姜黄素和芹菜素– 治疗阿尔茨海默病慢性神经炎症的新颖且有前景的疗法

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Curcumin and Apigenin – novel and promising therapeutics against chronic neuroinflammation in Alzheimer’s disease

Correspondence Address:
Gerald Münch
Department of Pharmacology, School of Medicine, University of Western Sydney, Campbelltown NSW; National Institute of Complementary Medicine, University of Western Sydney; Molecular Medicine Research Group, University of Western Sydney, NSW 
Australia

通信地址: 新南威尔士州坎贝尔敦西悉尼大学医学院药理学系; 西悉尼大学国家补充医学研究所; 澳大利亚新南威尔士州西悉尼大学分子医学研究组

Source of Support: None, Conflict of Interest: None

支持来源: 无,利益冲突: 无Check将军

  Abstract 摘要 

Alzheimer’s disease is a progressive neurodegenerative disorder, characterized by deposition of amyloid beta, neurofibrillary tangles, astrogliosis and microgliosis, leading to neuronal dysfunction and loss in the brain. Current treatments for Alzheimer’s disease primarily focus on enhancement of cholinergic transmission. However, these treatments are only symptomatic, and no disease-modifying drug is available for Alzheimer’s disease patients. This review will provide an overview of the proven antioxidant, anti-inflammatory, anti-amyloidogenic, neuroprotective, and cognition-enhancing effects of curcumin and apigenin and discuss the potential of these compounds for Alzheimer’s disease prevention and treatment. We suggest that these compounds might delay the onset of Alzheimer’s disease or slow down its progression, and they should enter clinical trials as soon as possible.

阿尔茨海默病是一种进行性的神经退行性疾病,β 淀粉样蛋白的拥有属性沉积,神经纤维缠结,星形胶质细胞增多症和小胶质细胞增多症,导致神经元功能障碍和大脑缺失。目前阿尔茨海默病的治疗主要集中在加强胆碱能传递。然而,这些治疗只是有症状的,而且没有治疗阿尔茨海默病的药物。本文综述了姜黄素和芹菜素的抗氧化、抗炎、抗淀粉样变、神经保护和认知增强作用,并讨论了这些化合物在阿尔茨海默病防治中的潜在作用。我们认为这些化合物可能延缓阿尔茨海默病的发作或者减缓其进展,并且它们应该尽快进入临床试验。

Keywords: Alzheimer′s disease; neuroinflammation; anti-inflammatory drugs; plant secondary metabolites; reactive oxygen species

关键词: 阿尔茨海默病; 神经炎症; 抗炎药; 植物次生代谢物; 活性氧类

Alzheimer’s disease (AD) is a complex and heterogeneous progressive disorder of the central nervous system (CNS) (Singh and Guthikonda, 1997; Fang et al., 2013). The incidence of AD is about 35 million people worldwide that accounts for 10-15% of people aged 65 or older and 35% of those 85 years and older. With increased expectation of life and aging population, it is estimated that this figure will triple in the next 40 years, resulting in increased health care costs worldwide (Massoud and Gauthier, 2010). 阿尔茨海默病(AD)是一种复杂的、异质性的中枢神经系统进行性紊乱(Singh 和 gutikonda,1997; Fang 等人,2013)。全世界的 AD 发病率约为3,500万人,占65岁及以上人口的10-15% ,占85岁及以上人口的35% 。随着人们对寿命和人口老龄化期望值的增加,估计这一数字在未来40年将增加两倍,导致全球卫生保健费用的增加(Massoud 和 Gauthier,2010年)

