats. This compound reduces the Aβ plaques amount in the hippocampus [9596], probably by reducing the inhibition of protein kinase A and cAMP response element-binding protein phosphorylation signaling cascade [97]. Nobiletin also stimulated long-term potentiation in organotypic hippocampal cultures [98]. Other compounds that can prevent Aβaggregation by inhibition of the metabolic pathway that generates Aβ plaques are berberine, palmatine, jateorrhizine, epiberberine, coptisine, groenlandicine, and magnoflorine, alkaloids isolated from Coptis chinensis rhizome [99]. These compounds also exhibit AChE inhibiting properties [100101] and antidepressant effects [59] and enhance cognitive improvements [102]. Also, jateorrhizine (Figure 2(b)) and groenlandicine have significant peroxynitrite scavenging activities, while coptisine and groenlandicine present moderate total ROS inhibitory activities [99].

隐丹参酮是丹参的活性成分,具有抗炎、抗氧化和抗凋亡特性[85,86]。这种化合物通过血脑屏障,减少了东莨菪碱引起的认知损伤雄性 IRC 小鼠的认知缺陷[87]。这种化合物也对缺血和脑梗死患者有益[88]。此外,隐丹参酮通过 α- 分泌酶途径促进淀粉样前体蛋白代谢,降低脑组织 aβ 聚集,改善 APP/PS1转基因小鼠的空间学习记忆能力[89]。水飞蓟素在体外也表现出抗淀粉样蛋白的特性,长期服用(半年)可显著降低小胶质细胞活化、 aβ 寡聚体形成、 APP 转基因小鼠的活动和行为紊乱所引起的 aβ 斑块负担[90]。水飞蓟素对 aβ 蓄积的保护作用是由于阻断了水飞蓟素的聚集,而不是抑制 β- 分泌酶[89]。在 PSAPP 小鼠痴呆模型中使用崩大碗可以改善啮齿动物的记忆保持[91,92] ,减少淀粉样蛋白沉积和自发性 aβ 斑块的形成[93]。同样,葡萄籽多酚提取物减轻了老年 AD 转基因小鼠的认知障碍,降低了脑内 aβ 斑块的沉积[94]。川陈皮素(图1(j)) ,一种从柑橘中提取的黄酮类化合物,可以防止 APP695转基因小鼠和 aβ 处理的大鼠的记忆丧失。这种化合物减少了海马中 aβ 斑块的数量[95,96] ,可能是通过减少对蛋白激酶A 和 cAMP 反应元件结合蛋白磷酸化信号级联的抑制[97]。诺必立汀也在器官型海马体培养中刺激长时程增强作用。其他能够通过抑制产生 aβ 斑块的代谢途径来阻止 aβ 聚集的化合物有小檗碱、巴马汀、玉簪根碱、表小檗碱、黄连碱、葛兰素和黄连生物碱,它们都是从根茎中分离出来的。这些化合物还表现出乙酰胆碱酯酶抑制特性[100,101]和抗抑郁作用[59] ,并提高认知改善[102]。此外,紫草根碱(图2(b))和葛兰地碱具有明显的过氧亚硝酸根清除活性,而黄连碱和葛兰地碱呈现中度总活性氧抑制活性[99]。

The ethanol extract from Cassia obtusifolia has potential use in AD, which reduced scopolamine-induced memory loss in mice by inhibiting AChE [103]. Similarly, methoxsalen, the main component of the aqueous extract of Poncirus trifoliata, inhibited AChE activity reducing memory loss and learning problems associated with a neurotoxicity in vivo model induced with trimethyltin [16]. In the AD model induced with ethylcholine aziridinium, which mimics the cholinergic hypofunction present in AD [104], piperine (Figure 2(d)), an alkaloid present in Piper longum, lowered the cognitive deficits and the hippocampal neurodegeneration associated with this AD model [105]. These effects could be probable due to its anti-inflammatory [106] and antioxidant activities [71].

决明乙醇提取物对 AD 有潜在的治疗作用,通过抑制 AChE [103] ,减轻东莨菪碱所致的记忆障碍。类似地,枳水提物的主要成分甲氧沙林,抑制 AChE 活性,减少记忆丧失和学习问题,这与三甲基锡体内神经毒性模型相关[16]。在模拟 AD [104]胆碱能减退的乙基胆碱 aziridinium 诱导的 AD 模型中,胡椒碱(图2(d)) ,一种存在于 Piper longum 中的生物碱,降低了认知缺陷和与 AD 模型相关的海马神经退行性疾病。这些作用可能是由于其抗炎和抗氧化活性[71]。

The treatment for 5 weeks with L-theanine (Figure 3(b)), an amino acid present in green tea Camellia sinensis, significantly decreased memory loss associated with intraventricular Aβ1–42 AD model. L-theanine as well reduced cortical and hippocampal neuronal death, also inhibited lipid peroxidation and protein damage, and increased GSH levels, suggesting its potential use in AD prevention and treatment [17]. Also, Dioscorea opposita chloroform extract, which has been used to treat memory-related diseases such as AD and others ND, prevented neuronal death, and significantly increased spatial learning and memory improvement, probably due to its antiexcitotoxic and antioxidant effects [107].

茶氨酸是一种存在于绿茶茶树中的氨基酸,给予茶氨酸治疗5周,可显著减少 Aβ1-42 AD 模型脑室内记忆丧失。茶氨酸可以减少大脑皮层和海马神经元的死亡,也可以抑制脂质过氧化和蛋白质的损伤,并且增加谷胱甘肽的水平,这表明它可能用于 AD 的预防和治疗[17]。此外,山药氯仿提取物,已用于治疗记忆相关疾病,如 AD 和其他 ND,防止神经元死亡,并显着增加空间学习和记忆改善,可能是由于其抗兴奋毒性和抗氧化作用[107]。

Sanmjuanhwan (Sjh), a multiherbal formula from oriental traditional medicine, composed of Morus alba, Lycium chinense, and Atractylodes japonica, showed neuroprotective effects on primary neuronal cultures exposed to Aβ25–35. Sjh increased the expression of antiapoptotic proteins such as Bcl-2 and avoided cytochrome c release and caspase-3 activation [108]. B. monnieri and its active components bacoside A, bacopaside I and II, and bacosaponin C [109110] have anti-inflammatory, antimicrobial, and antidepressant effects [111113]. Treatment with B. monnieri prevented neuronal death by the inhibition of AChE activity in primary cortical culture pretreated with Aβ25–35 [114]. Furthermore, animals and volunteers treated with this plant presented enhanced memory [115117]. The antioxidant effect of S-allyl cysteine (SAC), an amino acid isolated from aged garlic, was tested in the Aβ25–35-AD rat model, showing ROS scavenger activity in vivo [118]. Also, in the mice AD dementia model induced with the intracerebroventricular streptozotocin infusion, SAC pretreatment decreased p53 expression, restored Bcl-2 protein expression, reduced, and prevented DNA fragmentation [119].

