芹菜素和槲皮素: 治疗阿尔茨海默病的潜在挑战

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Abstract

摘要

Alzheimer`s disease (AD) is an accelerating neurodegenerative disorder, dementia in the world. Current treatments for Alzheimer’s disease primarily focus on enhancement of cholinergic transmission & leading to neuronal dysfunction and loss in the brain. Flavonoid bioactive compounds are the major role for the designer of a new generation of therapeutic agents that are clinically effective in treating neurodegenerative diseases. Apigenin & quercetin are attractive biomarkers in this regards which has been epidemiological studies height a Neuroprotective and related to a lower risk of developing dementia or gradual decline its progressive.  The continuing investigation of the potential preventive activity of quercetin and apigenin should be evaluated in long-term exposure clinical trials, using preparations with high bioavailability and promising to yield a possible remedy for this pervasive disease. Thus, the aim of the review, we analyzed the enhancing effects of apigenin and quercetin and discuss the potential of these compounds for Alzheimer’s disease prevention and treatment.

阿尔茨海默病(AD)是一种加速发展的神经退行性疾病,也就是痴呆症。目前阿尔茨海默病的治疗主要集中在提高胆碱能传递 & 导致神经元功能障碍和大脑损失。黄酮类生物活性化合物是新一代治疗神经退行性疾病临床有效药物设计者的主要作用。芹菜素和槲皮素在这方面是有吸引力的生物标志物,已被流行病学研究高度神经保护和相关的低风险发展中国家痴呆症或逐渐下降其进展。对槲皮素和芹菜素潜在预防活性的持续调查应在长期暴露临床试验中进行评估,使用具有高生物利用度的制剂,并有望为这种普遍存在的疾病提供一种可能的治疗方法。因此,本文分析了芹菜素和槲皮素对阿尔茨海默病的促进作用,并探讨了这两种化合物在阿尔茨海默病防治中的潜力。

1 Introduction

1引言

Alzheimer’s disease (AD) is one of the greatest widespread heterogeneous progressive neurodegenerative disorders of the central nervous system, dementia in the worldwide. Its pathological distinguishing attribute include synaptic degeneration, deposition of Aβ-containing senile plaques and phosphotau-containing tangles in brain. , which ultimately lead to neuronal dysfunction and loss in the brain1, 2. Dementia is a multifactorial syndrome that affects memory, thinking, language, behaviour and ability to perform everyday activities. According to the WHO Alzheimer Report today3, 4. dementia affects over 46 million people worldwide and this number is estimated to increase to 131.5 million by 2050 due to increased expectation of life and an aging population5 .The most common form of dementia is Alzheimer disease (AD) that possibly contributes to 60%–70% of cases, with a greater proportion in the higher age ranges6. AD is a multifactorial disease with genetic (70%) and environmental (30%) causes. The familial early-onset form of AD is caused by mutations in genes APP (amyloid precursor protein), PSEN1 (Presenilin 1) and PSEN2 (Presenilin 2). The main factors of neurodegeneration are several cellular and molecular events such as oxidative stress, impaired mitochondrial function, and deposition of aggregated proteins, neuroinflammation, and activation of apoptotic factors7, 8. Flavonoids are bioactive markers components that are derived from vegetables plants and fruits. Since ancient times, apigenin- and quercetin rich nutraceuticals have been used as food supplements in improving cognitive function and in prevention of neurodegenerative diseases in humans9. Apigenin and quercetin rich flavonoids may be able to target multiple sites in the brain and prevent neurodegenerative diseases (Fig 1). Better animal models and good biomarkers for patient sub grouping will be also instrumental for quick advancement in the field10. The review revises all these aspects with the objective to generate debate among scientists. In this review, we emphasize the protective and preventive functionsof apigenin and quercetin in neurodegenerative diseases by modulation of neurosignaling pathways11, 12. In general, the neuroprotective role of activated microglia cells are facilitated by removing damaged neurons and infectious agents by phagocytosis. However, their chronic activation exacerbates neuronal damage through excessive release of proinflammatory cytokines, and other inflammatory mediators which contribute to neuroinflammation and subsequent neurodegeneration in the CNS. Considering the possible role of neuroinflammation in the pathogenesis of neurodegenerative disorders, an intervention that targets this mechanism may have therapeutic potential. Epidemiological and genetic linkage data indicates strong support of neuroinflammation as drug discovery target for neurodegenerative disorders. Preclinical and animal model studies embody most of the research done and indicate the need for larger in-depth examinations13,14.