Neurofibrillary tangles (composed of hyper-phosphorylated tau) and senile plaques (composed of beta-amyloid, Aβ) combined with carbonyl and oxidant stress as well as glucose deficit are the major pathological hallmarks of the disease (Münch et al., 1998). In addition, pro-inflammatory activation of astroglia and microglia has been observed in many neurodegenerative diseases such as Parkinson’s disease and AD (Wong et al., 2001a), and even autism-spectrum and obsessive-compulsive disorders (Qian et al., 2010; Kern et al., 2013). AD is also characterized by a cholinergic deficit, thus current treatments for AD primarily focus on enhancement of cholinergic transmission. However, these treatments are only symptomatic, and no disease-modifying drug is available for AD (Rosenblum, 2014). With failure of so many anti-amyloid trials (Castello et al., 2014), alternative therapeutic interventions are more and more aiming to target other features of the neurodegenerative brain. Consequently, targeting AD-associated neuroinflammation with anti-inflammatory compounds and antioxidants has been suggested as a novel, promising disease-modifying treatment for AD (Wong et al., 2001b; Holmquist et al., 2007; Latta et al., 2014). 神经原纤维缠结(由过度磷酸化的 tau 蛋白组成)和老年斑(由 β 淀粉样蛋白组成,aβ)加上羰基和氧化应激以及葡萄糖缺乏是该病的主要病理特征(m ü nch et al. ,1998)。此外,在许多神经退行性疾病中,如帕金森病和 AD (Wong 等人,2001a) ,甚至自闭症谱系障碍和强迫症(Qian 等人,2010; Kern 等人,2013) ,都观察到星形胶质细胞和小胶质细胞的促炎症激活。AD 也是一种胆碱能缺陷,因此目前治疗 AD 的拥有属性主要集中在提高胆碱能传递上。然而,这些治疗只是有症状的,没有治疗 AD 的治疗药物(Rosenblum,2014)。随着众多抗淀粉样蛋白试验的失败(Castello et al. ,2014) ,替代性治疗干预越来越多地针对神经退行性大脑的其他特征。因此,通过抗炎化合物和抗氧化剂靶向治疗 AD 相关的神经炎症已被认为是一种新颖的、有希望的 AD 疾病修复治疗方法

The inflammatory response in AD is a double-edged sword. At first, it is a self-defence reaction aimed at eliminating harmful stimuli and restoring tissue integrity. However, neuroinflammation becomes harmful when it turns chronic. Analysis of the time-course of neuroinflammation in AD shows that neuroinflammation (measured as number of activated microglia) starts in patients with mild cognitive impairment peaks in moderately affected cases before it declines in the severe cases (Arends et al., 2000). Increased levels of pro-inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), interleukine-1 beta (IL-1β) and interleukin-6 (IL-6), prostaglandins and reactive oxygen and nitrogen species are also observed in AD at all stages of the disease (Mrak and Griffin, 2005). Activated microglia can be visualized by protein markers such as ionized calcium binding adaptor molecule 1 (Iba1) and translocator protein 18 kDa (TSPO) (Martin et al., 2010). In one key study, patients with AD, patients with mild cognitive impairment and older control subjects were scanned with the TSPO ligand (11)C-PBR28 ([methyl-(11)C]N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine). Patients with AD had greater (11)C-PBR28 binding in cortical brain regions than controls, and (11)C-PBR28 binding inversely correlated with the patient’s performance on a variety of neuropsychological tests (Kreisl et al., 2013). AD 的炎症反应是一把双刃剑。起初,这是一种自卫反应,旨在消除有害的刺激和恢复组织完整性。然而,当神经炎症变成慢性的时候,它就变得有害了。对 AD 神经炎症的时间-过程的分析表明,在中度发作的病例中,神经炎症(以活化的小胶质细胞数量衡量)在轻微认知障碍下降之前,在病情严重的病例中达到最高峰。在 AD 的各个阶段,还可观察到促炎症介质,如肿瘤坏死因子 -α (tnf-α)、白细胞介素 -1β (il-1β)和白细胞介素 -6(IL-6)、前列腺素和活性氧及氮的水平增加(Mrak 和 Griffin,2005)。激活的小胶质细胞可以通过蛋白质标记如离子化钙结合适配剂分子1(Iba1)和转位子蛋白18 kDa (TSPO)可视化。在一项关键的研究中,AD 患者、轻微认知障碍患者和老年对照组被扫描 TSPO 配体(11) C-PBR28([甲基-(11) c ] n- 乙酰基 -n-(2- 甲氧基苄基)-2-苯氧基 -5- 吡啶胺)。AD 患者大脑皮层区域的 C-PBR28结合强于对照组,而且(11) C-PBR28结合与患者在各种神经心理测试中的表现呈负相关(Kreisl 等人,2013年)

