黄酮类前瞻性神经保护剂及其对老年性神经系统疾病的治疗作用

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Flavonoids as Prospective Neuroprotectants and Their Therapeutic Propensity in Aging Associated Neurological Disorders

Muhammad Ayaz 穆罕默德 · 阿亚兹1* 1 *Abdul Sadiq 阿卜杜勒 · 萨迪克1Muhammad Junaid 穆罕默德 · 朱奈德1,2Farhat Ullah1Muhammad Ovais 穆罕默德 · 奥维斯3,4Ikram Ullah 伊克拉姆 · 乌拉5Jawad Ahmed 贾瓦德 · 艾哈迈德6 and 及Muhammad Shahid 穆罕默德 · 沙希德7

  • 1Department of Pharmacy, University of Malakand, Chakdara, Pakistan Chakdara 马拉坎大学药学系
  • 2Department of Pharmacy, University of Swabi, Swabi, Pakistan Swabi 斯瓦比大学药学系
  • 3University of Chinese Academy of Sciences, Beijing, China 中国科学院大学,北京
  • 4Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China 纳米材料和 Nanosafety 生物医学效应重点实验室,中国科学院纳米科学研究中心,国家纳米科学技术中心,北京
  • 5Suliman Bin Abdullah Aba-Alkhail Centre for Interdisciplinary Research in Basic Sciences, International Islamic University Islamabad, Islamabad, Pakistan 巴基斯坦伊斯兰堡国际伊斯兰大学科际整合基础科学中心
  • 6Institute of Basic Medical Sciences (IBMS), Khyber Medical University, Peshawar, Pakistan 巴基斯坦白沙瓦开伯尔医科大学基础医学研究所
  • 7Department of Pharmacy, Sarhad University of Science and Information Technology (SUIT), Peshawar, Pakistan 巴基斯坦白沙瓦萨哈德科学与信息技术大学药学系

Modern research has revealed that dietary consumption of flavonoids and flavonoids-rich foods significantly improve cognitive capabilities, inhibit or delay the senescence process and related neurodegenerative disorders including Alzheimer’s disease (AD). The flavonoids rich foods such as green tea, cocoa, blue berry and other foods improve the various states of cognitive dysfunction, AD and dementia-like pathological alterations in different animal models. The mechanisms of flavonoids have been shown to be mediated through the inhibition of cholinesterases including acetylcholinesterase (AChE), and butyrylcholinesterase (BChE), β-secretase (BACE1), free radicals and modulation of signaling pathways, that are implicated in cognitive and neuroprotective functions. Flavonoids interact with various signaling protein pathways like ERK and PI3-kinase/Akt and modulate their actions, thereby leading to beneficial neuroprotective effects. Moreover, they enhance vascular blood flow and instigate neurogenesis particularly in the hippocampus. Flavonoids also hamper the progression of pathological symptoms of neurodegenerative diseases by inhibiting neuronal apoptosis induced by neurotoxic substances including free radicals and β-amyloid proteins (Aβ). All these protective mechanisms contribute to the maintenance of number, quality of neurons and their synaptic connectivity in the brain. Thus flavonoids can thwart the progression of age-related disorders and can be a potential source for the design and development of new drugs effective in cognitive disorders.

现代研究表明,食用富含黄酮类化合物和黄酮类化合物的食物可以显著提高认知能力,抑制或延缓衰老过程和相关的神经退行性疾病,包括阿尔茨海默病(AD)。富含类黄酮的食物,如绿茶、可可、蓝莓和其他食物,可以改善不同动物模型的认知功能障碍、 AD 和类似痴呆的病理改变的各种状态。黄酮类化合物通过抑制乙酰胆碱酯酶(AChE)、丁酰胆碱酯酶(BChE)、 β- 分泌酶(BACE1)、自由基和信号通路调节等途径介导其作用机制,这些途径与认知和神经保护功能有关。黄酮类化合物与多种信号蛋白通路如 ERK 和 pi3激酶/akt 相互作用,调节其作用,从而产生有益的神经保护作用。此外,它们可以促进血管血流,刺激神经形成,尤其是在海马区。黄酮类化合物还通过抑制神经毒性物质(包括自由基和 β- 淀粉样蛋白(aβ))诱导的神经元凋亡,阻碍神经退行性疾病病理症状的进展。所有这些保护机制有助于维持数量,质量的神经元和他们的突触连接在大脑。因此,黄酮类化合物可以阻止年龄相关疾病的进展,并且可以成为设计和开发有效治疗认知障碍的新药物的潜在来源。

Introduction

引言

Flavonoids represent a diverse group of naturally occurring compounds which are biosynthesized from phenylalanine, and are ubiquitous to green pigments in the plant kingdom (Havsteen, 2002). Flavonoids have a long history of medical use for the treatment of various medical ailments (Rice-Evans and Packer, 2003). Their great diversity, distribution and easy isolation make them a dominant class of therapeutic agents. Flavonoids are the major building blocks for the synthesis of various drugs and may itself be used as natural products, thus play a pivotal role in the domain of drug design and discovery (Havsteen, 1983). Until now, more than 7,000 flavonoids have been reported from natural sources including medicinal plants, vegetables, fruits and wines. Flavonoids have the ability to bind with numerous body proteins and modify the transporters, enzymes, hormones, DNA, chelation of heavy metals and scavenge the free radicals; therefore, possess strong antioxidant properties (Havsteen, 1983Robak and Gryglewski, 1988Morel et al., 1993Cushnie and Lamb, 2005). A myriad number of pharmacological studies have been reported that suggest their usefulness in the management of diabetes mellitus (DM), cancer, cardiovascular diseases, neurological disorders, inflammation and microbial diseases (Middleton et al., 2000Marder and Paladini, 2002Galati and O’Brien, 2004Cushnie and Lamb, 2005).

黄酮类化合物代表了一组由苯丙氨酸生物合成的多样化合物,在植物界普遍存在于绿色色素(Havsteen,2002)。黄酮类化合物在医学上用于治疗各种疾病有着悠久的历史(Rice-Evans 和 Packer,2003)。它们的多样性、分布和易于分离使它们成为治疗药物的主要类别。黄酮类化合物是合成各种药物的主要组成部分,本身可以作为天然产物使用,因此在药物设计和发现领域起着关键作用(Havsteen,1983)。到目前为止,超过7000种黄酮类化合物已被报道来自自然资源,包括药用植物、蔬菜、水果和葡萄酒。黄酮类化合物具有结合大量人体蛋白质和修饰转运蛋白、酶、激素、 DNA、重金属螯合和清除自由基的能力; 因此,具有强大的抗氧化特性(Havsteen,1983; Robak 和 Gryglewski,1988; Morel 等人,1993; Cushnie 和 Lamb,2005)。大量的药理学研究已经被报道,表明它们在糖尿病、癌症、心血管疾病、神经系统疾病、炎症和微生物疾病的治疗中有用(Middleton et al. ,2000; Marder and Paladini,2002; Galati and o’ brien,2004; Cushnie and Lamb,2005)。

Recent studies have shown that regular use of flavonoid-rich foodstuffs can effectively enhance cognitive capabilities in humans (Macready et al., 2009Socci et al., 2017Bakoyiannis et al., 2019). Additionally, several flavonoids have been reported to restrain the progression of pathologies of Alzheimer’s disease (AD) and this has been stem from their ability to quash the cognitive deficits in numerous normal and transgenic preclinical animal models (Macready et al., 2009Spencer, 2010bBakoyiannis et al., 2019). The beneficial effects of flavonoids rich foods like cocoa, green tea and blue berry can be attributed to the interactions of flavonoids and their metabolites with numerous cellular and molecular targets (Yevchak et al., 2008Mastroiacovo et al., 2014). For instance, the specific interactions of flavonoids with receptors within the ERK and PI3-kinase/Akt signaling pathways have been reported to augment the expression of neuromodulatory and neuroprotective proteins as well as enhance the number and strength of different types of neurons (Schroeter et al., 2002Vauzour et al., 2007aSpencer, 2008). Concomitantly, their beneficial effects on the cerebrovascular system can improve the cognitive performance of individuals via an enhancement in blood flow and stimulation of neurogenesis in brain. Several other mechanisms regarding the beneficial use of flavonoids have been recently reported (Spencer, 2009Spencer et al., 2009). Flavonoids attenuate the initiation and progression of AD-like pathological symptoms and related neurodegenerative disorders (Williams and Spencer, 2012). The possible mechanisms for these effects include the inhibition of neuronal apoptosis induced by neuro-inflammation, oxidative stress, inhibition of key enzymes involved in the fabrication of amyloid plaques and other pathological products (Williams and Spencer, 2012). Flavonoids thus mediate their neuroprotective effects by maintaining the neuronal quality and number in the key brain areas and thus prevent the onset/progression of diseases responsible for the decrease in the cognitive function.

最近的研究表明,经常食用富含类黄酮的食物可以有效地提高人类的认知能力(Macready 等人,2009; socti 等人,2017; bakeyianis 等人,2019)。此外,几种黄酮类化合物已被报道可以抑制阿尔茨海默氏病(AD)的病理进展,这是由于它们能够抑制许多正常和转基因临床前动物模型的认知缺陷(Macready 等,2009; Spencer,2010b; bakoyianis 等,2019)。富含黄酮类化合物的食物,如可可、绿茶和蓝莓,其有益作用可归因于黄酮类化合物及其代谢物与众多细胞和分子靶标的相互作用(Yevchak 等,2008; Mastroiacovo 等,2014)。例如,据报道黄酮类化合物与 ERK 和 pi3激酶/akt 信号通路中受体的特定相互作用增加了神经调节和神经保护蛋白的表达,并增强了不同类型神经元的数量和强度(Schroeter et al. ,2002; Vauzour et al. ,2007a; Spencer,2008)。同时,它们对脑血管系统的有益作用可以通过改善血流量和刺激脑内神经发生来改善个体的认知能力。其他几个关于黄酮类化合物有益使用的机制最近已经被报道(Spencer,2009; Spencer et al. ,2009)。黄酮类化合物能够减轻类似 ad 的病理症状和相关的神经退行性疾病的发生和发展(Williams 和 Spencer,2012)。这些作用的可能机制包括抑制神经炎症诱导的神经细胞凋亡、氧化应激、抑制与淀粉样斑块和其他病理产物形成有关的关键酶(Williams and Spencer,2012)。因此,黄酮类化合物通过维持大脑关键区域的神经元质量和数量来调节其神经保护作用,从而防止导致认知功能下降的疾病的发生和进展。

Methods

方法

Recent scientific literature published in high quality journals were collected using various search engines including Google Scholar, SciFinder, Science Direct, PubMed, Web of Science, EBSCO, Scopus, JSTOR and other web sources. The scientific literature preferably on dietary flavonoids in context to their neuroprotective properties and their mechanism of action were selected. Literature with scientific rigor published up to 2017 was included.