阿尔茨海默病(AD)是世界范围内分布最广泛的进行性中枢神经系统退行性疾病之一。其病理学特征包括突触变性、脑内含 β- 淀粉样蛋白的老年斑沉积和含磷酸 tau 蛋白的神经纤维缠结。最终导致大脑神经元功能障碍和丢失。痴呆症是一种多因素综合症,影响记忆、思考、语言、行为和日常活动能力。根据世界卫生组织今天的老年痴呆症报告3,4。全世界有超过4600万人患有痴呆症,由于预期寿命增加和人口老龄化,预计到2050年这一数字将增加到1.315亿。痴呆最常见的形式是阿兹海默病,可能占60%-70% 的病例,在较高的年龄范围内占更大的比例。AD 是一种遗传性(70%)、环境性(30%)的多因素疾病。家族性早发型 AD 是由淀粉样前体蛋白 APP、早老素1和早老素2基因突变引起的。神经退行性疾病的主要因素是一些细胞和分子事件,如氧化应激、受损的线粒体功能、聚集蛋白质的沉积、神经炎症和凋亡因子7,8的激活。类黄酮是从蔬菜、植物和水果中提取的生物活性标记成分。自古以来,富含芹菜素和槲皮素的保健食品一直被用作改善认知功能和预防人类神经退行性疾病的食品补充剂。芹菜素和富含槲皮素的黄酮类化合物可以作用于大脑多个部位,预防神经退行性疾病(图1)。更好的动物模型和良好的患者分组生物标志物也将有助于在野外取得快速进展。审查修改了所有这些方面,目的是引起科学家之间的辩论。本文就芹菜素和槲皮素通过调节神经信号通路11、12在神经退行性疾病中的保护和预防作用作一综述。一般来说,活化的小胶质细胞的神经保护作用是通过吞噬去除受损的神经元和感染性因子来促进的。然而,它们的慢性激活通过过度释放促炎细胞因子和其他炎症介质加剧了神经元的损伤,这些炎症介质有助于中枢神经系统的神经炎症和随后的神经退行性疾病。考虑到神经炎症在神经退行性疾病发病机制中可能的作用,针对这一机制的干预可能具有治疗潜力。流行病学和遗传连锁数据表明强烈支持神经炎症作为药物发现目标的神经退行性疾病。临床前和动物模型研究体现了大部分已完成的研究,并表明需要进行更大规模的深入检查13、14。

Neuroinflammation is also involved in the complex cascade leading to AD pathology and symptoms. It has been shown that AD is associated with increased levels of cyclooxygenase 1 and 2 and of prostaglandins, release of cytokines and chemokines, acute phase reaction, astrocytosis and microgliosis15, 16. These pro-inflammatory factors may induce degeneration of normal neurons through up regulation of nuclear factor-κB, mitogen-activated protein kinase, and c-Jun N-terminal kinase17. Finally, in patients with AD epigenetic alterations such as changes in DNA methylation, histone modifications, or changes in miRNA expression have been reported. Histone acetyltransferases HATs) and histone deacetylases (HDACs) promote histone post-translational modifications, which lead to an epigenetic alteration in gene expression. Aberrant regulation of HATs and HDACs in neuronal cells results in pathological consequences such as neurodegeneration18 19 .

神经炎症还参与了导致 AD 病理和症状的复杂级联反应。研究表明,AD 与环氧化酶1和2、前列腺素水平升高、细胞因子和趋化因子释放、急性期反应、星形细胞增多和小胶质细胞增多有关。这些促炎因子可能通过上调核因子 -κb、有丝分裂原活化蛋白激酶和 c-Jun n 末端激酶17而诱导正常神经元的退化。最后,在 AD 表观遗传改变患者中,如 DNA 甲基化改变、组蛋白修饰或 miRNA 表达的改变已被报道。组蛋白乙酰转移酶 HATs)和组蛋白去乙酰化酶(HDACs)促进组蛋白翻译后修饰,从而导致基因表达的表观遗传改变。神经元细胞中 HATs 和 HDACs 的异常调节导致神经退行性分化等病理后果。