三木卷丸是一种来自东方传统中药的复方制剂,由白桑、枸杞子和关苍术组成,对 Aβ25-35诱导的原代培养神经元表现出神经保护作用。Sjh 增加 Bcl-2等抗凋亡蛋白的表达,避免细胞色素 c 释放和 caspase-3激活[108]。蒙氏菌及其活性成分 bacoside a,bacopaside i 和 II,bacosaponin c [109,110]具有抗炎、抗菌和抗抑郁作用[111-113]。通过抑制用 Aβ25-35预处理的原代培养皮层乙酰胆碱酯酶活性,蒙氏菌治疗可防止神经元死亡[114]。此外,用这种植物治疗的动物和志愿者表现出记忆增强[115-117]。在 Aβ25-35-AD 大鼠模型上测定了从陈蒜中分离得到的氨基酸 s- 烯丙基半胱氨酸(SAC)的抗氧化作用,结果表明,SAC 具有活性清除剂活性[118]。同时,SAC 预处理可以降低小鼠脑室注射链脲佐菌素诱导的 AD 痴呆模型 p53蛋白表达,恢复 Bcl-2蛋白表达,减少和防止 DNA 片段化[119]。

Mono- and diacetyled cyanidin and peonidin, the purple sweet potato anthocyanins (PSPA; Figure 1(o)) extracted from Ipomoea batatas, can easily attract ROS, which has high clinical value as antioxidant therapy in AD and other ND [120121]. For example, pretreatment of PC12 cells with PSPA reduced Aβtoxicity preventing lipid peroxidation, caspase-3 activation, and Aβ-induced apoptosis, suggesting a possible use in the treatment of AD [122].

紫甘薯花青素(PSPA,图1(o))是从 Ipomoea 中提取的单乙酰化和双乙酰化的花青素和 peonidin,能够吸引活性氧(ROS) ,在 AD 和其他 ND 的抗氧化治疗中具有很高的临床价值[120,121]。例如,用 PSPA 预处理 PC12细胞,可以减少 aβ 的毒性,防止脂质过氧化、 caspase-3激活和 aβ 诱导的细胞凋亡,这表明 PSPA 可能用于 AD 的治疗。

Finally, the use of ginseng, Panax ginseng, was evaluated in AD patients, those who received a daily dose 9 g of Korean red ginseng for 12 weeks showed a significant improvement in the AD assessment scale and the clinical dementia rating scale compared to control patients [123].

最后,对 AD 患者使用人参的情况进行评价,与对照组相比,每日服用9克朝鲜红参12周的 AD 评定量表和临床痴呆评定量表均有显著改善[123]。

7. Plant Compounds for Parkinson’s Disease Treatment

7. 治疗帕金森病的植物化合物

PD is the second most frequent ND and is primarily a movement disorder characterized by the loss of dopamine-producing neurons in substantia nigra. Activation of neuronal death pathways involves oxidative stress, neuroinflammation, and mitochondrial dysfunction [124].

帕金森病是第二常见的新城疫,主要是一种运动障碍,拥有属性是黑质中产生多巴胺的神经元丢失。神经元死亡通路的激活涉及氧化应激、神经炎症和线粒体功能障碍[124]。

Green tea extract and its isolated (–)-epigallocatechin-3-gallate polyphenol, as well as ginseng extract, have neuroprotective effects since their use diminished dopaminergic neuron loss in the substantia nigra and oxidative damage in an MPTP and its toxic metabolite MPP+ in PD animal models [125126]. Also,Chrysanthemum morifolium, which has antioxidant activity [126], inhibited MPTP-induced cytotoxicity and maintained cell viability of SH-SY5Y cell line, preventing ROS formation, decreasing Bax/Bcl2 ratio and caspase-3 activation [127]. The administration of 20 mg/kg of echinoside, a compound isolated fromCistanche salsa, before MPTP intoxication maintained striatal dopamine levels, reduced cell death, significantly increased the tyrosine hydroxylase enzyme expression, and reduced the activation of caspase-3 and caspase-8 expression, thus preventing neuronal death [128]. Likewise, silymarin treatment preserved dopamine levels, diminished the number of apoptotic cells, and preserved dopaminergic neurons in the substantia nigra of MPTP- and 6-hydroxydopamine-intoxicated mice (6-OHDA) [74129131]. Besides, pelargonidin (Figure 1(o)), an anthocyanidin with neuroprotective effects, reduced the motor deficit and histological damage and prevented lipid peroxidation in the 6-OHDA model [132134].

绿茶提取物及其分离的(-)-表没食子儿茶素没食子酸酯多酚,以及人参提取物,具有神经保护作用,因为他们使用减少多巴胺能神经元丢失的黑质和 MPTP 及其毒性代谢物 MPP + 在 PD 动物模型[125,126]的氧化损伤。此外,具有抗氧化活性的杭白菊能抑制 mptp 诱导的细胞毒性,维持 SH-SY5Y 细胞系的细胞活性,阻止活性氧的形成,降低 Bax/Bcl2比率和 caspase-3活化[127]。在 MPTP 中毒之前,给予从 Cistanche 盐地碱蓬中分离出的一种化合物棘果苷20mg/kg,可以维持纹状体多巴胺水平,减少细胞死亡,显著增加酪氨酸羟化酶的表达,降低 caspase-3和 caspase-8的表达,从而防止神经元死亡。同样,水飞蓟素治疗保存了多巴胺水平,减少了凋亡细胞的数量,并保存了 MPTP 和6- 羟基多巴胺中毒小鼠(6-OHDA)黑质的多巴胺能神经元。此外,pelargonidin (图1(o)) ,一种具有神经保护作用的花青素,减少运动障碍和组织损伤,并防止6-OHDA 模型中的脂质过氧化。

In the MPTP-intoxicated model of PD, SAC prevented lipid peroxidation and mitochondrial dysfunction [135], protected the striatum of mice from the morphological alterations with a reduction in TNF-α and iNOS expressions, and further reduction in astrocyte activation [136] and also, at 120 mg/kg dose by five days, partially ameliorated the MPTP-induced striatal and nigral dopamine and tyrosine hydroxylase depletion, attenuated the loss of manganese-dependent superoxide dismutase and heme oxygenase-1 activities, and preserved the protein content of these enzymes [137]. These findings suggest that SAC can exert neuroprotection since the origin of the dopaminergic lesion—at the substantia nigra—not only by using direct antioxidant actions but also through Nrf2 nuclear transactivation and phase 2 enzymes upregulation [137].