最近发表在高质量期刊上的科学文献通过各种搜索引擎收集,包括 Google Scholar,SciFinder,Science Direct,PubMed,Web of Science,EBSCO,Scopus,JSTOR 和其他网络资源。选取了较好的科学文献,结合黄酮类化合物的神经保护特性及其作用机制对膳食黄酮类化合物进行了研究。2017年以前发表的科学严谨的文献也包括在内。

Flavonoids Distribution in Nature

黄酮类化合物在自然界中的分布

Flavonoids represent a major group of secondary metabolites which are extensively distributed in nature especially in green plants. Majority of natural flavonoids are pigments, and are usually allied with some vital pharmacological functions. Flavonoids are differentiated from each other on the basis of differences in the aglycon ring structure and state of oxidation/reduction. Moreover, based on the extent of hydroxylation of aglycon, positions of the hydroxyl groups, saturation of pyran ring and differences in the derivatization of the hydroxyl groups are major differentiating features among the various classes of flavonoids. The major nutritional sources of flavonoids include fruits, juices, vegetables, tea, cereals and wines (Manach et al., 2004). Some common flavonoids include quercetin, kaempferol (flavonols), myricetin, predominantly present in the onions, leeks and broccoli, fruits flavones including luteolin and apigenin are abundant in celery and parsley. Other common types of flavonoids include isoflavones (daidzein, genistein), which are naturally distributed in soy and soy products, flavanones including naringenin and hesperetin, present in the citrus fruits and tomatoes. Flavanols, that are represented by epigallocatechin gallate (EGCG), catechin, epicatechin and epigallocatechin are mainly sequestered in the green tea, red wine, and chocolate, whereas, anthocyanidins including malvidin, pelargonidin and cyanidinare are widely distributed in the berry fruits and red wine (Manach et al., 2005Figure 1).

黄酮类化合物是自然界尤其是绿色植物中广泛存在的一类次生代谢产物。大多数天然黄酮类化合物是色素,通常与一些重要的药理作用相关。根据配基环结构和氧化/还原状态的不同,黄酮类化合物可以相互区分。此外,从配基羟化程度来看,吡喃环的羟基位置、吡喃环的饱和度以及衍生化过程中羟基的差异是各类黄酮类化合物的主要区别特征。黄酮类化合物的主要营养来源包括水果、果汁、蔬菜、茶、谷物和葡萄酒(Manach et al. ,2004)。一些常见的黄酮类化合物包括槲皮素、山奈酚(黄酮醇)、杨梅素,主要存在于洋葱、韭菜和西兰花中。水果类黄酮包括木犀草素和芹菜素在芹菜和欧芹中含量丰富。其他常见类型的黄酮类化合物包括大豆异黄酮(大豆黄酮、染料木素) ,它们天然存在于大豆和大豆制品中,黄烷酮包括柚皮素和橙皮素,存在于柑橘类水果和西红柿中。黄烷醇主要存在于绿茶、红酒和巧克力中,而包括表没食子儿茶素没食子酸酯、儿茶素、表儿茶素和表没食子儿茶素在内的花青素则广泛存在于浆果和红酒中。FIGURE 1 图1

Figure 1. The major classes of flavonoids and their dietary sources.

图1黄酮类化合物的主要类别及其膳食来源。

Chemistry

化学

Flavonoids are abundantly present as polyphenols in plants that are the products of secondary metabolites. The basic chemical structure of flavonoids contains two benzene rings (A and C) connected by a pyran ring B (Figure 2). One of the benzene ring (A) is fused with the pyran ring while the other benzene ring (C) is attached as substituent to the pyran ring. Depending upon the pattern of substitution of benzene rings, and that of substitution, oxidation and saturation of pyran ring, various derivatives of flavonoids can be synthesized that possess unique physicochemical properties and biological activities acceptable for the efficient management of neurodegenerative diseases.

黄酮类化合物以多酚的形式存在于植物体内,是植物次生代谢产物。黄酮类化合物的基本化学结构包含两个苯环(a 和 c) ,由一个吡喃环 b 连接(图2)。其中一个苯环(a)与吡喃环熔合,而另一个苯环(c)作为取代基附着到吡喃环上。根据苯环取代、吡喃环取代、氧化和饱和的模式,合成了各种类黄酮衍生物,这些衍生物具有独特的理化性质和生物活性,可用于神经退行性疾病的有效治疗。FIGURE 2 图2

Figure 2. The chemical structures of major classes of flavonoids.

图2主要类黄酮的化学结构。

Classification

分类

Flavonoids are classified into various groups depending on the position at which the benzene ring (C) is attached to the pyran and the degree of unsaturation and oxidation of pyran ring. These different flavonoids have a dominant role in various pharmacological activities. Each sub-type is discussed below.

根据苯环(c)附着在吡喃和不饱和度上的位置以及吡喃环的氧化程度,类黄酮被分为不同的组。这些不同类型的黄酮类化合物在多种药理活性中占主导地位。下面将讨论每个子类型。

Isoflavones

异黄酮

The class of flavonoids in which the benzene ring (C) is attached to the position 3 of the pyran ring is shown in Figure 3. Isoflavone are majorly found in various natural products especially soybean (Wang and Murphy, 1994). Several researchers have also synthesized various derivatives of isoflavone by different synthetic approaches. Wang in 2005 has synthesized various derivatives of isoflavones by Suzuki coupling (Ding and Wang, 2005). Various derivatives of this famous group of easily biodegradable antioxidant have also been synthesized with triazin (Jha et al., 1981). Similarly, utilizing the catalytic approaches, including enzymatic or using a heterogeneous catalyst have been reported for efficient synthesis of isoflavone (Kochs and Grisebach, 1986Hoshino et al., 1988). The structures of some well-known isoflavones are given in Figure 3.

其中苯环(c)连接到吡喃环的位置3的类黄酮如图3所示。异黄酮主要存在于各种天然产物中,尤其是大豆(Wang and Murphy,1994)。许多研究人员也通过不同的合成方法合成了各种异黄酮衍生物。王先生于2005年通过铃木偶联合成了多种异黄酮衍生物(丁先生,王先生,2005)。各种衍生物的这一著名的群容易生物降解的抗氧化剂也已与三嗪(杰哈等人,1981年)合成。类似地,利用催化方法,包括酶或使用多相催化剂异黄酮的有效合成已被报道(Kochs 和 grisabach,1986; Hoshino 等人,1988)。一些著名的异黄酮的结构见图3。FIGURE 3 图3

Figure 3. The major isoflavones and their chemical structures.

图3. 主要的异黄酮及其化学结构。

Neoflavonoids

新黄酮类化合物

In this class of flavonoids, the benzene ring (C) is attached to the position 4 of pyran ring. The general structure of neoflavonoids is shown in Figure 2. Neoflavonoids, are naturally occurring heterocyclic compounds, mostly famous for their antidiabetic activity (Donnelly and Boland, 1995). The neoflavonoids consist of neoflavones and neoflavenes. The most prominent source of neoflavonoids is natural but several researchers have also synthesized various analogs. Some natural sources, from which the neoflavonoids are reported, are Echinop sniveus (Singh and Pandey, 1990), Dalbergia odorifera (Chan et al., 1997), Nepalese propolis (Awale et al., 2005), Polygonum perfoliatum (Sun and Sneden, 1999) among other important medicinal plants.

在这类黄酮中,苯环(c)附着在吡喃环的4位。新类黄酮的一般结构如图2所示。新黄酮类化合物,是天然存在的杂环化合物,主要以其抗糖尿病活性而闻名(Donnelly 和 Boland,1995)。新黄酮类化合物由新黄酮和新黄酮组成。最突出的来源新类黄酮是天然的,但一些研究人员也合成了各种类似物。一些自然来源,从新黄酮报告,是棘波 sniveus (辛格和潘迪,1990年) ,降香黄檀(陈等人,1997年) ,尼泊尔蜂胶(Awale 等人,2005年) ,杠板归(Sun 和 Sneden,1999年)等其他重要药用植物。

Flavones

黄酮类

The flavones contain a double bond on the pyran ring between position 2 and 3, and a carbonyl (ketone) at position 4. Depending upon the taxonomic position of various plants, the flavones contain hydroxyl substituents at both the aromatic rings. Some commonly employed flavones from both the natural and synthetic origin are shown in Figure 4. The history of flavones from natural sources is very common since their synthetic history is also long (Fukui et al., 1968).

黄酮类化合物在吡喃环上位于第2和第3位,在第4位含有一个羰基(酮)。根据不同植物的分类位置,黄酮在两个芳香环上都含有羟基取代基。一些常用的天然和合成黄酮如图4所示。黄酮的历史来自自然来源是非常常见的,因为他们的合成历史也很长(福井等人,1968年)。FIGURE 4 图4

Figure 4. The chemical structures of major flavones derived from natural and synthetic origin.

图4. 天然和合成黄酮的主要化学结构。

Flavonols

黄酮醇

Chemically, flavonols are the alcoholic derivatives of flavones. The flavonols differ from the flavones in the hydroxyl group at position 3 of pyran ring. Generally, they can also be called as 3-hydroxyflavones. Mostly, the flavonols are synthesized by synthetic procedures. A very well-known synthesis of flavonols is by oxidation and cyclization of chalcones which ends with 3-hydroxyflavonols. Figure 5 shows the various important flavonols. In some cases, one or more hydrogen of hydroxyl group is replaced by a glucose moiety leading to a flavonol glycoside. As obvious from Figure 5 that pachypodol is not exactly a flavonol but its hydroxyl group is converted into a methoxy group. However, due to its structure resemblance, it can be classified as a derivative of 3-hydroxyflavone, a flavonol.

黄酮醇是黄酮类化合物的醇类衍生物。黄酮醇不同于吡喃环3位羟基上的黄酮类化合物。一般来说,它们也被称为3- 羟基黄酮。黄酮醇类化合物大多是通过合成工艺合成的。众所周知,黄酮醇的合成是以3- 羟基黄酮醇为结尾的查尔酮的氧化和环化反应。图5显示了各种重要的黄酮醇。在某些情况下,一个或多个羟基氢被葡萄糖部分所取代,从而产生黄酮醇糖苷。从图5可以明显看出,茯苓醇并不完全是一种黄酮醇,但它的羟基被转换成甲氧基。然而,由于它的结构相似,它可以被归类为3- 羟基黄酮,一种黄酮醇的衍生物。FIGURE 5 图5

Figure 5. The major naturally occurring flavonols.