Alzheimer’s appears to be a complex and multifactorial disorder in which extracellular Aβ and intraneuronal hyperphosphorylated tau protein are the hallmark neuropathological features, along with oxidative stress and inflammation. Actually, no current effective disease-modifying treatments are available20. Moreover, as Aβ-induced changes are believed to occur a long time before the impairment of cognitive function appears, so strategies to stop or to slow the progression of the disease are of greater importance as is an early diagnosis.Owing to the particular multifactorial nature of the disease, a novel approach consists in evaluating substances having multi-target mechanisms, such as flavonoids, apigenin and quercetin are naturally occurring flavonoids of emerging interest are shown in Table 1 and Fig 2. 

阿尔茨海默氏症似乎是一种复杂的多因素疾病,其中细胞外 aβ 和神经元内过度磷酸化 tau 蛋白是神经病理学特征的标志,同时还有氧化应激和炎症。事实上,目前还没有有效的治疗疾病的方法。此外,由于认为 β 受体诱导的改变发生在认知功能损害出现之前很长一段时间,因此阻止或减缓疾病进展的策略与早期诊断一样更为重要。由于这种疾病具有特殊的多因素性质,一种新的方法包括评价具有多目标机制的物质,如黄酮类、芹菜素和槲皮素是新兴兴趣的天然黄酮类化合物,如表1和图2所示。

2 Pharmacokinetics and Multimodal drug therapy of Alzheimer’s

2阿尔茨海默病的药代动力学和多模式药物治疗

The majority of studies on potential anti-AD therapies are per- formed on transgenic models to which the assayed substance(s) is administered. In a high percentage of these studies (i) the actual concentration that reaches the CNS, (ii) the plasma/brain ratio, and (iii) the half-life of the compound in blood or brain are undetermined.

大多数关于潜在的抗 ad 治疗的研究都是在转基因模型上进行的。在这些研究中,很大一部分(i)实际浓度达到中枢神经系统(CNS) ,(ii)血浆/脑比值,以及(iii)化合物在血液或大脑中的半衰期未确定。

These parameters are important to understand where, when, and how a given drug is acting. It may also occur that a given drug is acting on quite diverse targets whose distribution in the (rodent or human) body is uneven. For example, Okun et al. (2010)24, reported a very informative study on dimebon, originally developed as an anti-histamine drug. Dimebon seems to be a multimodal drug with many different targets including g serotonergic, α-adrenergic, anddopaminergic receptors. The results indicate something that should be consid ered  in drug discovery, namely that a drug with multiple targets may result in greater benefits than a “clean” drug acting only on a given target . Furthermore, Okun et al. (2010) suggest that it is necessary  to understand the role of different pathways in AD and in  any other disease with complex etiologies. Such knowledge would surely help in developing multitarget drugs 25.

这些参数对于了解给定的药物在何处、何时以及如何起作用很重要。它也可能发生,给定的药物是作用于相当不同的目标,其分布在(啮齿动物或人类)体内是不均匀的。例如,奥肯等人(2010)24,报告了一个非常翔实的研究二美邦,最初开发作为抗组胺药物。Dimebon 似乎是一种多模式药物,具有多种不同的作用靶点,包括血清素能、 α- 肾上腺素能和多巴胺能受体。研究结果表明,在药物发现中应该考虑到一些问题,即具有多个靶点的药物可能比仅作用于某一特定靶点的“干净”药物产生更大的效益。此外,奥肯等人(2010年)建议,有必要了解的作用,不同的途径在 AD 和任何其他疾病与复杂的病因。这些知识肯定会有助于开发多靶点药物。