在 mptp 中毒的 PD 模型中,SAC 阻止了脂质过氧化和线粒体功能障碍,保护了小鼠纹状体免受形态学改变,降低了 tnf-α 和 iNOS 的表达,进一步减少了星形胶质细胞的活化,并且,在120mg/kg 剂量下,5天,部分改善了 mptp 诱导的黑质多巴胺和酪氨酸羟化酶,减少了锰依赖性超氧化物歧化酶和血红素氧合酶 -1活性的损失,并保持了这些酶的蛋白质含量。这些结果表明,SAC 不仅可以通过直接的抗氧化作用,而且还可以通过 Nrf2核反式激活和2相酶上调来发挥神经保护作用。

The commercial extract of Anemopaegma mirandum, a Brazilian tree, and the crude extract of Valeriana officinalis increased the viability of SH-SY5Y cells after rotenone exposure [138139], while the extract of Rhus vernicifluadecreased ROS production, preserved the mitochondrial integrity, and decreased the number of apoptotic cells [140]. An extract from Tripterygium regelii, a plant with antioxidant properties, reduced oxidative stress-induced cell death through the inhibition of apoptotic cascades, preserved mitochondrial function, and promoted tyrosine hydroxylase expression and brain-derived neurotrophic factor (BDNF) production in H2O2 treated SH-SY5Y cells [141]. Also, in the MPP+-intoxicated SH-SY5Y cells, the orchid increased cell viability, decreased cytotoxicity and ROS production, and prevented caspase-3 activation by diminishing the Bax/Bcl2 ratio [142].

商业提取物的银莲花,一个巴西树,和粗提取物的缬草提高了 SH-SY5Y 细胞的活力后鱼藤酮暴露[138,139] ,而提取物的漆树降低了活性氧的产生,维护线粒体完整性,并减少了凋亡细胞的数量[140]。东北雷公藤,一种具有抗氧化特性的植物,通过抑制凋亡级联,减少氧化应激诱导的细胞死亡,保持线粒体功能,并促进酪氨酸羟化酶表达和脑源性神经营养因子(BDNF)的产生在 H2O2处理的 SH-SY5Y 细胞[141]。同时,在 MPP + 中毒的 SH-SY5Y 细胞中,兰花提高了细胞活力,降低了细胞毒性和活性氧的产生,并通过降低 Bax/Bcl2比值阻止了 caspase-3的活化[142]。

In the same model, the flavonoid luteolin (Figure 1(k))—a compound present in celery, green pepper, pear leaves, and chamomile tea—provided neuroprotection against oxidative stress [143]. Also, luteolin inhibited LPS induced microglial activation, as well as the production of TNFα, NO, and superoxide in a midbrain mixed primary cultures [144]. Pedicularoside A, a glycosylated phenylethanoid isolated from Buddleja lindleyana, has anti-inflammatory properties and is a good scavenger of superoxide anions and hydroxyl radicals [145]; it protected against MPP+-induced death in mixed midbrain primary culture by increasing tyrosine hydroxylase expression and decreasing caspase-3 cleavage [146]. The plant extract from Uncaria rhynchophylla decreased cell death and ROS production and increased GSH levels in cultured PC12 cells, while 6-OHDA-induced caspase-3 activation was attenuated preventing cell death and rotational behavior was significantly reduced in the 6-OHDA PD model [147]. The ethyl extract from Myracrodruon urundeuva displayed similar properties in mesencephalic cultured cells since it preserved cell viability and attenuated oxidative stress after 6-OHDA exposure [148].

在同样的模型中,类黄酮木犀草素(图1(k))ー存在于芹菜、青椒、梨叶和洋甘菊茶中的一种化合物ー提供了对氧化应激的神经保护。木犀草素还能抑制 LPS 诱导的小胶质细胞活化,以及中脑混合原代培养物中 tnfα、 NO 和超氧化物的产生[144]。花梗苷 a 是从醉鱼草中分离得到的一种糖基化苯乙醇苷,具有抗炎作用,是一种对超氧阴离子和羟基自由基很好的清除剂,通过增加酪氨酸羟化酶的表达和减少 caspase-3的裂解,在混合中脑原代培养中能够防止 MPP + 引起的死亡。在培养的 PC12细胞中,嘴叶钩藤提取物降低了细胞死亡和活性氧产生,提高了 GSH 水平,而6-OHDA 诱导的 caspase-3激活减弱了细胞死亡,6-OHDA PD 模型显著降低了转动行为。Myracrodruon 乙基提取物在中脑培养细胞中表现出类似的特性,因为它保存了细胞活性,并在6-OHDA 暴露后减弱了氧化应激。

Panax notoginseng (PN) has the property to increase the expression of certain molecules such as nestin and BDNF, promoting neural plasticity and recovery after cerebral ischemia [149150]. Also, PN induces the expression of thioredoxin-1, an oxidoreductase with antiapoptotic and cell growth promoter effects [151], reducing MPTP-induced cell death in PC12 cells [152]. Likewise, the root extract of Withania somnifera promoted axon and dendrite growth [153154] and also increased the levels of SOD1, catalase, and GSH, preventing deficit motor in MPTP-intoxicated animals [155].

三七具有增加某些分子如 nestin 和 BDNF 表达的特性,促进脑缺血后神经可塑性和恢复[149,150]。PN 还诱导 PC12细胞氧化还原酶硫氧还蛋白 -1的表达,具有抗凋亡和促细胞生长作用[151] ,减少 mptp 诱导的细胞死亡[152]。同样地,睡茄根提取物促进轴突和树突的生长,也增加了 SOD1、过氧化氢酶和谷胱甘肽的水平,防止了 mptp 中毒动物的运动障碍。

The isoflavones daidzin, daidzein, and genistein contained in Pueraria thomsoniiprotected PC12 cells stimulated with 6-OHDA through the inhibition of the caspase-3 activation [156]. Moreover, genistein, a soy phytoestrogen, protected neurons from substantia nigra pars compact and attenuated the rotational behavior in a hemiparkinsonian 6-OHDA model [157]. Interestingly, the administration of Mucuna pruriens preceding 6-OHDA intoxication was more efficient than levodopa in controlling motor symptoms, since it restored dopamine and norepinephrine levels in the nigrostriatal track exhibiting a neuroprotective effect [158]. The mechanism of action of Mucuna pruriens is not fully understood; however, it has been proposed that increases the mitochondrial complex I activity without affecting the monoamine oxidase B activity, probably due to its high content of NADH and Q-10 coenzyme (Figure 3(a)), and its ability to scavenge ROS [159].