Amyloid plaques have been identified as a major source of neuroinflammation in AD. In familial (early-onset) cases of AD, plaque formation is linked to mutations in the amyloid precursor protein (APP) or presenilin (PS1 and PS2) genes, which leads to altered proteolysis of APP producing increased higher levels of longer forms of β-amyloid peptide (Aβ) such as Aβ 淀粉样斑块已被确定为 AD 神经炎症的主要来源。在家族性(早发型) AD 病例中,斑块的形成与淀粉样前体蛋白(APP)或早老素(PS1和 PS2)基因突变有关,这导致 APP 蛋白水解的改变,增加了长形式的 β 淀粉样肽(aβ)的水平,如 aβ42 (Gotz et al., 2011). In sporadic AD, plaque formation is rather caused by impaired clearance than increased production of Aβ. Clearance of Aβ is suggested to be mediated by its transport across the blood-brain barrier by the receptor for advanced glycation end products and efflux (Gotz et al. ,2011).在散发性 AD 中,斑块的形成与其说是由于 aβ 的产生,不如说是由于清除功能受损。提示 aβ 的清除可能是通过晚期糖基化终产物受体和外排途径通过血脑屏障而实现的via 通过 the multi-ligand lipoprotein receptor LRP-1 and it is suggested that this process is impaired in sporadic AD patients (Bates et al., 2009; Srikanth et al., 2011). In cerebral interstitial fluid, Aβ aggregates to form oligomers and senile plaques, accelerated by crosslinking through advanced glycationend products (AGEs) (Loske et al., 2000). Plaques are associated with microglial activation and reactive astrocytosis and the release of free radicals and cytokines (Eikelenboom and Veerhuis, 1996; Wong et al., 2001a). Their release could cause multifaceted biochemical and structural changes in surrounding axons, dendrites and neuronal cell bodies. Also, the excessive generation of free radicals can cause oxidative damage to proteins and other macromolecules (Retz et al., 1998). Neuroinflammation also leads to hyperphosphorylation of tau by increased kinase or decreased phosphatase activity and might contribute to the formation of neurofibrillary tangles (Lee et al., 2010). 多配体脂蛋白受体 LRP-1和它是建议,这一进程是受损的散发性 AD 患者(贝茨等人,2009年; Srikanth 等人,2011年)。在大脑组织液,aβ 聚集体形成低聚物和老年斑,通过高级糖基化终产物(AGEs)加速交联(Loske et al. ,2000)。斑块与小胶质细胞活化、反应性星形细胞增多和自由基和细胞因子的释放有关(Eikelenboom 和 Veerhuis,1996; Wong 等人,2001a)。它们的释放可能导致周围轴突、树突和神经元细胞体多方面的生化和结构改变。同时,过多的自由基会导致蛋白质和其他大分子的氧化损伤(Retz 等人,1998)。神经炎症还通过增加激酶或降低磷酸酶活性导致 tau 蛋白的过度磷酸化,并可能促进神经原纤维缠结的形成(Lee et al. ,2010)

Genetic and pharmaco-epidemiological studies also suggest the importance of inflammation in AD pathogenesis. Genome-wide association studies have identified three immune-relevant genes that are associated with an increased risk of developing AD, clusterin (CLU), complement receptor 1 (CR1) and triggering receptor expressed on myeloid cells 2 (TREM2) (Patel et al., 2014). Furthermore, though non-steroidal anti-inflammatory drugs (NSAIDs) have an adverse effect in later stages of AD pathogenesis, long-term and pre-symptomatic use of NSAIDs such as naproxen was shown to reduce AD incidence but only after 2 to 3 years (Breitner et al., 2011). 遗传学和药物流行病学研究也表明炎症在 AD 发病机制中的重要性。全基因组关联研究已经确定了3个免疫相关基因,这些基因与 AD、 clusterin (CLU)、补体受体1(CR1)和髓细胞2(TREM2)上触发受体表达的风险增加相关(Patel 等人,2014)。此外,虽然非甾体抗炎药(NSAIDs)在 AD 发病后期有不利影响,但是长期和症状前使用 NSAIDs 如萘普生被证明可以降低 AD 的发病率,但仅在2至3年之后(Breitner 等人,2011年)