3 Source, Pharmacokinetics and Mechanism of Neuroprotective Action of Apigenin and Quercetin

芹菜素和槲皮素的来源、药代动力学及其神经保护作用机制

Apigenin is a polyphenol, nontoxic, nonmutagenic bioactive flavone (4, 5, 7-Trihydroxyflavone) found in a wide variety of fruits, plants, and vegetables in high level in cherries, onion, apples, grapes, celery and parsley has been reported to have numerous pharmacological properties and anticarcinogenic effects, anti-inflammatory and antioxidant 26, 27, 28. The cancer chemopreventive properties of apigenin were first demonstrated by Birt et al.2001 who described the antimutagenic and anti-promotion properties of apigenin through inhibition of TPA-induced ornithine decarboxylase activity in mouse skin. These initial studies with apigenin generated further interest in the development of apigenin as a chemopreventive and chemotherapeutic agent 29, 30. Apigenin has also been shown to suppress protein kinase cell activity and Prevents UVB-induced skin carcinogenesis. Recently, apigenin has been reported to alleviate learning and memory deficits and express the neurovascular protection by decreasing oxidative damage, improving cholinergic neuronal transmission, and preserving the blood-brain barrier integrity in Aβ25–35 intracerebroventricularly injected mice31. The inhibition of the influx of extracellular Ca2+ and release of intracellular Ca2+ in the rat thoracic aorta32. And the antagonism of NMDA and γ-aminobutyric acid (GABA) receptor channels in neurons might be part of the protective mechanisms.

芹菜素是一种多酚、无毒、无致突变性的生物活性黄酮(4,5,7- 三羟基黄酮) ,广泛存在于多种水果、植物和蔬菜中,在樱桃、洋葱、苹果、葡萄、芹菜和欧芹中含量较高。通过抑制 tpa 诱导的小鼠皮肤鸟氨酸脱羧酶活性,表明芹菜素具有抗突变和抗促癌作用。这些关于芹菜素的初步研究引起了人们对芹菜素作为化学预防和化学治疗剂的进一步兴趣。芹菜素还被证明可以抑制蛋白激酶细胞活性,防止紫外线 b 诱导的皮肤癌变。近年来研究发现,芹菜素可以减轻学习记忆障碍,通过减少氧化损伤、改善胆碱能神经元传递、维持 Aβ25-35侧脑室注射 mice31的血脑屏障完整性等途径表达神经血管保护作用。大鼠胸主动脉细胞外 Ca2 + 内流及胞内 Ca2 + 释放的抑制。神经元 NMDA 和 GABA 受体通道的拮抗作用可能是神经元保护机制的一部分。

Further, we demonstrated that apigenin exerted neuroprotection against Aβ-mediated toxicity mainly through the mechanisms of regulating redox imbalance, preserving mitochondrial function, inhibiting p38 MAPK-MAPKAP kinase-2 (MK2)-heat shock protein 27 (HSP27) and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK)-c-Jun pathways, and depressing apoptosis 33. Several groups have reported the anti-inflammatory action of apigenin in a number of human and animal inflammatory cell lines and animal models. Furthermore, analysis of the neuroprotective potential of apigenin in a double transgenic mouse model of AD (APP/PS1) indicated that apigenin could ameliorate AD-associated memory impairment, reduce the Aβ plaque burden and inhibit oxidative stress23. Several groups have reported anti-apoptotic effects of apigenin in murine HT2224 and human SH-SH5Y cell lines 25 and shown that apigenin can reduce glutamate-induced Ca2+ signalling in murine cortical neurons. Collectively, these results indicate that apigenin may have potent neuroprotective properties. However its contribution to neuroprotective mechanisms in human AD neurons is currently unknown 34,35.

进一步证实,芹菜素对 aβ 介导的毒性具有神经保护作用,主要通过调节氧化还原失衡、保持线粒体功能、抑制 p38 mapk 激酶 -2(MK2)-热休克蛋白27(HSP27)和应激激活蛋白激酶(SAPK)/c-Jun n- 末端激酶(JNK)-c-Jun 通路以及抑制凋亡33等机制实现。已有多个研究组报道了芹菜素在人、动物炎症细胞系和动物模型中的抗炎作用。此外,对双转基因 AD 小鼠模型(APP/PS1)中芹菜素的神经保护作用进行了分析,结果表明芹菜素能改善 AD 相关记忆障碍,减轻 aβ 斑块负荷,抑制氧化应激23。已有多组报道芹菜素对小鼠 HT2224和人 SH-SH5Y 细胞系25的抗凋亡作用,并显示芹菜素可减少谷氨酸诱导的小鼠皮层神经元 Ca2 + 信号传导。总的来说,这些结果表明芹菜素可能具有强有力的神经保护性能。然而,它对人类 AD 神经元神经保护机制的作用目前尚不清楚。

Pharmacokinetics studies of Apigenin crosses the brain-blood-barrier, and concentrations in rats reached 1.2 μM after daily intraperitoneal administration of 20 mg/kg of apigenin potassium salt (which was solubilized in water and stored frozen until use) for 1 week (Popovic et al., 2014).