图5. 主要的天然黄酮醇。

Flavanones

黄烷酮

The flavanones, saturated flavones, are also known as dihydroflavones. The only difference between flavones and flavanones is the absence of double bond between position 2 and 3. These types of compounds are shown in Figure 6.

饱和黄酮又称二氢黄酮。黄酮类化合物和黄酮类化合物的唯一区别是第2和第3位之间没有双键。这些类型的化合物如图6所示。FIGURE 6 图6

Figure 6. The chemical structures of important isolated flavanones.

图6. 重要分离黄烷酮的化学结构。

Flavanonols

黄烷醇

The flavanonols are the 3-hydroxy flavanones and are also called dihydroflavonols. These are the flavonoids with saturated pyran ring having a hydroxyl group at position 3 and a carbonyl group at position 4. Some common examples of this class of flavonoids are shown in Figure 7.

黄烷醇是3- 羟基黄烷酮,又称二氢黄酮醇。这些是具有饱和吡喃环的黄酮类化合物,在第3位有羟基,在第4位有羰基。这类黄酮的一些常见例子如图7所示。FIGURE 7 图7

Figure 7. The important members of the flavanonols class of flavonoids.

图7黄酮类黄烷醇类的重要成员。

Flavanols

黄烷醇

The flavanols, also called flavan-3-ol are the types of flavonoids which lack the carbonyl group at position 4. The pyran ring in these types of compounds is saturated and disubstituted at position 2 and 3. This property of the structure leads to four possible diastereomers of a flavanol. In flavanols, the benzene ring (C) is attached to position 2 while the hydroxyl groups at position 3 of pyran ring. The structures of this type of flavonoids are shown in Figure 8. Of these, flavonoids not exactly fit in the definition of flavanol because of a lack of hydroxyl group at position 3. But, still can be categorized under the heading of flavanols as it is structurally similar to other flavanol except the hydroxyl group at position 3.

黄烷醇又称黄烷 -3- 醇,是黄酮类化合物中第4位缺少羰基的类型。这些类型化合物中的吡喃环在第2和第3位是饱和的和双取代的。这种结构的特性导致了黄烷醇的四种可能的非对映异构体。在黄烷醇中,苯环(c)附着在第2位,而吡喃环第3位的羟基则附着在第3位。这类黄酮的结构如图8所示。其中,黄酮类化合物不完全符合黄烷醇的定义,因为在第3位缺少羟基。但是,除了第3位的羟基外,其结构与其他黄烷醇相似,仍可归入黄烷醇类。FIGURE 8 图8

Figure 8. The major flavanols derived from natural sources.

图8. 主要的黄烷醇来自天然来源。

Anthocyanidins

花青素

They are the only flavonoids which impart color. They are available in the cations form (as chloride salts). They are the salt derivatives of 2-phenylchromenylium (flavylium) cation. This group contains aurantinidin, capensinidin, cyaniding, delphinidin, europinidin, hirsutidin, malvidin, pelargonidin, peonidin, petunidin, pulchellidin and rosinidin. All of them are different from each other on the basis of the attached groups (denoted by R) as shown in Figure 2.

它们是唯一一种赋予颜色的黄酮类化合物。它们以阳离子的形式存在(如氯化盐)。它们是2- 苯基亚铬(黄)阳离子的盐衍生物。该类化合物包括耳抗菌素、刺参素、花青素、飞燕草素、欧洲粉蝶苷、毛地黄素、马尔维定、天竺葵苷、白芍苷、普通宁和罗辛苷。如图2所示,根据所附组别(以 r 表示) ,它们彼此不同。

Chalcones

查尔康

Although they do not have the pyran ring but are classified as flavonoids because of having a similar synthetic approach to flavonoids. Moreover, in chalcones, the pyran moiety is available as open structure. The open structure has a carbonyl conjugated to a double bond making an α, β-unsaturated ring system, an ideal Michael acceptor for many organic reactions. The structure of chalcone is shown in Figure 2.

虽然它们没有吡喃环,但是由于类似的合成方法,它们被归类为类黄酮。此外,在查尔酮类化合物中,吡喃部分以开放结构形式存在。开环结构中的羰基与双键共轭,形成 α,β- 不饱和环,是许多有机反应的理想 Michael 受体。查尔酮的结构如图2所示。

Flavonoids and Alzheimer’S Disease

黄酮类化合物与阿尔茨海默病

AD, a neurodegenerative disorder, which is characterized by a gradual memory loss, cognitive dysfunction, imperfection in the routine activities, and a decrease in the intellectual learning process (Sadiq et al., 2015Ayaz et al., 2017bOvais et al., 2018). AD is the most common cause of dementia and affects approximately 5%–8% of individuals over age 65, 15%–20% of individuals over age 75, and 25%–50% of individuals over age 85. It is estimated that 35.6 million people are living with dementia worldwide (Duthey, 2013). Although, the exact etiology of AD is still not known, several mechanistic features including the deficiency of cholinesterases, deposition of β-amyloid plaques, hyperphosphorylation of tau proteins and generation of oxidative stress have been implicated in the development as well as progression of AD (Kamal et al., 2015Ullah et al., 2016). Due to the diverse nature of these pathological targets, the development of useful anti-AD drugs is still a challenging task for the scientific community. Consequently, multiple targets including the inhibition of key enzyme implicated in AD like acetylcholinesterase (AChE), butyrylcholinesterase (BChE), β-amyloid cleaving enzyme (BACE-1), monoamine oxidase (MAO) and antioxidant agents are currently under investigation as a new therapeutic class of anti-Alzheimer’s agents (Grill and Cummings, 2010Ahmad et al., 2016Balducci and Forloni, 2018Chaudhary et al., 2018).

AD,一种神经退行性疾病,拥有属性为逐渐的记忆丧失,认知功能障碍,日常活动的不完善,以及智力学习过程的减少。AD 是痴呆症最常见的原因,影响大约5%-8% 的65岁以上人群,15%-20% 的75岁以上人群,以及25%-50% 的85岁以上人群。据估计,全世界有3560万人患有痴呆症(Duthey,2013)。虽然 AD 的确切病因尚不清楚,但是 AD 的发展和进展与一些机制特征有关,包括胆碱酯酶缺乏、 β 淀粉样蛋白斑块沉积、 tau 蛋白过度磷酸化和氧化应激的产生(Kamal 等人,2015; Ullah 等人,2016)。由于这些病理靶点的多样性,开发有效的抗 ad 药物对于科学界来说仍然是一项具有挑战性的任务。因此,作为一类新的抗阿尔茨海默病药物,目前正在研究多种靶点,包括抑制与 AD 相关的关键酶,如乙酰胆碱酯酶(AChE)、丁酰胆碱酯酶(BChE)、 β- 淀粉样蛋白裂解酶(BACE-1)、单胺氧化酶(MAO)和抗氧化剂(Grill and Cummings,2010; Ahmad et al. ,2016; balci and Forloni,2018; Chaudhary et al. ,2018)。

Currently, only five drugs have been marketed for the management of AD, among them four drugs including galantamine, tacrine, rivastigmine and donepezil are cholinesterase inhibitors whereas, the fifth one is the glutamatergic system modifier called memantine (Ayaz et al., 2015). No anti-amyloid drug is currently clinically available, though several agents are in the different phases of clinical trials (Vassar, 2014). Due to the toxicity associated with the use of currently available drugs and their limited therapeutic effectiveness, the search for new anti-AD drugs is still underway (Ayaz et al., 2014Ahmad et al., 2015). Consequently, the multi-targeting natural products based pure pharmacological moieties having more bio-safety and promising cognitive enhancing capabilities are among the potential therapeutic agents (Baptista et al., 2014Bakhtiari et al., 2017Farooqui, 2017Khan et al., 2018). Flavonoids including epicatechin-3-gallate, gossypetin, quercetin and myricetin are reported to block β-amyloid, and tau aggregation, scavenge free radicals and sequester metal ions at clinically low concentrations (Ono et al., 2003Weinreb et al., 2004Reznichenko et al., 2006Ansari et al., 2009). Furthermore, xanthone flavonoids have also been reported to scavenge the reactive oxygen species (ROS), inhibit MAO and AChE enzymes (Zhang et al., 2006Khan et al., 2009Jayasena et al., 2013). Hence, flavonoids are a promising lead class of compounds for the efficient design and development of multipotent anti-AD drugs.

目前,只有五种药物已经上市用于治疗 AD,其中包括加兰他敏、他克林、卡巴拉汀和多奈哌齐是胆碱酯酶抑制剂,而第五种是谷氨酸能系统修饰剂 memantine (Ayaz 等,2015)。目前临床上还没有抗淀粉样蛋白药物可用,尽管有几种药物正处于临床试验的不同阶段(Vassar,2014)。由于使用现有药物的毒性及其有限的治疗效果,寻找新的抗 ad 药物的工作仍在进行中(Ayaz 等人,2014年; Ahmad 等人,2015年)。因此,基于纯药理学的多靶点天然产品具有更多的生物安全性和有希望的认知增强能力,是潜在的治疗剂(Baptista 等人,2014; Bakhtiari 等人,2017; Farooqui,2017; Khan 等人,2018)。类黄酮包括表儿茶素 -3- 没食子酸酯、棉花素、槲皮素和杨梅素被报道可以阻断 β- 淀粉样蛋白和 tau 蛋白聚集,清除自由基和隔离临床低浓度的金属离子(Ono 等人,2003; Weinreb 等人,2004; Reznichenko 等人,2006; Ansari 等人,2009)。此外,黄酮类化合物也被报道可以清除活性氧类,抑制 MAO 和 AChE 酶。因此,黄酮类化合物是一类很有前途的化合物,可用于多功能抗 ad 药物的设计和开发。

Amyloid Precursor Protein (APP), Amyloid Beta (Aβ) and Alzheimer’s Disease

淀粉样前体蛋白(APP)、 β 淀粉样蛋白(aβ)与阿尔茨海默病

The amyloid precursor protein (APP) belongs to a group of transmembrane proteins having large extracellular domains (Wasco et al., 1993Ali et al., 2017Ayaz et al., 2017a). While members of the APP-like proteins family shares several extracellular domains like E1, E2; however, the amyloid beta (Aβ) domain is unique to the APP protein. APP is produced in the endoplasmic reticulum (ER) and subsequently transported viathe Golgi apparatus to the trans-Golgi-network (TGN) where APP is found abundantly (Hartmann et al., 1997). APP is transported from TNG by TNG-derived vesicles to the surface of cells where it is enzymatically cleaved by α-secretase, γ-secretases and resulting in the formation of a soluble molecule called sAPPα. 13. This usual process of APP breakdown is non-amylogenic and does not produce Aβ. However, the processing of APP via successive actions of beta amyloid cleaving enzyme (BACE-1) and γ-secretase lead to the formation of Aβ as shown in Figure 9(Nordstedt et al., 1993).