  Neuroinflammation as a Therapeutic Target in AD 神经炎症作为 AD 治疗靶点的研究 

In recent years, studies have focused on different nutritional approaches to benefit AD patients. More specifically, foods rich in ω-3 fatty acids like docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) (found abundantly in marine fish), vitamins, and diverse groups of secondary, polyphenolic plant metabolites have been shown to be effective against several AD pathologies (Stevenson and Hurst, 2007; Kamphuis and Scheltens, 2010; Kim et al., 2010; Willis et al., 2010). In the following sections, we will focus on the progress made with some of the most promising plant secondary metabolites such as curcumin and apigenin. 近年来,研究集中在不同的营养方法,使 AD 患者受益。更具体地说,富含 ω-3脂肪酸的食物,如二十二碳六烯酸(DHA)和二十碳五烯酸(EPA)(在海洋鱼类中大量发现) ,维生素,以及各种次生的多酚类植物代谢物已被证明能有效对抗几种 AD 病理(Stevenson 和 Hurst,2007; Kamphuis 和 Scheltens,2010; Kim 等人,2010; Willis 等人,2010)。在下面的章节中,我们将重点介绍一些最有希望的植物次生代谢物,如姜黄素和芹菜素的研究进展

  Curcumin 姜黄素 

Source 资料来源

Curcumin, a diarylheptanoid polyphenol isolated from the rhizomes of 姜黄素,一个二芳基庚烷多酚从根状茎分离Curcuma longa 姜黄 L. (Zingiberaceae, common name: turmeric) is a food additive in Indian cuisine and is used in Ayurvedic medicine (Ringman et al., 2005). 姜科植物,俗名姜黄,是印度菜肴中的食品添加剂,被用于印度草药中(Ringman 等,2005)

Pharmacokinetics 药代动力学

Curcumin penetrates into the CNS and exerts a broad range of anti-inflammatory effects. Considering the low bioavailability of curcumin, various physically redesigned curcumin preparations using nanoparticles, liposomes or inclusion complexes are available in the market (Prasad and Bondy, 2014). Highly bioavailable curcumin preparations, such as “Longvida” (VS Corp) can achieve μM concentrations in the brain (Dadhaniya et al., 2011). 姜黄素渗透到中枢神经系统,发挥广泛的抗炎作用。考虑到姜黄素的低生物利用度,市场上有各种使用纳米颗粒、脂质体或包合物的物理重新设计的姜黄素制剂(Prasad 和 Bondy,2014)。高生物可利用性的姜黄素制剂,如“长命达”(VS 公司)可以在大脑中达到微米的浓度(Dadhaniya 等人,2011年)

Safety 安全

Curcumin administered as standardized powder extract containing a minimum 95% concentrations of three curcuminoids (curcumin, bisdemethoxycurcumin and demethoxycurcumin) has an excellent safety profile with no toxicity being observed in single doses of up to 12 g per day (Lao et al., 2006). 姜黄素作为标准化粉末提取物,含有三种姜黄素(姜黄素、双去甲氧基姜黄素和去甲氧基姜黄素)至少95% 的浓度,具有良好的安全性,在每天最多12克的单一剂量下没有观察到毒性(Lao 等人,2006年)