Pueraria 中的大豆黄酮、大豆黄酮和染料木素通过抑制 caspase-3的激活,对6-OHDA 刺激的 PC12细胞产生保护作用[156]。此外,genistein,一种大豆植物雌激素,保护黑质的神经元,并减弱偏侧帕金森病6-OHDA 模型的旋转行为[157]。有趣的是,在6-OHDA 中毒之前给予 Mucuna pruriens 比左旋多巴更有效地控制运动症状,因为它恢复了黑质纹状体轨道中的多巴胺和去甲肾上腺素水平,显示出神经保护作用[158]。虽然对于毛霉的作用机制还没有完全的了解,但是已经有人提出增加线粒体复合物 i 的活性而不影响单胺氧化酶B 的活性,这可能是由于其高含量的 NADH 和 Q-10辅酶(图3 a) ,以及它清除 ROS 的能力。

The herbal mixture Toki To (TKT), prepared of ten different plants (Angelicae Radix, Pinelliae Tuber, Cinnamomi Cortex, Ginseng Radix, Magnoliae Cortex,Paeoniae Radix, Astragali Radix, Zanthoxyli fructus, Zingiberis siccatum Rhizoma, and Glycyrrhizae Radix), has excellent results against PD [159]. TKT orally administered reduced motor symptoms such as bradykinesia, prevented dopaminergic neurons loss in the substantia nigra, and increased tyrosine hydroxylase and dopamine transporter expression in MPTP-intoxicated mice [159]. Through microarray it was determined that TKT per se regulates the expression of serum- and glucocorticoid regulated kinase gene (sgk), which are implicated in the PD pathogenesis [159].

以当归、半夏、桂皮、人参、木兰、芍药、黄芪、花椒、干姜、甘草等10种植物为原料制成的中药合剂 tokito (TKT)对 PD [159]具有良好的防治效果。口服 TKT 可以减少运动症状,如运动迟缓,防止多巴胺能神经元在黑质中丢失,增加酪氨酸羟化酶和多巴胺转运蛋白在 mptp 中毒小鼠中的表达。通过微阵列检测 TKT 自身对 PD 发病机制中血清和糖皮质激素调节激酶基因 sgk 表达的调节作用[159]。

Psoralea corylifolia seeds, specifically Δ3,2-hydroxybakuchiol monoterpene, which has been used for years in Chinese medicine for the treatment of cerebral aging and dementia [102160], protected SK-N-SH cells from MPP+intoxication and prevented the dopaminergic neurons loss in MPTP-intoxicated mice by inhibition of the monoamine transporter [161162]. Also it is worth mentioning that Rosmarinus officinalis, a plant used as flavoring in Mediterranean cuisine, has antioxidant properties [163]. Rosmarinus officinalisinhibits NO production [164] and protects dopaminergic neurons in different degenerative disease models [165168], probably due to its a high content of polyphenols and terpenes such as carnosol, carnosic acid, and rosmarinic acid and antiapoptotic effects [169].

补骨脂,特别是 δ3,2-hydroxybakuchiol monoterpene,多年来一直用于中药治疗脑老化和痴呆[102,160] ,保护 SK-N-SH 细胞免受 MPP + 中毒,并通过抑制单胺转运蛋白[161,162]防止 mptp 中毒小鼠多巴胺能神经元的丢失。同样值得一提的是,迷迭香,一种在地中海饮食中用作调味品的植物,具有抗氧化特性。迷迭香抑制 NO 的产生并保护不同神经退行性疾病模型的多巴胺能神经元,可能是因为它含有大量的多酚和萜类物质,如鼠尾草醇、鼠尾草酸和迷迭香酸,以及抗凋亡作用。

8. Plant Compounds for Cerebral Ischemia Management

8. 用于脑缺血治疗的植物化合物

In cerebral ischemia, severe neuronal damage occurs during the reperfusion period due to excitotoxicity, which consists of an overstimulation of N-methyl-D-aspartate (NMDA) receptors leading to glutamate production, which in turn triggers oxidative and inflammatory processes [26]. The intraperitoneal administration of 200 mg/kg of cactus polysaccharides, the active component isolated from Opuntia dillenii, prior to the middle cerebral artery occlusion showed neuroprotective effects [170171]. Opuntia dillenii significantly reduced infarct volume, decreased neuronal loss in the cerebral cortex, and diminished importantly the nitric oxide synthase (NOS) synthesis, which is usually induced during the experimental period of reperfusion and ischemia [171]. Also, oral pretreatment with 30 and 50 mg/kg daily of Smilacis chinaerhizome (SCR) methanol extract reduced the histological changes associated with ischemic injury [172]. It is possible that SCR prevented excitotoxicity-induced neuronal death by decreasing ROS generation, similar to the observations made in vitro in primary cultures of cortical cells treated with 1 mM NMDA [172]. Additionally, intravenous pretreatment with silymarin reduced infarcted area size, as well as neurological deficits associated with ischemic damage [173]. Also, silymarin inhibited protein expression associated with inflammation such as iNOS, cyclooxygenase-2, myeloperoxidase, the nuclear transcription factor NF-κB, and proinflammatory cytokines like IL-1β and TNFα, avoiding neurodegeneration associated with ischemia [173]. Similarly, SAC administration reduced infarct volume in a rat brain ischemia model [174] and decreased lipid peroxidation to basal levels suggesting SAC beneficial effects in brain ischemia and that the major protective mechanism may be the inhibition of free radical-mediated lipid peroxidation [175].

在脑缺血中,由于兴奋性毒性,在再灌注期间会发生严重的神经元损伤,这种损伤包括 n- 甲基 -d- 天冬氨酸(NMDA)受体的过度刺激导致谷氨酸的产生,从而触发氧化和炎症过程[26]。在大脑中动脉闭塞之前,腹腔注射200mg/kg 仙人掌多糖(从 Opuntia 分离出的活性成分) ,显示出神经保护作用。仙人掌显著减少梗死体积,减少大脑皮层神经元丢失,并且重要地减少了一氧化氮合酶合成,这种合成通常是在实验性再灌注和缺血期间诱导的[171]。同时,每日口服30和50mg/kg 的菝葜甲醇提取物可以减少缺血性损伤的组织学改变[172]。可能是 SCR 通过减少活性氧的产生来阻止兴奋毒性诱导的神经元死亡,类似于用1mm NMDA 处理的皮层细胞的体外原代培养的观察[172]。此外,静脉注射水飞蓟素可以减少梗死面积,以及与缺血性损伤相关的神经缺损[173]。此外,水飞蓟素还能抑制与炎症相关的蛋白质表达,如 iNOS、环氧化酶2、髓过氧化物酶、核转录因子因子 NF-κB 和促炎症细胞因子如 il-1β 和 tnfα,避免与缺血相关的神经退行性疾病。同样,SAC 可以减少大鼠脑缺血模型的梗死体积,降低脂质过氧化至基础水平,提示 SAC 对脑缺血有益,主要的保护机制可能是抑制自由基介导的脂质过氧化。

9. Conclusions

9. 结论

Neurodegenerative diseases (ND) are chronic and progressive conditions, characterized by neuronal loss secondary to oxidative stress and neuroinflammation (Figure 4). Until now ND have no cure and represent high costs for the health system and patients families. Exploring alternative sources for ND therapy has led to set eyes on herbal medicine since most herbal compounds have antioxidant and anti-inflammatory properties. At present, the use of several plants in the treatment of ND is being supported by numerous scientific investigations (the main effects of herbal plants against ND are listed in Table 1). However, information is still missing on relevant aspects such as metabolism, pharmacokinetics, and bioavailability in the brain as well as any changes that they may have in the CNS. Nevertheless, plant compounds or extracts remain interesting therapeutic candidates for ND management.