淀粉样前体蛋白(APP)属于一组具有大量胞外区的跨膜蛋白(沃斯科等人,1993; Ali 等人,2017; Ayaz 等人,2017a)。虽然类 APP- 蛋白家族成员共享一些细胞外区域,如 E1,E2; 然而,淀粉样 β 蛋白(aβ)区域是 APP 蛋白所特有的。APP 在内质网中产生,然后通过高尔基体运输到高尔基网络中,在那里可以大量发现 APP。APP 通过 TNG 衍生的囊泡从 TNG 转运到细胞表面,在那里它被 α 分泌酶、 γ 分泌酶酶切,从而形成一种可溶性分子,称为 sappα。图13。APP 的这种常见分解过程是非淀粉原性的,不产生 aβ。然而,通过 β 淀粉样蛋白裂解酶(BACE-1)和 γ 分泌酶连续作用的 APP 导致 aβ 的形成,如图9所示(Nordstedt 等,1993)。FIGURE 9 图9

Figure 9. The probable mechanism of flavonoids activating non-amyloidogenic pathway through stimulation of α, γ secretases activities, while inhibiting the neurotoxic amylogenic pathway by inhibition of BACE-1 enzyme.

图9。黄酮类化合物通过刺激 α,γ 分泌酶活性激活非淀粉样变途径,抑制 BACE-1酶活性抑制神经毒性淀粉样变途径的可能机制。

Pathological Aspects and Drug Targets

病理学与药物靶点

Flavonoids as Cholinesterase Inhibitors

类黄酮类胆碱酯酶抑制剂

Cholinesterases including AChE, and BChE are involved in the breakdown of acetylcholine (ACh), which is responsible for the impulse transmission across various synapses (Voet and Voet, 1995). Due to the scarcity of ACh in AD, the use of cholinesterase inhibitors is among the useful therapeutic options to maintain the accumulation of neurotransmitter for a long time at the synapse (Bachman et al., 1992). The data regarding the currently available drugs indicate that employing this approach is the most useful target in AD symptomatic therapy, thus streamlining the eventual clinical approval of four drugs (Atta-Ur-Rahman et al., 2004). This approach is also successfully employed in the management of Parkinson’s disease, ataxia and dementia (Ahmad et al., 2003). Owing to the unwanted effects and limited efficacy of the currently available drugs, there is a dire need to develop more safe and effective drugs (Schneider, 2001). Several flavonoids including genistein, kaempferol, apigenin, naringin, quercetin, diosmin, silymarin and silibinin were tested against cholinesterases (AChE, BChE). Among these flavonoids, quercetin was found most active and exhibiting a 76.2% inhibition of AChE. Other compounds including genistein, leteolin and silibinin showed a 65.7, 54.9 and 51.4% inhibitions against BChE, respectively (Orhan et al., 2007). In a published report, Uriarte-Pueyo and Calvo (2011) summarized 128 flavonoids with respect to their AChE inhibitory potentials. Based on their potency as cholinesterase inhibitors, they were considered to be promising therapeutic agents in the development of new anti-Alzheimer drugs.

胆碱酯酶包括 AChE 和 BChE 参与乙酰胆碱(ACh)的分解,乙酰胆碱负责各种突触间的冲动传递(Voet 和 Voet,1995)。由于乙酰胆碱在 AD 中的缺乏,使用胆碱酯酶抑制剂是维持神经递质在突触长时间积累的有效治疗选择之一(Bachman 等人,1992年)。关于目前可用药物的数据表明,采用这种方法是 AD 症状治疗中最有用的目标,从而简化了四种药物的最终临床批准(Atta-Ur-Rahman et al. ,2004)。这种方法也成功地应用于治疗帕金森氏症、共济失调和痴呆症(Ahmad et al. ,2003)。由于现有药物的不良影响和有效性有限,迫切需要开发更安全和有效的药物(Schneider,2001年)。研究了染料木素、山奈酚、芹菜素、柚皮苷、槲皮素、香豆素、水飞蓟素和水飞蓟宾等几种黄酮类化合物对胆碱酯酶的抑制作用。其中槲皮素活性最强,对乙酰胆碱酯酶的抑制率为76.2% 。其他化合物,包括染料木黄酮、赖替林和水飞蓟宾,对 BChE 的抑制率分别为65.7% 、54.9% 和51.4% (Orhan 等人,2007)。在一篇发表的报告中,Uriarte-Pueyo 和 Calvo (2011)总结了128种黄酮类化合物对乙酰胆碱酯酶的抑制作用。由于它们作为胆碱酯酶抑制剂的潜力,它们被认为是开发新的抗阿尔茨海默病药物的有希望的治疗剂。

Flavonoids as Free Radicals’ Scavengers

黄酮类化合物清除自由基

Free radicals are generated during the aerobic respiration and are counteracted by the bodily diverse system of antioxidants. When the free radicals are generated in excess, they lead to oxidative stress and thus disturb the functions of different proteins, lipids and essential body elements (Markesbery and Lovell, 2007). Besides their role in several disease processes, free radicals are implicated in the inflammatory damage to neurons and development of AD. The oxidative stress is a key aspect of AD as indicated from the elevated level of oxidative stress markers (Lovell and Markesbery, 2007). Moreover, low concentrations of antioxidants and antioxidant activity have been detected in the plasma of patients diagnosed with AD (Mecocci et al., 2002Rinaldi et al., 2003). Additionally, the elevated lipid and protein oxidation byproducts were also observed in the transgenic animal models of AD (Resende et al., 2008). The AD pathogenic markers including Aβ and neurofibrillary tangles (NFTs) were also high in animals having oxidative stress, which may suggest that the free radicals are among the initiators of AD (Dumont and Beal, 2011). Nearly all the ROS are generated in the mitochondria (Kowaltowski et al., 2009). In AD patients a deficiency of cytochrome c oxidase leads to the mitochondrial dysfunction and results in the excessive generation of ROS (Müller et al., 2010). Aβ is also considered as mitochondrial poison and is known to initiate the excessive release of free radicals in the presence of metal ions (Butterfield et al., 2007). In this regard, the use of ions like clioquinol is known to exhibit useful effects in transgenic animal models of AD (Grossi et al., 2009).

自由基是在有氧呼吸过程中产生的,并被身体不同的抗氧化剂系统抵消。当自由基产生过量时,它们会导致氧化应激,从而干扰不同蛋白质、脂类和人体必需元素的功能。自由基除了在多种疾病过程中发挥作用外,还与神经元的炎症损伤和 AD 的发生有关。氧化应激是 AD 的一个关键方面,从氧化应激标记物水平的升高可以看出。此外,低浓度的抗氧化剂和抗氧化活性已被检测出患有 AD 的患者的血浆中(Mecocci 等人,2002; Rinaldi 等人,2003)。此外,在 AD 的转基因动物模型中也观察到脂质和蛋白质氧化副产物的升高。AD 的致病标志物,包括 aβ 和神经原纤维缠结(nft)在患有氧化应激的动物中也较高,这可能表明自由基是 AD 的发起者之一(Dumont and Beal,2011)。几乎所有的活性氧都是在线粒体中产生的(科瓦尔托夫斯基等人,2009)。阿尔茨海默病患者缺乏细胞色素c氧化酶导致线粒体功能障碍,并导致过度产生 ROS (m ü ller et al. ,2010)。Aβ 也被认为是线粒体毒药,并已知在金属离子存在时引发自由基的过度释放(Butterfield 等人,2007)。在这方面,已知使用类似氯碘醌的离子在 AD 转基因动物模型中展示了有用的效果(Grossi 等人,2009年)。

Activation of glial cells is another hallmark of AD and neurodegenerative disorders (Craft et al., 2005Balducci and Forloni, 2018). The activation of microglia not only generates pro-inflammatory cytokines but also increases the formation of superoxide anions using NADPH oxidase (NOX). The presence of elevated levels of NOX subunits in the brains of AD and the subsequent improvement of cognitive and cerebrovascular functions after NOX gene removal from the transgenic animals support its potential involvement in the pathogenesis of AD (Park L. et al., 2008). Moreover, in the activated glial cells, inducible nitric oxide synthase (iNOS) sets free the NO, which subsequently reacts with the superoxide and forms peroxinitrite thereby exerting nitrosative stress. Their involvement has been supported by the genetic removal of iNOS which results in the amelioration of gliosis, reduction in Aβ load and phosphorylation of tau proteins in the transgenic animals (Nathan et al., 2005). Catechins and polyphenols of green tea are strong antioxidants, which chelate metal ions and scavenge free radicals (Singh et al., 2008). EGCG prevents oxidative stress-induced DNA damage by transferring an electron to the ROS-induced radical sites (Singh et al., 2008). The green tea suppresses propagation of chain reaction during the lipid peroxidation initiated by the iron ascorbate in the mitochondrial membranes of brain. Among the catechins, EGCG is observed to be the most efficient scavenger (Mandel et al., 2008). EGCG inhibits fibril formation during Aβ aggregation and attenuates the lipid peroxidation as initiated by the Aβ (Choi et al., 2001Lee et al., 2009). EGCG also inhibits Aβ-induced apoptosis, caspase activity, thus enhancing the survival of hippocampus neurons (Choi et al., 2001).