Mechanistic pathways and cellular studies 机械通路和细胞研究

Curcumin is known to exhibit various pleiotropic properties, including antioxidant, anti-inflammatory, anti-amyloidogenic, lipophilic and cognition/memory enhancing actions, which suggests a potential neuroprotective nature of this compound (Cole et al., 2007; Mishra and Palanivelu, 2008). Furthermore, curcumin has a broad cytokine-suppressive anti-inflammatory action, it down-regulates the expression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), TNF-α, IL-1, -2, -6, -8, and -12 (Abe et al., 1999). Curcumin inhibits IL-6 mediated signalling 众所周知,姜黄素具有多种多效性,包括抗氧化、抗炎、抗淀粉样变性、亲脂性和认知/记忆增强作用,这表明该化合物具有潜在的神经保护性(Cole 等人,2007; Mishra 和 Palanivelu,2008)。此外,姜黄素具有广泛的细胞因子抑制抗炎作用,它下调环氧合酶2(COX-2)、诱导型一氧化氮合酶(iNOS)、 tnf-α、 IL-1、-2、-6、-8和-12的表达(Abe 等人,1999)。姜黄素抑制 IL-6介导的信号传导via 通过inhibition of IL-6 induced signal transducer and activator of transcription 3 (STAT3) phosphorylation and consequent STAT3 nuclear translocation (Bharti et al., 2003), and interferes with the first signalling steps downstream of the IL-6 receptor in microglial activation (Ray and Lahiri, 2009). It also inhibits lipoxygenase (LOX), COX-2 and iNOS expression leading to decreased levels of prostaglandin E2 (PGE2) and nitric oxide (NO) (Lev-Ari et al., 2006; Menon and Sudheer, 2007). It has an inhibitory effect on TNF-α-induced IL-1, and IL-6 that is most likely mediated through inhibition of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPK) pathways (Shi et al., 2015). Curcumin also reduces levels of the astrocyte marker glial fibrillary acidic protein (GFAP) in the brain, as well as protein oxidation and reversed increases in blood monocyte chemoattractant protein 1 (MCP-1) (Giri et al., 2003). Also, curcumin has well-established anti-inflammatory effects in various pathologic conditions in humans including rheumatoid arthritis, gastrointestinal conditions and several forms of cancer (Jurenka, 2009). At last, but not least, curcumin inhibits Aβ 抑制 IL-6诱导的 STAT3磷酸化和随之而来的 STAT3核转位(Bharti 等人,2003年) ,并干扰 IL-6受体下游信号传递的第一步在小胶质细胞激活(Ray 和 Lahiri,2009年)。它还能抑制脂氧合酶(LOX)、环氧化酶2(COX-2)和诱导型一氧化氮合酶(iNOS)的表达,从而降低前列腺素E2(PGE2)和一氧化氮(NO)的水平。它对肿瘤坏死因子 α 诱导的 IL-1和 IL-6有抑制作用,这很可能是通过抑制核因子 -κb (NF-κB)和丝裂原活化蛋白激酶(MAPK)途径介导的。姜黄素还可以降低大脑中星形胶质细胞标记物胶质纤维酸性蛋白(GFAP)的水平,以及蛋白质氧化和逆转血液中单核细胞趋化蛋白1(MCP-1)的增加(Giri 等人,2003)。此外,姜黄素在人类的各种病理状态下,包括类风湿性关节炎、胃肠道疾病和几种癌症中,都具有良好的抗炎作用(Jurenka,2009)。姜黄素最终抑制了 aβ 的产生40aggregation and prevents Aβ 聚集和防止 aβ42 oligomer formation and toxicity (Yang et al., 2005). 齐聚物的形成和毒性(Yang 等人,2005)