神经退行性疾病(ND)是慢性和进行性疾病,继发于拥有属性氧化应激和神经炎症的神经元丢失(图4)。到目前为止,新城疫还没有治愈方法,而且对卫生系统和患者家属来说代价高昂。由于大多数草药化合物具有抗氧化和抗炎的特性,探索新城疫治疗的替代来源已经引起了人们对草药的关注。目前,多项科学研究支持使用多种植物治疗 ND (草药植物对 ND 的主要效果列于表1)。然而,有关大脑的新陈代谢、药代动力学、生物利用度以及中枢神经系统的变化等相关方面的信息仍然缺失。然而,植物化合物或提取物仍然是 ND 治疗的有趣候选药物。

Effect 效果Plant compound/extract 植物化合物/提取物Model模型Disease/condition 疾病/病况Reference参考资料Antiapoptotic and/or cell viability 抗凋亡和/或细胞活性Anemopaegma mirandum 怀疑风草extracts. 提取物In vitro体外培养Rotenone model in SH-SY5Y cells. SH-SY5Y 细胞鱼藤酮模型的建立[137]Pueraria thomsonii.粉葛In vitro体外培养6-OHDA model in PC12 cells. PC12细胞中的6- 羟多巴胺模型[155]Cistanche salsa. 肉苁蓉In vivo活体内MPP 计算机辅助程序+ mice model. 小鼠模型[127]Gastrodia elata 天麻extract. 提取In vitro体外培养MPP 计算机辅助程序+model in SH-SY5Y cells. SH-SY5Y 细胞模型[141]Rosmarinus officinalis 迷迭香extract. 提取In vitro体外培养Aβ model in cortical neurons. 皮层神经元模型[168]Chrysanthemum morifolium 杭白菊extract. 提取In vitro体外培养MPP 计算机辅助程序+model in SH-SY5Y cells. SH-SY5Y 细胞模型[126]Panax notoginseng.三七In vitro体外培养MPTP model in mesencephalic neurons. 中脑神经元的 MPTP 模型[151]Piperine (Figure 胡椒碱(图2(d)).In vitro体外培养Rotenone model in SH-SY5Y cells. SH-SY5Y 细胞鱼藤酮模型的建立[104]L-theanine, 茶氨酸,from green tea (Figure 从绿茶(图3(b)).In vitro体外培养H2O2 model in SH-SY5Y cells. SH-SY5Y 细胞模型[16]Toki-to, mixed medicinal herbs. 东京到,混合草药In vitro体外培养
In vivo活体内6-OHDA model in PC12 cells. PC12细胞中的6- 羟多巴胺模型
6-OHDA rat model. 6- 羟多巴胺大鼠模型[158]Nobiletin, 诺比莱汀,a flavonoid from citrus peels. 柑橘皮中的一种黄酮类化合物In vitro体外培养
In vivo活体内H2O2 model in PC12 cells.   PC12细胞模型
Rat artery occlusion model. 大鼠动脉闭塞模型[95]Psoralea corylifolia.补骨脂In vitro体外培养
In vivo活体内MPP 计算机辅助程序+model in CHO cells and SK-N-SH cells.   CHO 细胞和 SK-N-SH 细胞模型的建立
MPTP mice and rat model.MPTP 小鼠和大鼠模型[161]Chrysanthemum morifolium 杭白菊extract. 提取In vitro体外培养MPP 计算机辅助程序+model in SH-SY5Y cell. SH-SY5Y 细胞模型[126]Uncaria rhynchophylla 嘴叶钩藤extract 提取.In vitro体外培养Rotenone model in SH-SY5Y cells. SH-SY5Y 细胞鱼藤酮模型的建立[146]Polyphenolic extract from 多酚提取物 Vitis vinifera.葡萄In vitro体外培养Rotenone model in SH-SY5Y cells. SH-SY5Y 细胞鱼藤酮模型的建立[93]Withania somnifera睡茄extract 提取.In vitro体外培养
In vivo活体内MPP 计算机辅助程序+model in CHO cells and SK-N-SH cells. CHO 细胞和 SK-N-SH 细胞模型的建立
MPTP mice and rat model.MPTP 小鼠和大鼠模型[154]Paeonol from 丹皮酚 Paeonia suffruticosa 牡丹or或 Paeonia lactiflora. 芍药In vitro体外培养
In vivo活体内MPP 计算机辅助程序+model in PC12 cells. PC12细胞模型
MPP 计算机辅助程序+ mice model. 小鼠模型[14]Ipomoea batatas 甘薯PoirCv.In vitro体外培养Aβ model in PC12 cells. PC12细胞模型[121]Biotransformed blueberry juice by生物转化的蓝莓汁Serratia vaccinii bacteria. 疫苗沙雷氏菌In vitro体外培养H2O2 model in neuronal cells. 神经元细胞模型[61]Polyphenolic from cocoa. 可可中的多酚类物质In vivo活体内Aged rats. 老鼠[76]Salvia miltiorrhiza.丹参In vitro体外培养
In vivo活体内Cortical neurons overexpressing APP695. 过表达 APP695的皮层神经元
APP/PS1 transgenic mice. APP/PS1转基因小鼠[88]Opuntia dillenii. 仙人掌In vitro体外培养
In vivo活体内NMDA model in cortical neurons. 大脑皮质神经元 NMDA 模型的建立
Rat artery occlusion model. 大鼠动脉闭塞模型[169]Selaginellin 卷柏属from 从 Saussurea pulvinata. 垫风毛菊In vivo活体内Aβ mice model. 小鼠模型[63]Mucuna pruriens. 毛霉属In vivo活体内APP-SL 7-5 transgenic mice APP695. App-sl7-5转基因小鼠 APP695[157]Urundeuvines A, B, and C chalcones from 和 c 的查尔康Myracrodruon urundeuva. 桃金娘属In vivo活体内6-OHDA model in mesencephalic cells. 6- 羟多巴胺中脑细胞模型的建立[147]Cell survival细胞存活Bacopa monnieri 蒙氏杆菌extract 提取.In vitro体外培养Aβ model in cortical neurons. 皮层神经元模型[113]Dioscorea opposita.怀山药In vitro体外培养
In vivo活体内H2O2 or glutamate model in cortical neurons. 皮层神经元的谷氨酸盐模型
Scopolamine mice model.东莨菪碱小鼠模型[106]Nobiletin, flavonoid 黄酮类化合物 from citrus peels. 从柑橘皮中提取的In vitro体外培养
In vivo活体内H2O2 model in PC12 cells.PC12细胞模型
Rat artery occlusion model. 大鼠动脉闭塞模型[95]Opuntia dillenii. 仙人掌In vitro体外培养
In vivo活体内NMDA model in cortical neurons. 大脑皮质神经元 NMDA 模型的建立
Rat artery occlusion model. 大鼠动脉闭塞模型[169]Pelargonidin 天竺葵属(Figure (图一)1(o)).In vivo活体内Ethylcholine aziridinium ion model (AF64A). 乙胆碱氮杂环丙烷离子模型(AF64A)[133]Psoralea corylifolia.补骨脂In vitro体外培养
