Modulation of the Innate Immune System by Fisetin for the Treatment of AD

漆黄素调节先天免疫系统治疗 AD

• 批准号: 8591030
• 负责人: Pamela Anne Maher
• 金额: $ 30万
• 依托单位: VIROGENICS, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8591030
• 关键词: Acute; Adoption; Age; Alzheimer' s Disease; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Automobile Driving; Behavior; Biological; Biological Assay; Biological Factors; Body part; Brain; Cell Surface Proteins; Cells; Chemistry; Chronic; Clinical; Clinical Research; Clinical Trials; Cognition; Development; Diabetes Mellitus; Disease; Disease Progression; Drug Kinetics; Flavonoids; Glutathione; Goals; Hematopoietic; Huntington Disease; Hyperglycemia; Immune; Immune response; Immune system; Immunosuppressive Agents; In Vitro; Inflammation; Institutes; Intellectual Property; Ischemia; Ischemic Stroke; Kidney; Laboratories; Legal patent; MAPK8 gene; Memory; Microglia; Modeling; Mus; Nature; Neurodegenerative Disorders; Neurons; Oryctolagus cuniculus; Oxidative Stress; PTPRC gene; Pathogenesis; Pathology; Patients; Peripheral; Pharmaceutical Preparations; Phenotype; Play; Process; Production; Property; Protein Tyrosine Phosphatase; Proteins; Rheumatoid Arthritis; Rodent Model; Role; Series; TNF gene; Testing; Transgenic Mice; Transgenic Organisms; Up-Regulation; age related; base; brain cell; chemical property; diabetic; fisetin; fly; in vivo; innate immune function; insight; macrophage; mouse model; nervous system disorder; neurotoxic; novel; novel strategies; prevent; public health relevance; response; small molecule

DESCRIPTION (provided by applicant): An increasing variety of diseases are being shown to be due to immunological processes, including diabetes, and now Alzheimer's disease (AD). AD is the most prevalent age-associated disease and growing evidence suggests that aspects of the innate immune system play a major role its progression. Based on this evidence, we propose a new approach to the treatment of AD by targeting key properties of the innate immune system involved in the progression of the disease. Microglia (or brain macrophages) are the resident immune cells of the brain. Not only are they implicated in the pathogenesis of a variety of neurological disorders including AD but they also play important, protective roles in the CNS. Thus, modulating the response of microglia following activation to favor their neuroprotective over their neurotoxic properties may be the key to harnessing the immune system to treat AD. Our studies have led to the identification of a molecule that controls microglial properties in ways that are beneficial for modulating AD progression. This is the flavonoid fisetin which our in vitro and animal studies have demonstrated inhibits TNF production in activated macrophages and microglia. Fisetin promotes the adoption of the M2 anti-inflammatory phenotype by microglia as manifested by an increase in the expression of CD45, a cell surface protein tyrosine phosphatase expressed exclusively by cells of hematopoietic lineages and by inhibition of iNOS induction. CD45 has been implicated in the inhibition of classical M1 microglial activation while driving the anti-inflammatory M2 microglial phenotype. Fisetin, a rare natural flavonoid, was initially identified in the Maher laboratory as a orally active, novel neuroprotective and cognition-enhancing molecule. Fisetin protects nerve cells from multiple toxic insults and is therapeutically active in rigorous rodent models for memory, rabbit and mouse models for ischemic stroke, mouse and fly models of Huntington's disease and in transgenic AD mice. A series of much more potent fisetin derivatives, many of which maintain in vitro anti-inflammatory activity, has recently been synthesized by SAR-driven iterative chemistry. From the 150 derivatives synthesized, we selected the best seven derivatives that maintain the biological activities of fisetin, including its anti-inflammatory actvity. Preliminary assays to assess their pharmacological properties indicate that these derivatives have the potential to be good CNS drugs. In addition, the derivatives do not suffer from the intellectual property challenges of the natural product fisetin and are covered under several issued and/or pending patents held by the Salk Institute. We propose to advance fisetin derivatives as modulators of innate immune function and clinical candidates for the treatment of AD. Specifically, we plan to (1) further characterize the induction of the M2 microglial phenotype by fisetin and fisetin derivatives in vitro; (2) identify which of the pre-selected fisetin derivatves induce the M2 phenotype in vivo and then determine which have pharmacokinetic properties most consistent with good CNS drugs and (3) test the best two fisetin derivatives in AD transgenic mice for effects on behavior and pathology.

描述(申请人提供)：越来越多的疾病被证明是由于免疫过程，包括糖尿病，现在是阿尔茨海默病(AD)。AD是最常见的与年龄相关的疾病，越来越多的证据表明，先天性免疫系统的某些方面在其进展中起着重要作用。基于这一证据，我们提出了一种新的治疗方法，通过靶向参与疾病进展的先天免疫系统的关键特性来治疗AD。小胶质细胞(或脑巨噬细胞)是大脑的常驻免疫细胞。它们不仅与包括阿尔茨海默病在内的多种神经系统疾病的发病机制有关，而且在中枢神经系统中也发挥着重要的保护作用。因此，调节小胶质细胞激活后的反应，使其有利于神经保护而不是神经毒性特性，可能是利用免疫系统治疗AD的关键。我们的研究导致了一种分子的鉴定，该分子以有利于调节AD进展的方式控制小胶质细胞的属性。这就是我们的体外和动物研究证明的类黄酮非瑟素抑制激活的巨噬细胞和小胶质细胞产生肿瘤坏死因子。Fisetin促进小胶质细胞采用M2抗炎表型，表现为CD45的表达增加，CD45是一种细胞表面蛋白酪氨酸磷酸酶，仅由造血系细胞表达，并通过抑制iNOS诱导而表现出来。CD45参与抑制经典的M1小胶质细胞活化，同时驱动抗炎M2小胶质细胞表型。非瑟素是一种罕见的天然黄酮类化合物，最初在Maher实验室被鉴定为一种具有口服活性的新型神经保护和认知增强分子。非瑟素可保护神经细胞免受多种毒性损伤，并在严格的记忆啮齿动物模型、兔和小鼠缺血性中风模型、亨廷顿病小鼠和苍蝇模型以及转基因AD小鼠中具有治疗活性。最近，通过SAR驱动的迭代化学合成了一系列更有效的非瑟素衍生物，其中许多在体外保持抗炎活性。从合成的150个衍生物中，我们选出了最好的7个保持鱼腥草素生物活性的衍生物，包括其抗炎活性。对其药理性质的初步分析表明，这些衍生物有可能成为良好的中枢神经系统药物。此外，这些衍生品不会受到天然产品鱼腥草素的知识产权挑战，并由索尔克研究所持有的几项已颁发和/或正在申请的专利涵盖。我们建议将非瑟素衍生物作为先天免疫功能的调节剂和治疗AD的临床候选药物。具体地说，我们计划(1)在体外进一步鉴定Fesetin和Fisetin衍生物对M2小胶质细胞表型的诱导作用；(2)在体内鉴定哪两种预先选定的Fisetin衍生物能诱导M2表型，然后确定哪些药代动力学特性与良好的中枢神经系统药物最为一致；以及(3)在AD转基因小鼠中测试最佳的两种Fisetin衍生物对行为和病理的影响。