Animal studies 动物研究

In a study by Lim et al. (2001), curcumin was tested for its ability to inhibit the combined inflammatory and oxidative damage in Tg2576 transgenic mice. In this study, Tg2576 mice aged 10 months old were fed a curcumin diet (160 ppm) for 6 months. Their results showed that the curcumin diet significantly lowered the levels of oxidised proteins, IL-1β, GFAP (a marker of activated astroglia), soluble and insoluble Aβ, and also plaque burden. Following this work, Yang et al. (2005) evaluated the effect of feeding a curcumin diet (500 ppm) in 17-month-old Tg2576 mice for 6 months. When fed to the aged Tg2576 mice with advanced amyloid accumulation, curcumin resulted in reduced soluble amyloid levels and plaque burden. Yang et al. (2005) also demonstrated that when curcumin was injected peripherally ( 在 Lim 等人的一项研究中(2001年) ,姜黄素在 Tg2576转基因小鼠中被测试其抑制炎症和氧化损伤的能力。在这项研究中,10个月大的 Tg2576小鼠被喂食姜黄素饮食(160ppm)6个月。结果表明,姜黄素饮食能显著降低氧化蛋白、 il-1β、 GFAP (活化星形胶质细胞的标志物)、可溶性和不可溶性 aβ 的水平以及斑块负荷。在这项工作之后,Yang 等人(2005年)评估了17个月大的 Tg2576小鼠饲喂姜黄素饮食(500ppm)6个月的效果。当给老年 Tg2576淀粉样蛋白严重堆积的小鼠喂食姜黄素时,可导致可溶性淀粉样蛋白水平降低和斑块负担减轻。杨等人(2005年)也证明,当姜黄素被注射周边(via 通过 the carotid artery), it could enter the brain and bind amyloid plaques. The ability of curcumin to bind amyloid is thought to be due to its structural similarity to the water-soluble dye Congo red, which is able to stain amyloid plaques. In addition, curcumin has been shown to inhibit Aβ 它可以进入大脑,结合淀粉样蛋白斑块。姜黄素结合淀粉样蛋白的能力被认为是由于它对水溶性染料刚果红的结构相似性,这种染料能够染色淀粉样蛋白斑块。此外,姜黄素已被证明能抑制 aβ42 oligomer formation as well as, or better than Congo red, without any toxic effects (Yang et al., 2005). These data raise the possibility that dietary supplementation with curcumin may provide a potential preventative treatment for AD, by decreasing Aβ levels and plaque load 齐聚物形成以及,或比刚果红更好,没有任何毒性作用(Yang 等人,2005年)。这些数据提高了饮食补充姜黄素可能提供了一个潜在的预防性治疗 AD 的可能性,通过降低 aβ 水平和斑块负荷via 通过 inhibition of Aβ oligomer formation and fibrilisation, along with decreasing oxidative stress and inflammation. 抑制 aβ 寡聚体的形成和纤维蛋白化,同时减少氧化应激和炎症

Human studies 人类研究

In humans, “Longvida” curcumin (400 mg) has been shown to significantly improve working memory and mood after 4 weeks of treatment in a randomized, double-blind, placebo-controlled human trial (Cox et al., 2014). 在人类中,“ Longvida”姜黄素(400毫克)在随机、双盲、安慰剂对照的人体试验中显示,经过4周的治疗,可以显著改善工作记忆和情绪(Cox 等人,2014)

  Apigenin 芹菜素 

Source 资料来源

Apigenin (4′, 芹菜素(4′ ,5, 7-trihydroxyflavone) is a flavonoid particularly abundant in the ligulate flowers of the chamomile plant (68% apigenin of total flavanoids) (McKay and Blumberg, 2006) and found in lesser concentrations in other sources such as celery, parsley, grapefruit (Shukla and Gupta, 2010). ,7- 三羟基黄酮)是一种黄酮类化合物,在洋甘菊的舌状花中尤其丰富(总黄酮中有68% 的芹菜素)(McKay 和 Blumberg,2006年) ,在其他来源如芹菜、欧芹、葡萄柚中发现的黄酮类化合物含量较低(Shukla 和 Gupta,2010年)

Pharmacokinetics 药代动力学

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). 芹菜素通过脑血屏障,每天腹腔注射20毫克/千克芹菜素钾盐(在水中溶解并冷冻直至使用)1周后,大鼠体内的浓度达到1.2微米(Popovic 等人,2014年)