In vivo活体内MPP 计算机辅助程序+model in CHO cells and SK-N-SH cells. CHO 细胞和 SK-N-SH 细胞模型的建立
MPTP mice and rat model.MPTP 小鼠和大鼠模型[161]Withania somnifera睡茄extract 提取.In vitro体外培养
In vivo活体内MPP 计算机辅助程序+model in CHO cells and SK-N-SH cells. CHO 细胞和 SK-N-SH 细胞模型的建立
MPTP mice and rat model.MPTP 小鼠和大鼠模型[154]Paeonol from 丹皮酚 Paeonia suffruticosa 牡丹or或 Paeonia lactiflora. 芍药In vitro体外培养
In vivo活体内MPP 计算机辅助程序+model in PC12 cells. PC12细胞模型
MPP 计算机辅助程序+ mice model. 小鼠模型[14]Pedicularioside A from 马先蒿甲苷Buddleia lindleyana. 林德利亚醉鱼草In vivo活体内6-OHDA rat model. 6- 羟多巴胺大鼠模型[145]Silybum marianum.乳蓟In vivo活体内MPTP mice model. MPTP 小鼠模型[172]Toki-to, mixed medicinal herbs. 东京到,混合草药In vitro体外培养
In vivo活体内6-OHDA model in PC12 cells. PC12细胞中的6- 羟多巴胺模型
6-OHDA rat model. 6- 羟多巴胺大鼠模型[158]Urundeuvines A, B and C chalcones from 和 c 的查尔酮Myracrodruon urundeuva. 桃金娘属In vivo活体内6-OHDA model in mesencephalic cells. 6- 羟多巴胺中脑细胞模型的建立[147]Salvia miltiorrhiza.丹参In vitro体外培养
In vivo活体内Cortical neurons overexpressing APP695. 过表达 APP695的皮层神经元
APP/PS1 transgenic mice. APP/PS1转基因小鼠[88]Centella asiatica 崩大碗extract 提取.In vivo活体内PSAPP mice. 鼠标[92]Ipomoea batatas 甘薯PoirCv.In vitro体外培养Aβ model in PC12 cells. PC12细胞模型[121]Mucuna pruriens. 毛霉属In vivo活体内APP-SL 7-5 model in transgenic mice APP695. App-sl7-5转基因小鼠模型的建立[157]Valeriana officinalis缬草extract 提取.In vivo活体内Tg2576 transgenic mice. Tg2576转基因小鼠[138]Luteolin. 木犀草素In vitro体外培养LPS model in mesencephalic neuron-glia and microglia cells. LPS 模型在中脑神经胶质细胞和小胶质细胞中的应用[143]Panax notoginseng.三七In vitro体外培养MPTP model in mesencephalic neuron. 中脑神经元 MPTP 模型[151]Piperine 胡椒碱(Figure (图一)2(d)).In vitro体外培养Rotenone model in SH-SY5Y cells. SH-SY5Y 细胞鱼藤酮模型的建立[104]L-theanine, 茶氨酸,from green tea (Figure 从绿茶(图3(b)).In vitro体外培养H2O2 model in SH-SY5Y cells. SH-SY5Y 细胞模型[16]Tripterygium regelii methanolic 东北雷公藤extract. 提取In vitro体外培养6-OHDA model in mesencephalic cells. 6- 羟多巴胺中脑细胞模型的建立[140]Antioxidant 抗氧化剂Biotransformed blueberry juice by生物转化的蓝莓汁Serratia vaccinii bacteria. 疫苗沙雷氏菌In vitro体外培养H2O2 model in neuronal cell. 神经元细胞模型[61]Rosmarinus officinalis. 迷迭香In vitro体外培养
In vivo活体内H2O2 or rotenone model in SH-SY5Y cells. Dieldrin model in SN4741 cells. 在 SH-SY5Y 细胞中建立鱼藤酮模型,在 SN4741细胞中建立狄氏剂模型
Aged rats. 老鼠[166]Centella asiatica 崩大碗extract 提取.In vivo活体内PSAPP mice. 鼠标[92]Chrysanthemum morifolium 杭白菊extract 提取.In vitro体外培养MPP 计算机辅助程序+model in SH-SY5Y cell. 细胞模型[126]Ipomoea batatas 甘薯PoirCv.In vitro体外培养Aβ model in PC12 cells. PC12细胞模型[121]Gastrodia elata 天麻extract 提取.In vitro体外培养MPP 计算机辅助程序+model in SH-SY5Y cells. 细胞模型[141]Nobiletin, 诺比莱汀,flavonoid from citrus peels. 柑橘皮中的黄酮In vitro体外培养
In vivo活体内H2O2 model in PC12 cells. PC12细胞模型
Rat artery occlusion model. 大鼠动脉闭塞模型[95]Opuntia dillenii. 仙人掌In vitro体外培养
In vivo活体内NMDA model in cortical neurons. 大脑皮质神经元 NMDA 模型的建立
Rat artery occlusion model. 大鼠动脉闭塞模型[169]Methanolic extracts from 甲醇提取物Salvia species. 鼠尾草属种In vitro体外培养Glutamate model in PC12 cells. PC12细胞的谷氨酸模型[62]Toki-to, mixed medicinal herbs. 东京到,混合草药In vitro体外培养
In vivo活体内6-OHDA model in PC12 cells. PC12细胞中的6- 羟多巴胺模型
6-OHDA rat model. 6- 羟多巴胺大鼠模型[158]Tripterygium regelii东北雷公藤methanolic extract. 甲醇提取物In vitro体外培养6-OHDA model in mesencephalic cells. 6- 羟多巴胺中脑细胞模型的建立[140]Vincamine from 长春碱来自 Vinca minor 小长春花(Figure (图一)2(c)).In vivo活体内Mice. 老鼠[80]Paeonol from 丹皮酚 Paeonia suffruticosa 牡丹or或 Paeonia lactiflora. 芍药In vitro体外培养
In vivo活体内MPP 计算机辅助程序+model in PC12 cells. PC12细胞模型
MPP 计算机辅助程序+ mice model. 小鼠模型[14]Oxyresveratrol and resveratrol from 白藜芦醇和白藜芦醇Smilacis chinae rhizome 菝葜(Figure(图一)1(c)).In vivo活体内d-galactose mice model. D- 半乳糖小鼠模型[171]Rhus verniciflua 漆树extract 提取.In vitro体外培养H2O2 model in PC12 cells. PC12细胞模型[139]Salvia miltiorrhiza.丹参In vitro体外培养
In vivo活体内Cortical neurons overexpressing APP695. 过表达 APP695的皮层神经元