芹菜素的药代动力学研究跨越了脑血屏障,每天腹腔注射20毫克/千克芹菜素钾盐(在水中溶解并冷冻保存直到使用) ,大鼠体内的浓度达到1.2微米(Popovic 等人,2014年)。

Quercetin (3,5,7,3′,4′-pentahydroxyflavone), the major flavonoid in the human diet, is widely found in fruits and vegetables, such as onions and apples, and red wine, has potential nutraceuticals and pharmaceutical uses 36. These potential uses may be due to its high oxygen radical scavenging activity or its ability to inhibit xanthine oxidase and lipid peroxidation in vitro. Furthermore, quercetin reliably exerts neuroprotective effects against agent induced toxicity and increases the resistance of neurons to oxidative stress and excitotoxicity by modulating the mechanisms of cell death38,39. There has been increasing interest in quercetin in the sports science and athletic communities because research has shown that its antioxidant, anti-inflammatory, psycho-stimulant and other properties are likely to improve mental and physical performance. Human clinical trials have confirmed that quercetin enhances endurance and performance. Also, emerging research suggests quercetin may reduce infection risk during intense physical exercise. In addition, quercetin has demonstrated the ability to stimulate mitochondrial biogenesis in vivo (mice)40.

槲皮素(3,5,7,3′ ,4′-五羟基黄酮)是人类饮食中的主要黄酮类化合物,广泛存在于水果和蔬菜中,如洋葱、苹果和红酒中,具有潜在的保健品和药用价值36。这些潜在用途可能是由于其高氧自由基清除活性或其抑制黄嘌呤氧化酶和脂质过氧化的能力体外。此外,槲皮素通过调节细胞死亡机制可靠地对抗药物引起的神经保护作用,并增强神经元对氧化应激和兴奋毒性的抵抗力。由于研究表明槲皮素具有抗氧化、消炎、心理兴奋和其他特性,有可能改善心理和身体状况,因此在体育科学和体育界对槲皮素的兴趣日益增加。人体临床试验已经证实槲皮素能增强耐力和运动能力。此外,新出现的研究表明,槲皮素可能减少感染的风险在剧烈的体育锻炼。此外,槲皮素已证明能够刺激体内(小鼠)40线粒体的生物合成。

4 Molecular mechanisms of neuroprotection by apigenin and quercetin

4芹菜素和槲皮素神经保护作用的分子机制

Apigenin and quercetin are known to provide neuroprotective effects by interacting with brain tissue at multiple sites. The neuroprotective action of dietary flavonoids includes their potential to protect neurons against oxidative stress and neuronal injury via their potential as antioxidants, an ability to suppress neuroinflammation, and the potential to modulate cell signaling pathways. Apigenin and quercetin are well-known antioxidants, and they may protect cell constituents against oxidative stress and therefore reduce the risk of neurodegenerative disease associated with oxidative stress. Apigenin and quercetin also protect neurons against some neurotoxic drugs whose toxicity is linked to the stimulation of oxidative stress. In addition, MPTP-induced neurotoxicity is also decreased by EGCG and quercetin41. Flavonoids interact not only through their antioxidant potential in protecting neurons but they also modulate various cell signaling pathways. It has become evident that flavonoids interact with critical neuronal intracellular signaling pathways and are able to exert neuroprotective actions42.