Safety 安全

Apigenin is considered very safe and even at high doses no toxicity was observed. However, apigenin may induce muscle relaxation and sedation at high doses (Viola et al., 1995; Ross and Kasum, 2002). 芹菜素被认为是非常安全的,即使高剂量也没有观察到毒性。然而,芹菜素在大剂量时可能诱导肌肉松弛和镇静(Viola 等人,1995; Ross 和 Kasum,2002)

Mechanistic pathways and cellular studies 机械通路和细胞研究

Extensive studies have shown that apigenin has potent antioxidant, anti-inflammatory, and anti-carcinogenic properties (Panes et al., 1996; Gupta et al., 2001). Apigenin has been shown to have inhibitory effects 大量的研究表明芹菜素具有强有力的抗氧化、抗炎和抗致癌特性(Panes 等人,1996; Gupta 等人,2001)。芹菜素具有抑菌作用in vitro 在试管中 on the release of several pro-inflammatory mediators in lipopolysaccharide (LPS)-induced settings of murine cell lines. Apigenin strongly inhibited levels of IL-6 in mouse macrophages (Smolinski and Pestka, 2003) and suppressed CD40, TFN-α and IL-6 production 在 LPS 诱导的小鼠细胞系中释放几种促炎症介质的脂多糖。芹菜素强烈抑制小鼠巨噬细胞(Smolinski 和 Pestka,2003)的 IL-6水平,并抑制 CD40、 tfn-α 和 IL-6的产生via 通过 inhibition of interferon gamma (IFN-γ)-induced phosphorylation of STAT1 in murine microglia (Rezai-Zadeh et al., 2008). Evidence of its anti-inflammatory properties is also exemplified in studies that show dose-dependent suppression of the inflammatory mediators NO and prostaglandin, through inhibition of iNOS and COX-2 in both microglial and macrophage mouse cells (Liang et al., 1999). Furthermore, apigenin conferred protection against Aβ 抑制干扰素 γ (ifn-γ)诱导的小鼠小胶质细胞 STAT1磷酸化(Rezai-Zadeh et al. ,2008)。其抗炎特性的证据还体现在一些研究中,这些研究表明,通过抑制小胶质细胞和小鼠巨噬细胞中的 iNOS 和 COX-2,剂量依赖性地抑制炎症介质 NO 和前列腺素(Liang 等人,1999年)。此外,芹菜素对 aβ 具有保护作用25-35 -induced toxicity in rat cerebral microvascular endothelial cells (Zhao et al., 2011). In human monocytes and mouse macrophages, apigenin has been shown to attenuate the release of inflammatory cytokines by inactivation of NF-κB, mediated by suppression of LPS-induced phosphorylation of the p65 subunit (Nicholas et al., 2007). Other effects reported for apigenin include decreasing expression of adhesion molecules (Panes et al., 1996) and its well-known defensive properties against oxidative stress, such as free radical scavenging and increasing intracellular glutathione concentrations (Myhrstad et al., 2002; Shukla and Gupta, 2010). Apigenin is reported to exert many of its effects through interactions with the signaling molecules in the 3 major MAPK pathways (extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK) and p38) in both murine and human cell culture models (Yin et al., 1999; Ha et al., 2008). – 对大鼠脑微血管内皮细胞的毒性作用(赵等,2011)。在人类单核细胞和小鼠巨噬细胞中,芹菜素通过抑制 lps 诱导的 p65亚单位磷酸化介导的 NF-κB 失活,减少炎症因子的释放(Nicholas et al. ,2007)。其他报道的芹菜素的影响包括降低粘附分子的表达(Panes 等人,1996年)及其众所周知的防御性能对氧化应激,如自由基清除和增加细胞内谷胱甘肽浓度(Myhrstad 等人,2002; Shukla 和 Gupta,2010年)。在小鼠和人类细胞培养模型中,芹菜素通过与3条主要的 MAPK 通路(细胞外信号调节蛋白激酶(ERK)、 c-Jun n 末端激酶(JNK)和 p38)中的信号分子相互作用发挥许多作用(Yin 等人,1999; Ha 等人,2008)