神经胶质细胞的激活是 AD 和神经退行性疾病的另一个标志(Craft et al. ,2005; Balducci 和 Forloni,2018)。小胶质细胞的活化不仅产生促炎性细胞因子,而且使用 NADPH 氧化酶(NOX)增加超氧阴离子的形成。从转基因动物中去除 NOX 基因后,AD 大脑中 NOX 亚基水平的升高以及随后认知和脑血管功能的改善,支持了它在 AD 发病机制中的潜在作用(Park l. 等人,2008)。此外,在被激活的神经胶质细胞中,诱导型一氧化氮合酶(iNOS)释放 NO,NO 随后与超氧化物发生反应,形成过氧化物盐,从而施加硝化应力。他们的参与得到了基因去除诱导型一氧化氮合酶的支持,这导致了转基因动物胶质增生症的改善,aβ 负荷的减少和 tau 蛋白的磷酸化(Nathan 等人,2005年)。儿茶素和绿茶中的多酚是强有力的抗氧化剂,能螯合金属离子并清除自由基(Singh 等,2008)。EGCG 通过向 ros 诱导的自由基位点传递电子来防止氧化应激引起的 DNA 损伤(Singh 等,2008)。绿茶抑制了脑线粒体膜中抗坏血酸铁引发的脂质过氧化过程中链式反应的传播。在儿茶素中,EGCG 被认为是最有效的清道夫(Mandel 等人,2008)。EGCG 抑制 aβ 聚集过程中的原纤维形成,并减弱 aβ 引起的脂质过氧化。EGCG 还能抑制 aβ 诱导的细胞凋亡和半胱氨酸蛋白酶活性,从而提高海马神经元的存活率。

Effectiveness in Alzheimer’s Disease and Dementia

阿尔茨海默病和痴呆的疗效

The effectiveness of flavonoids in the prevention of AD and cognitive dysfunctions in animal models has been reported, which signify their therapeutic use in the management of neurological disorders. Flavonoids mediate their anti-amyloidogenic effect by targeting key enzymes implicated in the pathological production and accumulation of amyloid plaques (Aβ). Anthocyanin-rich flavonoids found in bilberry and black currant extracts have been recently reported to prevent behavioral abnormalities and alter APP processing in APP/PS1 mouse model of AD (Vepsäläinen et al., 2013). Likewise, chronic therapy with tannic acid using transgenic PSAPP animal model of cerebral amyloidosis has revealed potential amelioration of transgene-mediated deficits in the memory and behavior of animals. A citrus flavonoid nobiletin, has been reported to improve Aβ mediated memory deficits and reduce Aβ load in the hippocampus of transgenic animals (Onozuka et al., 2008). Furthermore, chronic administration of grapes polyphenols leads to improvement in the memory and diminish the level of soluble Aβ oligomers in the brain tissues of Tg2576 animals (Wang et al., 2008). Luteolin, a citrus flavonoid has been shown to decrease the formation of Aβ peptides in APP transgenic neuronal cells and lower the activity of BACE1 (Rezai-Zadeh et al., 2009). Moreover, chronic administration of polyphenol-rich grape seed extracts and curcumin for 9 months inhibit the deposition of Aβ in the brain of AD animals (Rezai-Zadeh et al., 2009).

黄酮类化合物在动物模型中预防 AD 和认知功能障碍的有效性已被报道,这标志着它们在神经系统疾病治疗中的应用。黄酮类化合物通过靶向与淀粉样斑块(aβ)病理生成和积累有关的关键酶,介导其抗淀粉样变性作用。在越桔和黑加仑提取物中发现的富含花青素的黄酮类化合物最近被报道用于预防 APP/ps1 AD 小鼠模型中的行为异常和改变 APP 加工。同样,用单宁酸长期治疗脑淀粉样变性的转基因 PSAPP 动物模型也显示了改善转基因介导的动物记忆和行为缺陷的潜力。一种柑橘类黄酮川陈皮素,已被报道用于改善 aβ 介导的记忆缺陷和降低转基因动物海马中的 aβ 负荷(Onozuka et al. 2008)。此外,长期服用葡萄多酚可以改善记忆,降低 Tg2576动物脑组织中可溶性 aβ 寡聚体的水平(Wang 等,2008)。木犀草素,一种柑橘类黄酮已被证明可以减少 APP 转基因神经细胞中 aβ 肽的形成,降低 BACE1的活性(Rezai-Zadeh 等,2009)。此外,长期服用富含多酚的葡萄籽提取物和姜黄素9个月可抑制 AD 动物大脑中 aβ 的沉积(Rezai-Zadeh et al. ,2009)。

Numerous studies have demonstrated various beneficial aspects of green tea. Epigallocatechin-3-gallate (EGCG), a green tea polyphenol has been reported to reduce the Aβ load via inhibition of APP modulating enzyme (Rezai-Zadeh et al., 20052008). The naturally occurring flavonoids including curcumin and EGCG are reported to restrain Aβ-mediated BACE1 upregulation in the neuronal cultures (Shimmyo et al., 2008). Isorhamnetin has shown a neuroprotective effect against Aβ-induced memory impairment (Asha and Sumathi, 2016). It enhances cognition and memory by uplifting antioxidant defense system, cholinergic signaling, and synaptic plasticity (Ishola et al., 2019). Kaempferol attenuates cognitive deficit through regulating antioxidants and neuro-inflammation (Kouhestani et al., 2018), promotes memory retention and density of hippocampal CA1 neurons (Darbandi et al., 2016). The flavonoid, quercetin has potential therapeutic benefit in AD. Quercetin produces a reduction in plaque burden and mitochondrial dysfunction through the activation of AMPK and may be one of the mechanisms by which quercetin improves cognitive functioning (Wang et al., 2014).

许多研究已经证明了绿茶的各种有益方面。表没食子儿茶素没食子酸酯,一种绿茶多酚已被报道通过抑制 APP 调节酶降低 aβ 负荷(Rezai-Zadeh et al. 2005,2008)。姜黄素和 EGCG 等天然黄酮类化合物在神经细胞培养中具有抑制 aβ 介导的 BACE1表达的作用(Shimmyo 等,2008)。异鼠李素对 β 受体诱导的记忆障碍有神经保护作用(Asha and Sumathi,2016)。它通过提升抗氧化防御系统、胆碱能信号和突触可塑性来增强认知和记忆。山奈酚通过调节抗氧化剂和神经炎症来减轻认知缺陷(Kouhestani 等人,2018) ,促进记忆保持和海马 CA1神经元的密度(Darbandi 等人,2016)。类黄酮、槲皮素对 AD 有潜在的治疗作用。槲皮素通过激活 AMPK 减少斑块负担和线粒体功能障碍,可能是槲皮素改善认知功能的机制之一(Wang 等人,2014)。

The EGCG-induced increase of non-amyloidogenic APP processing was observed to be carried out through the estrogen receptor-α/phosphoinositide 3-kinase/Ak-transforming based mechanisms. As the post-menopausal depletion of estrogen has been linked to an increased risk of AD development, thus, selective estrogen receptor modulators can be an alternative therapeutic option in the treatment of AD. The use of EGCG mediated estrogen receptor modulation could be an alternative to estrogen-based therapy in the management of this disease (Fernandez et al., 2010). EGCG also produce beneficial neuroprotective effects via inhibition of amyloid fibrils sheet rich in Aβ and inhibition of fibrillogenesis. The fibrillogenesis reticence is mediated by direct binding with unfolded polypeptides and inhibition of their conversion to neurotoxic intermediates (Ehrnhoefer et al., 2008). Moreover, EGCG is capable of splitting large size Aβ fibrils to small proteins and thus are not able to aggregate and thereby devoid of any toxic effects (Bieschke et al., 2010). The flavonoid, myricetin has shown potential in vitro anti-amyloid activity and thus possesses prospective beneficial effect for neurodegeneration related cognitive disorders (Ono et al., 2003Hirohata et al., 2007). In general, these reports advocate that some flavonoids have the capability to interrupt fibrillization process of Aβ formation, inhibit a vital enzyme BACE1 implicated in the formation of Aβ, which lead to inhibition of Aβ production. Nevertheless, further studies are required to uncover the neuro-modulating potentials and underlying mechanisms of flavonoids for clinical use.

通过雌激素受体 α/磷酸肌醇3- 激酶/ak-转化机制观察 egcg 诱导的非淀粉样变性 APP 加工增加。由于绝经后雌激素的消耗与 AD 发展的风险增加有关,因此,选择性雌激素受体调节剂可以作为 AD 的替代治疗选择。使用 EGCG 介导的雌激素受体调节可以替代雌激素为基础的治疗方法来治疗这种疾病。EGCG 还通过抑制富含 aβ 的淀粉样纤维片和抑制纤维形成而产生有益的神经保护作用。纤维生成网状结构是通过与未折叠多肽直接结合并抑制它们转化为神经毒性中间体而介导的。此外,EGCG 能够将大尺寸的 aβ 纤维分裂成小蛋白质,因此不能聚集,因此没有任何毒性作用(Bieschke et al. ,2010)。类黄酮杨梅素在体外具有抗淀粉样蛋白活性,因此对神经退行性疾病相关性认知障碍具有前瞻性的有益作用。一般认为,黄酮类化合物具有阻断 aβ 形成的纤维化过程,抑制参与 aβ 形成的重要酶 BACE1,从而抑制 aβ 的生成。然而,还需要进一步的研究来揭示黄酮类化合物的神经调节潜力和潜在的机制,以供临床使用。

Flavonoids as Tau Modifying Agents

类黄酮类化合物作为 Tau 蛋白修饰剂的研究

Several reported studies describe the effects of flavonoids in the formation of highly phoshorylated tau proteins, a pathological hallmark of AD (Calcul et al., 2012Baptista et al., 2014). For instance, myrecetin and epicatechin-5-gallate have been reported to avert heparin-mediated tau formation (Taniguchi et al., 2005). Epicatechin-5-gallate administration in the transgenic animal models of AD has been shown to modulate tau profiles by suppressing the formation of sarkosyl-soluble phosphorylated tau isoforms (Rezai-Zadeh et al., 2008). In other studies using grape seed proanthocyanidin extract (GSPE), tau neuropathology was significantly reduced in animals model of AD via inhibition of tau peptide aggregations, its destabilization and its eventual clearance (Pasinetti et al., 2010Wang et al., 2010). Hyperphosphorylation of tau proteins with subsequent accumulation as NFTs is a major contributor in the cognitive dysfunctions. Several kinases like GSK-3β are known to contribute to the phosphorylation of tau protein and are implicated in the pathogenesis of AD. Flavonoids inhibit the activities of several kinases and thus aid in the prevention of AD. For instance, indirubins restrain the activities of protein kinases including CDK5/p25 and GSK-3β, both of which are implicated in the abnormal phosphorylation of tau proteins observed in the AD patients (Figure 10Leclerc et al., 2001). Another flavonoid, morin is reported to inhibit the activity of GSK-3β and obstruct GSK-3β-mediated phosphorylation of tau proteins. Morin also diminishes Aβ-mediated phosphorylation of tau proteins and provides protection against Aβ induced cytotoxicity in human neuroblastoma cells. Furthermore, morin therapy has been shown to reduce tau hyperphosphorylation in the hippocampal neurons of transgenic animals (3xTg-AD mice; Gong et al., 2011). Cyanidin 3-O-glucoside (Cy3G) has also afforded a significant protection against cognitive dysfunctions induced by administration of Aβ in animal models which is mediated by modulation of GSK-3β/tau (Qin et al., 2013).