芹菜素和槲皮素通过在多个位点与脑组织相互作用而提供神经保护作用。饮食中的黄酮类化合物的神经保护作用包括它们作为抗氧化剂的潜力,抑制神经炎症的能力,以及调节细胞信号通路的潜力,保护神经元免受神经细胞和神经元损伤的潜力。芹菜素和槲皮素是众所周知的抗氧化剂,它们可以保护细胞成分对抗氧化应激,因此降低神经退行性疾病与氧化应激相关的风险。芹菜素和槲皮素还能保护神经元免受一些神经毒性药物的毒性作用,这些药物的毒性与氧化应激刺激有关。表没食子儿茶素没食子酸酯(EGCG)和槲皮素41也可降低 mptp 所致的神经毒性。黄酮类化合物不仅通过其保护神经元的抗氧化潜能相互作用,而且还调节各种细胞信号通路。黄酮类化合物与神经元细胞内信号通路相互作用,能够发挥神经保护作用。

5 Discussions

5讨论

The current study further clarified the beneficial effects of apigenin on AD-associated pathology. Our findings indicate a clear rescue of learning and memory deficits in apigenin-treated APP/presenilin-1 (PS1) double-transgenic mice. Apigenin also showed effects on affecting APP processing and preventing Aβ burden involving the decrease of BACE1 and β-CTF levels, the relief of Aβ deposition, and the reduction of insoluble Aβ levels. Alzheimer’s is a multifactorial disorder that requires drugs capable of operating on multiple brain targets. Flavonoids, mainly Apigenin and quercetin, having neuroprotective effects appear to be ideal candidates to prevent or treat neurodegenerative disorders however, their clinical efficacy and utility is still an open question. Better animal models and good biomarkers for patient sub grouping will be also instrumental for quick advancement in the field. The review revises all these aspects with the objective to generate debate among scientists.

本研究进一步阐明了芹菜素对 ad 相关病理学的有益作用。我们的研究结果表明,芹菜素处理的 app/早老素 -1(PS1)双转基因小鼠的学习和记忆缺陷得到了明确的解救。芹菜素还可通过降低 BACE1和 β-ctf 水平,缓解 aβ 沉积,降低不溶性 aβ 水平,影响 APP 加工和预防 aβ 负荷。阿尔茨海默氏症是一种多因素疾病,需要能够对多个大脑靶点进行治疗的药物。黄酮类化合物,主要是芹菜素和槲皮素,具有神经保护作用,似乎是预防或治疗神经退行性疾病的理想候选人,但其临床疗效和实用性仍然是一个有待解决的问题。更好的动物模型和良好的生物标志物患者分组也将有助于在该领域的快速进展。审查修改了所有这些方面,目的是引起科学家之间的辩论。

6 Conclusion

6总结

Apigenin and quercetin has been demonstrated to have therapeutic potential for various chronic Neuroinflammation diseases, essentially due to its anti-inflammatory and anti-oxidative properties against a vast array of molecular targets. A large body of investigation has provided important insights into the anti-inflammation effects of Apigenin and quercetin which will constitute the basis for the further design and clinical application of extraordinarily potent drugs with potential therapeutic significance. Alzheimer’s is a multifactorial disorder that requires drugs capable of operating on multiple brain targets. Flavonoids, mainly Apigenin and quercetin, having neuroprotective effects appear to be ideal candidates to prevent or treat neurodegenerative disorders however, their clinical efficacy and utility is still an open question.

芹菜素和槲皮素已被证明具有治疗各种慢性神经炎症疾病的潜力,主要是由于其对大量分子靶点的抗炎和抗氧化作用。大量的研究为 Apigenin 和槲皮素的抗炎作用提供了重要的见解,这将为进一步设计和临床应用具有潜在治疗意义的特强药物奠定基础。阿尔茨海默氏症是一种多因素疾病,需要能够对多个大脑靶点进行治疗的药物。黄酮类化合物,主要是芹菜素和槲皮素,具有神经保护作用,似乎是预防或治疗神经退行性疾病的理想候选人,但其临床疗效和实用性仍然是一个有待解决的问题。

7 Acknowledgement

7确认收到

Authors would like to thank library of Pt. Ravishankar Shukla University for providing e-resources available through UGC-INFLIBNET.

作者要感谢拉维尚卡尔 · 舒克拉大学图书馆通过 UGC-INFLIBNET 提供电子资源。

8 Conflict of interest

8利益冲突

The authors have declared no conflict of interest.

作者声明没有利益冲突。

7 Author’s contributions

7作者的贡献

MSJ, AG and KS collected the data from different sources. MSJ has drafted the manuscript.

MSJ,AG 和 KS 从不同的来源收集数据,MSJ 已经起草了手稿。

8 References

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