Animal studies 动物研究

There are very few studies on apigenin in AD animal models. One recent study by Zhao et al. (2013) tested the neuroprotective effects of apigenin in the APP/PS1 double transgenic AD mouse model. Four month-old mice were orally treated with apigenin (40 mg/kg) for 3 months. Their results showed that apigenin-treated mice displayed improvements in memory and learning deficits, and a reduction of fibrillar amyloid deposits with lowered insoluble Aβ concentrations, mediated by a decrease in β-C-terminal fragment (β-CTF) and β-site AβPP-cleaving enzyme 1 (BACE1). Additionally, the apigenin-treated mice showed restoration of the cortical ERK/cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) pathway involved in learning and memory typically affected in AD pathology. Enhanced activities of superoxide dismutase and glutathione peroxidase were also observed and increased superoxide anion scavenging (Zhao et al., 2013). Similarly, in another study, Aβ 关于芹菜素在 AD 动物模型中的研究很少。赵等人最近的一项研究(2013年)测试了芹菜素在 APP/PS1双转基因 AD 小鼠模型中的神经保护作用。4月龄小鼠口服芹菜素(40mg/kg)3个月。他们的结果表明,芹菜素处理小鼠显示改善记忆和学习障碍,并减少淀粉样蛋白沉积与降低不溶性 aβ 浓度,介导的 β c 末端片段(β-ctf)和 β 位点 Aβpp- 裂解酶1(BACE1)的减少。此外,芹菜素治疗小鼠表现出皮层 ERK/cAMP 反应元件结合蛋白(CREB)/脑源性神经营养因子(BDNF)通路的恢复,该通路参与 AD 病理学中典型的学习和记忆过程。还观察到超氧化物歧化酶和谷胱甘肽过氧化物酶的活性增强,清除超氧阴离子的能力增强(赵等人,2013)。同样,在另一项研究中,aβ25-35 -induced amnesia mouse models were treated with apigenin (20 mg/kg), resulting in improvements in spatial learning and memory, in addition to neurovascular protective effects (Liu et al., 2011). Other 用芹菜素(20mg/kg)治疗诱导性遗忘小鼠模型,除了神经血管保护作用外,还改善了空间学习和记忆(Liu et al. 2011)。其他in vivo 在活体内 studies with non-AD-related animal models report significant reductions in LPS-induced IL-6 and TFN-α production in apigenin pre-treated mice (50 mg/kg) (Smolinski and Pestka, 2003). Another study indicated neuroprotective effects in apigenin pre-treated mice (10-20 mg/kg) subjected to contusive spinal cord injury, including reduction in IL-1β, TFN-α, intercellular cell adhesion molecule-1 (ICAM-1) and caspase-3, with an increase in Bcl-2/Bax ratio (Zhang et al., 2014). 非 ad 相关动物模型的研究报告显著减少 lps 诱导的芹菜素预处理小鼠(50mg/kg) IL-6和 tfn-α 的产生(Smolinski 和 Pestka,2003年)。另一项研究表明,芹菜素预处理小鼠(10-20毫克/千克)对挫伤性嵴髓损伤有神经保护作用,包括降低 il-1β,tfn-α,细胞间粘附分子 -1(ICAM-1)和 caspase-3,增加 Bcl-2/Bax 比例(Zhang 等人,2014)

Human studies 人类研究

Based on the published literature, no studies in humans have been conducted with apigenin with respect to inflammation or cognitive performance. 根据已发表的文献,还没有关于芹菜素对人类的炎症或认知表现的研究

  Conclusion 总结 

Based on the results emerging from cell culture, animal and human studies, we conclude that both curcumin and apigenin are exceptional candidates for an anti-inflammatory therapy against AD and other related degenerative disorders, ready to enter clinical trials within a short time frame. 根据细胞培养、动物和人体研究的结果,我们得出结论,姜黄素和芹菜素都是治疗 AD 和其他相关退行性疾病的抗炎治疗的特殊候选药物,可以在短时间内进入临床试验[64]

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