一些报道的研究描述了黄酮类化合物在形成高度磷酸化 tau 蛋白中的作用,这是 AD 的一个病理标志(Calcul 等人,2012; Baptista 等人,2014)。例如,已经有报道说 myrecetin 和表儿茶素 -5- 没食子酸盐可以避免肝素介导的 tau 形成(Taniguchi 等人,2005年)。表儿茶素 -5- 没食子酸盐在 AD 转基因动物模型中的应用已被证明可通过抑制 sarkosyl 可溶性磷酸化 tau 异构体的形成来调节 tau 蛋白的表达谱(Rezai-Zadeh 等人,2008年)。在其他使用葡萄籽原花色素提取物(GSPE)的研究中,通过抑制 tau 肽聚集、其不稳定性及其最终清除,tau 神经病理学在 AD 动物模型中显著降低。Tau 蛋白的过度磷酸化与随后的 nft 积累是认知功能障碍的主要因素。一些激酶如 gsk-3β 被认为与 tau 蛋白的磷酸化有关,并且与 AD 的发病机制有关。黄酮类化合物抑制多种激酶的活性,从而有助于 AD 的预防。例如,靛蓝抑制包括 CDK5/p25和 gsk-3β 在内的蛋白激酶的活性,这两种蛋白激酶都与 AD 患者中观察到的 tau 蛋白的异常磷酸化有关(图10; Leclerc 等人,2001)。另一种黄酮类化合物桑色素可抑制 gsk-3β 的活性,阻断 gsk-3β 介导的 tau 蛋白磷酸化。桑色素还能减少 tau 蛋白的 β 介导的磷酸化,并对 aβ 诱导的人神经母细胞瘤细胞的细胞毒性有保护作用。此外,桑色素疗法已被证明可以减少转基因动物海马神经元的 tau 过度磷酸化。花青素3-o- 葡萄糖苷(Cy3G)也具有显著的保护作用,可以通过调节 gsk-3β/tau 蛋白(Qin et al. ,2013)介导的动物模型,对 aβ 导致的认知功能障碍有明显的保护作用。FIGURE 10 图10

Figure 10. The probable mechanisms of flavonoids in inhibiting different signaling pathways implicated in the formation of neurofibrillary tangles (NFTs) and amyloid plaques (Aβ).

图10。黄酮类化合物抑制不同信号通路可能参与了神经原纤维缠结和淀粉样斑块的形成。

Neuro-Inflammation and Neurotoxins Modulating Effects

神经炎症与神经毒素的调节作用

The neurodegenerative outcomes observed in various neurological disorders appear to be elicited by several events like neuro-inflammation, depletion of endogenous antioxidants, glutamatergic excitotoxicity and neurotoxicity mediated by various metabolic products (Jellinger, 2001). Scientific evidence suggest that flavonoids might counteract the underlying mechanisms of neuronal injuries and can hamper the progression of different neurodegenerative disorders (Mandel and Youdim, 2004Spencer, 2008). Consumption of green tea has been reported to reduce the risk of Parkinson’s disease, attenuate neurodegeneration and ischemic hippocampal injury, which can be attributed to the presence of EGCG (Lee et al., 2000Weinreb et al., 2004). EGCG is also known to modulate various signaling pathways particularly protein kinase C and PI3-kinase which are implicated in the neuroprotection and reduce the nigral damage by chelating free radicals (Mandel et al., 2005Weinreb et al., 2009).

在各种神经系统疾病中观察到的神经退行性结果似乎是由几个事件引起的,如神经炎症、内源性抗氧化剂的耗竭、谷氨酸兴奋毒性和由各种代谢产物介导的神经毒性(Jellinger,2001)。科学证据表明,黄酮类化合物可能会抵消神经元损伤的潜在机制,并可能阻碍不同神经退行性疾病的进展(Mandel 和 Youdim,2004; Spencer,2008)。据报道,饮用绿茶可以降低帕金森氏症的风险,减轻神经退行性疾病和缺血性海马损伤,这可以归因于 EGCG 的存在(Lee 等人,2000; Weinreb 等人,2004)。EGCG 也被认为可以调节各种信号通路,特别是蛋白激酶C 和 PI3-kinase,它们涉及神经保护和减少螯合自由基引起的黑质损伤。

Various in vitro studies also corroborated the idea that flavonoids prevent the pathological aspects of Parkinson’s disease by inhibiting the formation of endogenous neurotoxin 5-S-cysteinyldopamine (Vauzour et al., 2007b). Moreover, the neuroprotective effects of flavonoids have also been reported in other diseases like Huntington disease, mediated via ERK pathway (Maher et al., 20062011). Naringenin, a citrus flavanone has been reported to reduce the neuronal injury via inhibition of lipopolysaccharide/interferon-γ-induced glial cells activation and inhibition of p38/STAT-1 pathway (Vafeiadou et al., 2009). Naringenin also inhibits the production of nitric oxide in the activated microglia cells. Blueberry flavonoids also have been shown to attenuate the production of TNF-α, nitric oxide and IL-1β in activated microglia cells (Lau et al., 2007). Other flavonoids including quercetin, wogonin, bacalein and EGCG have been shown to modulate neuro-inflammation and microglial/astrocyte-mediated nitric oxide production (Lee et al., 2003Chen et al., 2005). All these actions are mediated by transformation of protein, lipid kinase signaling pathways, nitric oxide production, pro-inflammatory transcription factors, downstream regulation of iNOS and cyclooxygenase (COX-2) expression, free radicals scavenging, NOX activation and liberation of cytokine (Jang et al., 2008Zheng et al., 2008). EGCG and genistein are reported to enhance the production of glutathione via PI3-kinase-reliant regulation of nuclear factor erythroid 2–related factor 2 (Nrf2)-induced antioxidant pathway (Hernandez-Montes et al., 2006).

各种体外研究也证实了这样的观点,即黄酮类化合物通过抑制内源性神经毒素5-s- 半胱氨酸多巴胺的形成来预防帕金森病的病理学方面。此外,黄酮类化合物的神经保护作用也被报道在其他疾病中,如亨丁顿舞蹈症,通过 ERK 途径介导(Maher 等,2006,2011)。报道了柑橘黄酮类化合物柚皮素(Naringenin)通过抑制脂多糖/γ- 干扰素诱导的神经胶质细胞活化和抑制 p38/STAT-1通路而减轻神经元损伤(Vafeiadou 等,2009)。柚皮素还抑制活化的小胶质细胞中一氧化氮的生成。蓝莓黄酮类化合物也被证明可以减弱活化的小胶质细胞中 tnf-α、一氧化氮和 il-1β 的产生(Lau 等,2007)。其他黄酮类化合物包括槲皮素、汉黄芩素、杆菌素和 EGCG 已被证明可以调节神经炎症和小胶质/星形胶质细胞介导的一氧化氮的产生(Lee 等人,2003; Chen 等人,2005)。所有这些作用都是通过蛋白质转化、脂激酶信号通路、一氧化氮生成、促炎症转录因子、诱导型一氧化氮合酶(iNOS)和环氧合酶(COX-2)表达的下游调节、自由基清除、 NOX 活化和细胞因子的释放而介导的(Jang 等人,2008; Zheng 等人,2008)。EGCG 和 genistein 被报道通过 pi3激酶依赖性调节核因子红系因子2(Nrf2)诱导的抗氧化途径来增加谷胱甘肽的生成(Hernandez-Montes et al. ,2006)。

Flavonoids for Better Cognition

提高认知能力的黄酮类化合物

Several studies highlight the beneficial effects of flavonoid-rich foodstuffs’ consumption on cognition (Commenges et al., 2000Letenneur et al., 2007Spencer, 2010a). Isoflavones from soy and soy-derived foods have been reported to improve learning and memory possibly by their potential to mimic the activity of estrogens in brain (File et al., 2001). These isoflavones also modulate the neuronal concentrations of ACh and neurotrophic factors including the brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the hippocampus and frontal cortex regions of brain (Pan et al., 1999a,b).

一些研究强调了食用富含黄酮类化合物的食物对认知的有益影响(Commenges et al. 2000; Letenneur et al. 2007; Spencer 2010a)。来自大豆和大豆衍生食品的异黄酮已被报道,以改善学习和记忆,可能是由于他们的潜力,模仿大脑中的雌激素活动(文件等人,2001年)。这些异黄酮还可以调节大脑海马和额叶皮质区域的神经元乙酰胆碱和神经营养因子的浓度,这些神经营养因子包括脑源性神经营养因子和神经生长因子。

The use of flavonoids rich foods including grapes juice, cocoa and blueberry have shown to possess potential cognition-enhancing effects (Krikorian et al., 2010Scholey et al., 2010Shukitt-Hale, 2012). Behavioral evidences suggest that periodic consumption of flavonoids rich fruits like pomegranate, blueberry, grapes, strawberry, as well as pure compounds including quercetin and EGCG are able to improve cognitive performance as indicated from the improvement in the overall scores of memory acquisition, short and long term memory, memory retention and retrieval (Joseph et al., 1999Hartman et al., 2006). The above mentioned fruits are rich in flavanols and anthocyanins which improve cognitive and spatial working memory deficits in animal models (Joseph et al., 1998Shukitt-Hale et al., 2009). Additionally, pure EGCG can improve the retention of spatial memory (van Praag et al., 2007). Flavonoids from blueberry also improve the processing of spatial memory viaits action on the dentate gyrus (DG), which is highly sensitive to the effects of aging (Small et al., 2004Burke and Barnes, 2006). Blueberry flavonoids have been reported to boost up precursor cells proliferation in the DG of animal models, thus increasing DG neurogenesis and improve cognitive capabilities (Casadesus et al., 2004). However, further characterization of these food supplements, isolation of pure natural compounds and their comparison to the already established flavonoids may provide more useful insights into the memory enhancing properties of dietary flavonoids.