APP/PS1 transgenic mice. APP/PS1转基因小鼠[88]Bacopa monnieri 蒙氏杆菌extract. 提取In vivo活体内Aβ model in cortical neurons. 皮层神经元模型[113]Buddleia lindleyana. 林德利亚醉鱼草In vivo活体内6-OHDA rat model. 6- 羟多巴胺大鼠模型[145]Pelargonidin 天竺葵属(Figure (图一)1(o)).In vivo活体内Ethylcholine aziridinium ion model (AF64A). 乙胆碱氮杂环丙烷离子模型(AF64A)[133]Samjunghwan, multiherbal extract. 三君丸,复方草药提取物In vivo活体内Acute ischemic stroke model. 急性缺血性卒中模型[107]Motor/cognitive improvement 运动/认知改善Silybum marianum.乳蓟In vivo活体内MPTP mice model. MPTP 小鼠模型[172]Methanolic extracts from 甲醇提取物species of Salvia. Salvia 的物种In vitro体外培养Glutamate model in PC12 cells. PC12细胞的谷氨酸模型[62]Pedicularioside A from 马先蒿甲苷Buddleia lindleyana. 林德利亚醉鱼草In vivo活体内6-OHDA rat model. 6- 羟多巴胺大鼠模型[145]Paeonol from 丹皮酚 Paeonia suffruticosa 牡丹or或 Paeonia lactiflora. 芍药In vitro体外培养
In vivo活体内MPP 计算机辅助程序+model in PC12 cells. PC12细胞模型
MPP 计算机辅助程序+ mice model. 小鼠模型[14]Oxyresveratrol & resveratrol from 白藜芦醇和白藜芦醇Smilacis chinae rhizome 菝葜(Figure(图一)1(c)).In vivo活体内d-galactose mice model. D- 半乳糖小鼠模型[171]Magnolia officinalis.厚朴In vivo活体内SAMP8 mice. 8小鼠[81]Cistanche salsa. 肉苁蓉In vivo活体内MPP 计算机辅助程序+ mice model. 小鼠模型[127]Polyphenolic compounds extracted from cocoa. 从可可中提取的多酚化合物In vivo活体内Aged rats. 老鼠[76]Luteolin. 木犀草素In vitro体外培养LPS model in mesencephalic neuron-glia and microglia cells. LPS 模型在中脑神经胶质细胞和小胶质细胞中的应用[143]Cassia obtusifolia.决明In vivo活体内Scopolamine model. 东莨菪碱模型
Transient cerebral hypoperfusion model. 短暂性脑灌注不足模型[102]Dioscorea opposita.怀山药In vitro体外培养
In vivo活体内H2O2 or glutamate model in cortical neurons. 皮层神经元的谷氨酸盐模型
Scopolamine mice model.东莨菪碱小鼠模型[106]Korean red ginseng.高丽红参Clinical trials临床试验AD patients. 老年痴呆症患者[122]Pelargonidin 天竺葵属(Figures (数字1(d) and 及1(e)).In vivo活体内Ethylcholine aziridinium ion model (AF64A). 乙胆碱氮杂环丙烷离子模型(AF64A)[133]Saussurea pulvinata. 垫风毛菊In vivo活体内Aβ mice model. 小鼠模型[63]Toki-to, mixed medicinal herbs. 东京到,混合草药In vitro体外培养
In vivo活体内6-OHDA model in PC12 cells. PC12细胞中的6- 羟多巴胺模型
6-OHDA rat model. 6- 羟多巴胺大鼠模型[158]Valeriana officinalis缬草extract 提取.In vivo活体内Tg2576 transgenic mice. Tg2576转基因小鼠[138]Piperine 胡椒碱(Figure (图一)2(d)).In vitro体外培养Rotenone model in SH-SY5Y cells. SH-SY5Y 细胞鱼藤酮模型的建立[104]L-theanine, 茶氨酸,from green tea (Figure 从绿茶(图3(b)).In vitro体外培养H2O2 model in SH-SY5Y cells. SH-SY5Y 细胞模型[16]Anti-inflammatory 消炎药Zingiberis Rhizoma干姜hexane extract 己烷萃取物.In vitro体外培养LPS model in BV-2 microglia cells. BV-2小胶质细胞内毒素模型的建立[69]Ficus religiosa 信仰榕leaf 叶子.In vitro体外培养LPS model in BV-2 microglia cells. BV-2小胶质细胞内毒素模型的建立[68]Luteolin. 木犀草素In vitro体外培养LPS model in mesencephalic neuron-glia and microglia cells. LPS 模型在中脑神经胶质细胞和小胶质细胞中的应用[143]Samjunghwan, multiherbal extract. 三君丸,复方草药提取物In vivo活体内Acute ischemic stroke model. 急性缺血性卒中模型[107]Saussurea pulvinata. 垫风毛菊In vivo活体内Aβ mice model. 小鼠模型[63]Silybum marianum.乳蓟In vivo活体内MPTP mice model. MPTP 小鼠模型[172]Rosmarinus officinalis. 迷迭香In vitro体外培养 H2O2 or rotenone model in SH-SY5Y cells. 用 SH-SY5Y 细胞制备鱼藤酮模型 Dieldrin model in SN4741 cells. SN4741细胞中的狄氏剂模型[166]In vivo活体内Aged rats. 老鼠 Nobiletin, flavonoid from citrus peels. 柑橘皮中的黄酮类化合物In vitro体外培养
In vivo活体内H2O2 model in PC12 cells. PC12细胞模型
Rat artery occlusion model. 大鼠动脉闭塞模型[95]Cassia obtusifolia.决明In vivo活体内Scopolamine model. 东莨菪碱模型
Transient cerebral hypoperfusion model. 短暂性脑灌注不足模型[102]Methoxsalen from 甲氧沙伦来自Poncirus trifoliate.三叶枳In vivo活体内Trimethyltin mice model. 三甲基锡小鼠模型[15]Pelargonidin 天竺葵属(Figure (图一)1(o)).In vivo活体内Ethylcholine aziridinium ion model (AF64A). 乙胆碱氮杂环丙烷离子模型(AF64A)[133]Tripterygium regelii东北雷公藤methanolic extract. 甲醇提取物In vitro体外培养6-OHDA model in mesencephalic cells. 6- 羟多巴胺中脑细胞模型的建立[140]
6-OHDA: 6-hydroxydopamine; A 6-OHDA: 6- 羟基多巴胺; a: beta-peptide amyloid aggregation; LPS: lipopolysaccharide; MPP β- 淀粉样蛋白聚集; 脂多糖: 脂多糖; MPP+:1-methyl-4-phenylpyridinium; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NMDA: MPP+ ; MPTP: 1-甲基-4-苯基-1,2,3,6-四氢吡啶; NMDA:-methyl-D-aspartate. – 甲基 -d- 天冬氨酸