富含黄酮类化合物的食物,包括葡萄汁、可可和蓝莓,已被证明具有潜在的认知增强效果(Krikorian et al. ,2010; Scholey et al. ,2010; Shukitt-Hale,2012)。行为学证据表明,定期食用富含黄酮类化合物的水果,如石榴、蓝莓、葡萄、草莓,以及纯化合物,如槲皮素和 EGCG,能够提高认知能力,从记忆获取、短期和长期记忆、记忆保持和提取的整体评分中可以看出这一点。上面提到的水果富含黄烷醇和花青素,可以改善动物模型的认知和空间工作记忆缺陷(Joseph et al. ,1998; Shukitt-Hale et al. ,2009)。此外,单纯的 EGCG 可以改善空间记忆的保持(van Praag et al. ,2007)。蓝莓中的黄酮类化合物也通过其对齿状回的作用改善空间记忆的加工,齿状回对衰老的影响高度敏感(Small 等人,2004; Burke 和 Barnes,2006)。据报道,蓝莓类黄酮可以促进动物模型 DG 中前体细胞的增殖,从而增加 DG 神经发生,提高认知能力(Casadesus 等,2004)。然而,进一步研究这些食物补充剂的角色塑造,分离纯天然化合物,并与已经建立的黄酮类化合物进行比较,可能会对饮食中黄酮类化合物增强记忆的特性提供更多有用的见解。

Flavonoids Interactions With Useful Signaling Pathways

黄酮类化合物与有用信号通路的相互作用

Flavonoids are able to preferentially bind with the neuronal receptors including GABAA, tyrosine receptor kinase B (TrkB), δ-opioid, estrogen, testosterone, nicotinic and adenosine receptors and mediate the various neuropharmacological actions (Ji et al., 1996Katavic et al., 2007Fernandez et al., 2008Lee et al., 2010). Several reports regarding the beneficial neuroprotective effects of flavonoids and their metabolites viainteractions with neuronal signaling pathways have been published (Spencer, 2007Incani et al., 2010). They interact with several protein kinase and lipid kinase signaling pathways like tyrosine kinase, mitogen-activated kinase (MAPK), PI3K/Akt, protein kinase C and nuclear factor κB pathway (Gamet-Payrastre et al., 1999Schroeter et al., 2001Incani et al., 2010). When flavonoids bound to these receptors, they may stimulate or inhibit the receptors and thus mediate their actions via modulation of gene expression or phosphorylation. Subsequently, they modulate the synaptic protein synthesis, neuronal plasticity and other morphological changes responsible for neurodegenerative disorders and impairment in cognition. For instance, flavonoids and their metabolites have been reported to interact with MAPKs signaling pathways (MEK1 and MEK2 receptors) which result in downstream activation of cAMP response element binding protein (CREB), thus leading to significant changes in synaptic plasticity and memory (Finkbeiner et al., 1997Impey et al., 1998). Supplementation of flavanols and anthocyanins rich blueberry have been reported to enhance cognitive performance in animals via activation of CREB and elevation of BDNF levels in hippocampus (Williams et al., 2008). Furthermore, chronic administration of green tea catechins can reduce the levels of Aβ1–42 oligomers, elevate the activities of kinase A/cAMP-response element binding protein (PKA/CREB) pathway and up-regulated the action of synaptic plasticity related proteins in the hippocampus (Li et al., 2009). Moreover, flavonoids stabilize hypoxia-inducible factor-1 (HIF-1) and Nrf2 transcription factors (Park S. S. et al., 2008), activate peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1α) pathway (Zhang et al., 2010), and act as modulators of peroxisome proliferator-activated receptor gamma (PPAR-γ; Feng et al., 2016). These molecular changes produced by flavonoids may improve AD pathophysiology by protecting neurons against oxidative stress, improve mitochondrial dysfunction, reduce insulin resistance, and thus ameliorate cognitive impairment (Figure 11).

黄酮类化合物能够优先结合神经元受体包括 GABAA,酪氨酸受体激酶 b (TrkB) ,δ 阿片类,雌激素,睾丸激素,烟碱和腺苷受体和调解各种神经药理学作用(Ji et al. ,1996; Katavic et al. ,2007; Fernandez et al. ,2008; Lee et al. ,2010)。一些关于黄酮类化合物及其代谢物通过与神经元信号通路相互作用而产生的有益神经保护作用的报告已经发表(Spencer,2007; inci et al. ,2010)。它们与一些蛋白激酶和脂肪激酶信号通路相互作用,如酪氨酸激酶,丝裂原激活激酶(mitogen-activated kinase,MAPK) ,PI3K/Akt,蛋白激酶C 和核因子 κb 通路(Gamet-Payrastre et al. ,1999; Schroeter et al. ,2001; inci et al. ,2010)。当黄酮类化合物与这些受体结合时,它们可能会刺激或抑制这些受体,从而通过调节基因表达或磷酸化介导它们的作用。随后,他们调节突触蛋白质合成,突触可塑性和其他形态变化负责神经退行性疾病和认知障碍。例如,黄酮类化合物及其代谢产物被报道与 mapk 信号通路(MEK1和 MEK2受体)相互作用,从而导致 cAMP 反应元件结合蛋白(CREB)的下游激活,从而导致突触可塑性和记忆的显著改变(Finkbeiner 等,1997; impy 等,1998)。补充黄烷醇和花青素丰富的蓝莓已被报告,以提高认知能力的动物通过激活 CREB 和海马 BDNF 水平的提高(威廉斯等人,2008年)。此外,长期服用绿茶儿茶素可以降低 Aβ1-42寡聚体的水平,提高激酶 A/cAMP-response element binding protein (PKA/CREB)通路的活性,并上调突触可塑性相关蛋白在海马的作用(Li et al. 2009)。此外,黄酮类化合物稳定缺氧诱导因子 -1(HIF-1)和 Nrf2转录因子(Park s. s. et al. 2008) ,激活过氧化物酶体增殖物激活受体 -γ 辅激活因子 -1(pgc-1α)通路(Zhang et al. 2010) ,并作为过氧化物酶体增殖物活化受体γ 的调节因子(ppar-γ; Feng et al. 2016)。这些由黄酮类化合物产生的分子改变可能改善 AD 的病理生理学,通过保护神经元对抗氧化应激,改善线粒体功能障碍,降低胰岛素抵抗,从而改善认知障碍。FIGURE 11 图11

Figure 11. The probable mechanisms of flavonoids stimulating/inhibiting signaling pathways implicated in cognitive performance and neurodegeneration.

图11. 黄酮类化合物刺激/抑制信号通路的可能机制与认知能力和神经退行性疾病有关。

Flavonoids possess PI3-kinase modulating potentials (Figure 12), by directly interacting with its ATP binding site (Vlahos et al., 1994). Moreover, quercetin and its metabolites inhibit prosurvival Akt/PKB signaling pathways through inhibition of PI3-kinase activity (Spencer et al., 2003). On the contrary, some flavanones like hesperetin activate Akt/PKB signaling pathway and impart prosurvival characteristics in the cortical neurons (Vauzour et al., 2007a). Moreover, epicatechin-5-gallate has been reported to modulate neurotransmission, synaptogenesis and plasticity mediated through stimulation of extracellular signal regulated kinase (ERK), PI3K reliant raise in CREB phosphorylation and upregulation of GluR2 levels in cortical neurons (Schroeter et al., 2007).

黄酮类化合物通过直接与其 ATP 结合位点相互作用,具有 pi3激酶调节潜能(图12)。此外,槲皮素及其代谢物通过抑制 pi3激酶活性来抑制 Akt/PKB 信号通路的前生存(Spencer 等人,2003)。相反,一些黄酮类化合物如橙皮素激活 Akt/PKB 信号通路,并在大脑皮层神经元中传递前存活特性(Vauzour et al. 2007a)。此外,表儿茶素 -5- 没食子酸酯已被报道通过刺激细胞外信号调节激酶(ERK)、 PI3K 依赖性增加 CREB 磷酸化和上调皮质神经元 GluR2水平来调节神经传导、突触发生和可塑性(Schroeter et al. 2007)。FIGURE 12 图12

Figure 12. The PI3-kinases activation mediated neuroprotective action of flavonoids.

图12。 pi3激酶激活介导的黄酮类化合物的神经保护作用。

In a study, the chronic ingestion of blueberry is reported to increase Akt phosphorylation, activation of downstream mammalian target of rapamycin (mTOR) receptor and increase the content of Arc/Arg3.1 (activity-regulated cytoskeletal-associated protein) in the hippocampus (Williams et al., 2008). As Arc is regulated by BDNF and is important in the long term potentiation (LTP), therefore these changes may be related to the improvement of spatial memory and cognition (Waltereit et al., 2001Yin et al., 2002). This has been supported by various studies regarding the effects of flavonoids on changes in the neuronal morphologies (van Praag et al., 2007).

在一项研究中,长期摄入蓝莓会增加 Akt 磷酸化,激活下游哺乳动物雷帕霉素受体(mTOR) ,增加海马中 Arc/Arg3.1(活性调节细胞骨架相关蛋白)的含量(Williams 等人,2008)。由于 Arc 受 BDNF 调节,在长时程增强(LTP)中起重要作用,因此这些变化可能与空间记忆和认知能力的改善有关(Waltereit 等,2001; Yin 等,2002)。关于黄酮类化合物对神经元形态变化的影响的各种研究(van Praag 等人,2007)支持了这一观点。

Overview of Mechanisms Underpinning the Therapeutic Effects of Flavonoids in Neurodegeneration

神经退行性疾病中黄酮类化合物治疗作用的机制综述

Flavonoids by virtue of their low molecular weight, impact multiple cellular targets simultaneously and thus mediate their beneficial neuropharmacological effects in neurodegeneration. Flavonoids interact with several neuronal and glial signaling pathways implicated in neuronal functions and survival (Williams et al., 2004Spencer, 2010a). They also up-regulate the body antioxidant system and expression of proteins related to neuronal repair and synaptic plasticity (Kong et al., 2000Eggler et al., 2008). They modulate cerebral blood flow and inhibit neuropathological processing in different regions of brain (Dinges, 2006). The probable mechanism underlying these neuromodulatory properties of flavonoids is shown in Figure 13.

黄酮类化合物由于其低分子量,同时影响多个细胞靶点,因此在神经退行性疾病中介导其有益的神经药理学作用。黄酮类化合物与神经元功能和存活相关的几个神经元和神经胶质信号通路相互作用(Williams et al. ,2004; Spencer,2010a)。它们也上调机体抗氧化系统和与神经元修复和突触可塑性相关的蛋白质的表达。它们调节大脑血流量,抑制大脑不同区域的神经病理过程(Dinges,2006)。黄酮类化合物的这些神经调节特性的可能机制如图13所示。FIGURE 13 图13

Figure 13. The probable abridged mechanism of flavonoids in enhancing cognition and suppression of neurodegeneration.

图13: 黄酮类化合物增强认知和抑制神经退行性疾病的可能机制。

Toxicological Propensity of Flavonoids

黄酮类化合物的毒理学性质

The wide availability of flavonoids and their recent increase consumption by humans has raised important questions regarding the potential toxicity of these dietary components. Although majority of natural products are well tolerated; however, flavonoids and related phytochemicals have been shown to induce neurobehavioral and endocrine disrupting effects (Bugel et al., 2016Patisaul, 2017). The toxicity of flavonoids is very low in animals. For rats, the LD50 has been reported as 2–10 g per animal for most flavonoids. Similar doses in humans are quite unrealistic. As a precaution, doses less than 1 mg per adult per day have been recommended for humans (Galati and O’Brien, 2004). High doses of quercetin over several years has shown to result in the formation of tumors in mice. However, in other long-term studies, no carcinogenicity was found (Dunnick and Halley, 1992). Flavonoids can either inhibit or induce human cytochrome P450 (CYPs) depending upon their structures, concentrations. The interactions of flavonoids with CYP3A4, the predominant human hepatic and intestinal CYP responsible for metabolizing 50% of therapeutic agents is of particular interest. The simultaneous administration of flavonoids and clinically used drugs may cause flavonoid–drug interactions by modulating the pharmacokinetics of certain drugs (Hodek et al., 2002Galati and O’Brien, 2004).