Table 1 表一Main biological effects of phytodrugs in neurodegenerative diseases models. 植物药在神经退行性疾病模型中的主要生物学作用

Figure 4 图4Main neuronal death pathways caused by oxidative stress. Oxidative stress can lead to neuronal death via several mechanisms such as mitochondrial dysfunction, DNA damage, membrane permeability loss, protein aggregation, and apoptosis. Phytodrugs, mainly polyphenols and alkaloids, can prevent this neuronal damage and, therefore, cellular death. Thus, these natural compounds can be used in the treatment of ND and also could serve as models for developing new specific drugs against these pathologies. 氧化应激引起的主要神经元死亡通路。氧化应激可以通过几种机制导致神经元死亡,如线粒体功能障碍、 DNA 损伤、膜通透性损失、蛋白质聚集和凋亡。植物药物,主要是多酚和生物碱,可以防止这种神经损伤,因此,细胞死亡。因此,这些天然化合物可用于治疗新城疫,也可作为开发新的特异性药物治疗这些疾病的模型

Abbreviations

缩写

AChE: 乙酰胆碱酯酶:Acetyl cholinesterase 乙酰胆碱酯酶
AD: 广告:Alzheimer’s disease 老年痴呆症
Aβ:Amyloid beta-peptide 淀粉样 β 肽
ALS: 肌萎缩侧索硬化症:Amyotrophic lateral sclerosis 肌萎缩性嵴髓侧索硬化症
Bax: 巴克斯:Apoptosis regulator 细胞凋亡调节剂
Bcl-2:B cell lymphoma 2; family of regulator proteins of apoptosis B 细胞淋巴瘤2; 凋亡调节蛋白家族
BDNF: 脑源性神经营养因子:Brain-derived neurotrophic factor 脑源性神经营养因子
CNS: 中枢神经系统:Central nervous system 中枢神经系统
CAMP: 营地:Cyclic adenosine monophosphate 环腺苷酸
DNA:Deoxyribonucleic acid 脱氧核糖核酸
ERK:Extracellular signal-regulated kinase 细胞外信号调节激酶
GSH: 谷胱甘肽:Glutathione reduced 谷胱甘肽
H2O2:Hydrogen peroxide 过氧化氢
IL-1 白介素 -1β:Interleukin 1 白细胞介素1β
IL-6: 白介素 -6:Interleukin 6 白细胞介素6
iNOS: 诱导型一氧化氮合酶:Inducible nitric oxide synthase 诱导型一氧化氮合酶
LPS:Lipopolysaccharide 脂多糖
MAPK:Mitogen-activated protein kinase 有丝分裂原活化蛋白激酶
MEK: 甲乙视:Mitogen/extracellular signal-regulated kinase 有丝分裂原/细胞外信号调节激酶
MPP 计算机辅助程序+:1-Methyl-4-phenylpyridinium MPP+
MPTP:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine 1-甲基-4-苯基-1,2,3,6-四氢吡啶
MS:Multiple sclerosis 多发性硬化症
NADPH:Reduced form of nicotinamide adenine dinucleotide phosphate 烟酰胺腺嘌呤二核苷酸磷酸的简化形式
NO: 答案:Nitric oxide 一氧化氮
NMDA: 门冬氨酸:N-Methyl-D-aspartate N- 甲基 -d- 天冬氨酸
ND: 查询:Neurodegenerative diseases 神经退行性疾病
NF-κB: 乙:Nuclear factor- 核因子-κB
Nrf2:Nuclear factor (erythroid-derived 2)-like 2 类核因子(红系衍生物2)2
NOS: 号码:Nitric oxide synthase 一氧化氮合酶
6-OHDA:6-Hydroxydopamine-intoxicated mice 6- 羟基多巴胺中毒的小鼠
PC12:Cell line derived from a pheochromocytoma of the rat adrenal medulla 来源于大鼠肾上腺髓质嗜铬细胞瘤的细胞系
PD: 问:Parkinson’s disease 帕金森氏症
PN: 返回文章页面纽约时报译者:Panax notoginseng 三七
ROS: 活性氧:Reactive oxygen species 活性氧类
SAC: 战略行动指挥中心:S-Allyl cysteine S- 烯丙基半胱氨酸
Sjh:Sanmjuanhwan 三木卷湾
SCR: 可控硅:Smilacis chinae rhizome 菝葜
SOD1: 1:Superoxide dismutase 1 超氧化物歧化酶1
TKT:Toki To
TNF 肿瘤坏死因子α:Tumor necrosis factor 肿瘤坏死因子-αα.

Conflict of Interests

利益冲突

The authors declare that there is no conflict of interests regarding the publication of this paper.

作者声明,在发表这篇论文方面没有利益冲突。

Authors’ Contribution

作者的贡献

Jesús Pérez-Hernández and Víctor Javier Zaldívar-Machorro contributed equally to this paper.

赫苏斯 · 佩雷斯-埃尔南德斯和维克托 · 哈维尔 · 扎尔德瓦尔-马舍罗对本文作出了同样的贡献。

Acknowledgments

鸣谢

Funding for this research was provided by the Medical School and grants from Dirección General de Asuntos del Personal Académico (DGAPA; IN217612 and IN222215), National Autonomous University of Mexico (UNAM). Jesús Pérez-Hernández and David Villanueva-Porras are recipient of a fellowship sponsored by the Consejo Nacional de Ciencia y Tecnología (CONACyT) and Víctor Javier Zaldívar-Machorro is recipient of a postdoctoral fellowship sponsored by DGAPA, UNAM.

这项研究的资金由医学院提供,并由个人研究项目总监督管理委员会(DGAPA; IN217612和 in22215)、墨西哥国立自治大学提供资助。赫苏斯佩雷斯埃尔南德斯和大卫 villanueva-波拉斯获得了由萨尔瓦多国家科学技术委员会发起的奖学金,维克托 Javier Zaldívar-Machorro 获得了由 UNAM DGAPA 发起的博士后奖学金。

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