黄酮类化合物的广泛可用性以及近来人类对它们的消费量增加,引起了关于这些饮食成分潜在毒性的重要问题。虽然大多数天然产品都具有良好的耐受性,但是,黄酮类化合物和相关的植物化学物质已经被证明可以诱导神经行为和内分泌干扰效应(Bugel et al. ,2016; Patisaul,2017)。黄酮类化合物对动物的毒性很低。对于大鼠来说,大多数黄酮类化合物的 LD50已被报道为每只动物2-10克。相似的剂量在人类身上是很不现实的。作为预防措施,建议人类每天服用少于1毫克的剂量(Galati 和 o’ brien,2004年)。几年来,高剂量的槲皮素已经显示在小鼠体内形成肿瘤。然而,在其他长期研究中,没有发现致癌性(Dunnick 和 Halley,1992)。黄酮类化合物可以抑制或诱导人类细胞色素 P450(cyp) ,这取决于它们的结构、浓度。黄酮类化合物与 CYP3A4的相互作用特别令人感兴趣,CYP3A4是人体肝脏和肠道中代谢50% 治疗药物的主要细胞色素。同时给药黄酮类化合物和临床使用的药物可能会引起黄酮类化合物-药物相互作用的调节某些药物的药代动力学。

Conclusion and Future Directions

总结及未来路向

The dietary use of flavonoid-rich foodstuffs has the propensity to lessen age-related decline in cognition and may restore memory functions as well as attenuate the development of conditions associated with dementia. The therapeutic importance of natural products in neurodegeneration has been attributed from their various modulatory neuropharmacological properties (Table 1). Further studies are required especially well-designed clinical trials to endorse the clinical effectiveness of flavonoids in neurodegeneration associated clinical signs and symptoms. Moreover, various in vivo studies should be designed to obtain a better insight of flavonoids efficacy with regard to their bioavailability, potential toxicities and accumulation at the target sites in the aging brain. For instance, providing a direct link between behavioral responses in test animals/humans to changes in the cortical, and hippocampal areas, the underlying molecular events linked to synaptic plasticity, effects on neuronal stem cells proliferation and changes in the cerebral blood flow will provide guidelines for flavonoids-based dietary applications and subsequent clinical recommendations in neurological disorders. The use of imaging and spectroscopic techniques like MRI and NMR can provide a better understanding of flavonoids-based changes in cerebral blood flow, quantitative changes in neuronal stem cells, progenitor cells and gray matter density along with electrophysiological changes. All these efforts will provide mechanism based links between flavonoids therapy and brain functions and information related to their effective doses. In relation to AD and dementia, it is most important to explore the anti-amyloid and tau modifying effects of flavonoids both in in vitro and in vivo models. In this regard, tau modifying potentials of flavonoids have been investigated at preliminary level, yet detail studies on destabilization effects of β-amyloid, tau proteins and effects on microglial activation need to be explored. Furthermore, a recommendation regarding the dose/daily intake and duration of therapy must be provided for safe and efficacious results. Molecules which improve the function of CREB are reported to consolidate memory by promoting the gene expression responsible for the synaptic morphology and long term memory. Compounds which activate the function of upstream regulators of CREB, like Akt and ERK are considered to be highly potential memory enhancer drugs. Flavonoids are reported to concentrate in the brain and activate ERK–CREB and Akt–CREB mediated memory and are thus are promising candidates for the development of memory enhancing drugs. Regardless of significant progress in the understanding of flavonoids biology, majority of clinicians mistakenly considered them only as simple antioxidants, which is a major barrier in the development of bioactive flavonoids at the preclinical level. Now it is well known that flavonoids are much more likely to prevent both normal and disease-mediated decline in cognitive functions by modulating cellular and molecular functions of brain. Thus, flavonoids represent a group of vital precursor molecules in the quest to discover new generation of memory-enhancing agents that may be able to counteract and perhaps even quash age-related decline in cognitive functions.

饮食中使用富含类黄酮的食物可以减轻与年龄有关的认知能力下降,可以恢复记忆功能,并减缓与痴呆症有关的条件的发展。天然产物在神经退行性疾病的治疗重要性来自于它们的各种调节性神经药理学特性(表1)。还需要进一步的研究,特别是精心设计的临床试验,以支持黄酮类化合物对神经退行性疾病相关临床症状和体征的临床疗效。此外,还应设计各种体内研究,以更好地了解黄酮类化合物的生物利用度、潜在毒性和在衰老大脑靶点的积累。例如,在实验动物/人类对大脑皮层和海马区变化的行为反应之间提供直接的联系,与突触可塑性有关的潜在分子事件,对神经干细胞增殖的影响和脑血流的变化,将为基于黄酮类化合物的饮食应用提供指南,以及随后的神经系统疾病的临床建议。利用 MRI 和 NMR 等成像和光谱技术可以更好地了解脑血流量中基于类黄酮的变化、神经干细胞、祖细胞和灰质密度的定量变化以及电生理变化。所有这些努力将提供基于机制的黄酮类化合物疗法和大脑功能之间的联系以及与其有效剂量相关的信息。在 AD 和痴呆的研究中,黄酮类化合物的体内外抗淀粉样蛋白和 tau 蛋白修饰作用的研究尤为重要。在这方面,黄酮类化合物的 tau 蛋白修饰作用已经初步研究,但是 β 淀粉样蛋白、 tau 蛋白的不稳定作用和对小胶质细胞激活作用的详细研究还有待于进一步探讨。此外,为了获得安全有效的结果,必须提供关于剂量/每日摄入量和治疗持续时间的建议。据报道,改善 CREB 功能的分子通过促进负责突触形态和长时记忆的基因表达来巩固记忆。激活 CREB 上游调节因子功能的化合物,如 Akt 和 ERK,被认为是潜在的增强记忆药物。据报道,黄酮类化合物主要集中在大脑中,激活 ERK-CREB 和 Akt-CREB 介导的记忆,因此是研制记忆增强药物的有希望的候选药物。尽管对类黄酮生物学的理解已经取得了重大进展,但大多数临床医生错误地认为它们只是简单的抗氧化剂,这是临床前生物活性类黄酮开发的主要障碍。现在,众所周知,类黄酮通过调节大脑的细胞和分子功能,更有可能预防正常和疾病介导的认知功能下降。因此,黄酮类化合物代表了一组重要的前体分子,用于寻找新一代的记忆增强剂,这些增强剂可能能够抵消甚至抑制与年龄相关的认知功能下降。TABLE 1 表一

Table 1. Summary of the prospective neuropharmacological activities of essential oils and bioactive compounds isolated from medicinal plants.

表1. 从药用植物中分离的精油和活性成分的前瞻性神经药理活性概述。

Author Contributions

作者贡献

MA conceived the idea, carried out literature survey and drafted the manuscript. AS helped in chemistry of flavonoids and corrected the final version of the manuscript. MJ, FU, MO and IU provided useful guidelines, technical support at every step of the manuscript drafting and technical editing. MS and JA performed language and improved technical/scientific aspects of the manuscript, drafted and refined the final version of manuscript. All authors have read and approved the final version of manuscript for publication.

马构思了这个想法,进行了文献调查并起草了手稿。在化学方面对黄酮类化合物有所帮助,并修正了手稿的最终版本。MJ,FU,MO 和 IU 为稿件起草和技术编辑的每一步都提供了有用的指导和技术支持。MS 和 JA 对手稿进行了语言和技术/科学方面的改进,起草并完善了手稿的最终版本。所有的作者都已经阅读并批准了稿件的最终版本。

Funding

资金

This work has received no specific grant from any funding agency in the public, commercial, or not for-profit sectors.

这项工作没有得到任何公共、商业或非营利部门的资助机构的具体拨款。

Abbreviations

缩写

AD, Alzheimer disease; NFTs, Neurofibrillary tangles; Aβ, Amyloid beta; iNOS, Inducible nitric oxide synthase; BACE1, Beta amyloid cleaving enzyme; APP, Amyloid precursor protein; ACh, Acetylcholine; AChE, Acetylcholinesterase; BChE, Butyrylcholinesterase; TGN, trans-Golgi-network; EGCG, Epigallocatechin-3-gallate; Cy3G, Cyanidin 3-O-glucoside; ROS, Reactive oxygen species; RNS, Reactive nitrogen species; CAT, catalase; CREB, cAMP response element binding protein; JNK, c-jun N-terminal kinase; p38, protein kinases; BDNF, Brain derived neurotrophic factor; SOD, Superoxide dismutase; COX-2, Cyclooxygenase 2; DG, dentate gyrus; HIF-1, Hypoxia-inducible factor 1; TrkB, Tyrosine receptor kinase beta; MAPKs, Mitogen-activated kinases; mTOR, Mammalian target of rapamycin; Nrf2, Nuclear factor erythroid 2–related factor 2; PGC-1α, Peroxisome proliferator-activated receptor-γ coactivator-1; PPAR-γ, Peroxisome proliferator-activated receptor gamma.

阿尔茨海默病; 阿兹海默病; 神经纤维缠结; aβ,β 淀粉样蛋白; iNOS,诱导型一氧化氮合酶; BACE1,β 淀粉样蛋白裂解酶; APP,淀粉样蛋白前体; 乙酰胆碱; 乙酰胆碱; 乙酰胆碱酯酶; BChE,丁酰胆碱酯酶;反式高尔基体网络; EGCG,表没食子儿茶素没食子酸酯; Cy3G,花青素3-o- 葡萄糖苷; 活性氧,活性氧类; 活性氮; CAT,过氧化氢酶;C-jun n 端激酶; p38蛋白激酶; BDNF,脑源性神经营养因子; SOD,超氧化物歧化酶; COX-2,环氧合酶2; DG,齿状回; HIF-1,缺氧诱导因子1; TrkB,酪氨酸受体激酶 β;Mapk,丝裂原活化激酶; mTOR,雷帕霉素靶蛋白; Nrf2,红系核因子2相关因子2; pgc-1α,过氧化物酶体增殖物激活受体 -γ 辅激活因子1; ppar-γ,过氧化物酶体增殖物活化受体γ。

Conflict of Interest Statement

利益冲突声明

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

作者宣称,这项研究是在没有任何商业或金融关系的情况下进行的,这种关系可能被解释为潜在的利益冲突。

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