Anthocyanins and Structural Derivatives for Drug Discovery in Age-Related Neurode

用于年龄相关神经节药物发现的花青素和结构衍生物

• 批准号: 8094072
• 负责人: David A Colby
• 金额: $ 14.8万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8094072
• 关键词: Address; Age; Anthocyanidin; Anthocyanins; Antioxidants; Automobile Driving; Biological; Biological Availability; Biological Factors; Black Currant; Blood - brain barrier anatomy; Blueberries; Botanicals; Brain; Cell Death; Cell model; Cessation of life; Complex; Data; Deposition; Development; Digestion; Disease; Disease Progression; Disease model; Dopaminergic Cell; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; Exhibits; Family suidae; Fruit; Grapes; Human; Individual; Lead; Link; Metabolic; Methodology; Methods; Midbrain structure; Mitochondria; Modeling; Modification; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oral; Oral Administration; Oxidative Stress; Oxygen; Parkinson Disease; Pharmacologic Substance; Plasma; Population; Positioning Attribute; Primary Cell Cultures; Proteins; Rattus; Reporting; Risk; Rodent Model; Rotenone; Source; Stress; Structure; Substantia nigra structure; Symptoms; System; Techniques; absorption; age related; age related neurodegeneration; brain metabolism; brain tissue; dopaminergic neuron; drug development; drug discovery; in vivo; inhibitor/antagonist; innovation; loss of function; methyl group; mitochondrial dysfunction; neuron loss; polyphenol; presynaptic; prevent; sugar; synuclein; treatment strategy

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a debilitating, age-related neurodegenerative disorder that results from a loss of dopamine neurons in the substantia nigra. This neuronal death is believed to involve: 1) a loss of function in mitochondria; 2) oxidative stress; and 3) aggregation of the presynaptic protein 1-synuclein. Current pharmaceutical treatments address the symptoms resulting from the loss of neurons, but they do not prevent the progression of the disease and the underlying continued neuronal death. Thus, there is a critical biomedical need to discover new treatments to slow the progression of PD and other age-related neurodegenerative disorders. Fruits such as blueberries, grapes, and black currants are an abundant source of a diverse class of biologically active, polyphenolic molecules called anthocyanins. These natural products (which exist in a glycosylated form) are potent antioxidants. Previous studies have shown that only the glycosylated anthocyanins are present in the brain after oral administration; however, the sugar moiety is rapidly hydrolyzed during digestion to give the anthocyanin aglycone (called anthocyanidin), and high oral doses must be given to observe any biological effects. In this study, we will address whether anthocyanins found in various botanical extracts and metabolically stable derivatives, where the sugar group cannot be hydrolyzed, are reasonable lead structures for drug discovery to promote neuron survival in Parkinson's disease. Our key data driving this effort is the identification of neuroprotective effects of anthocyanin-rich extracts (and two individual anthocyanins) in a primary cell culture model of PD. Additional in vivo studies in rats and pigs following administration of anthocyanin-rich extracts led to the identification of one of the same individual anthocyanins in the brain tissue. Also, we have developed a new synthetic method to replace the unstable glycosyl linkage of the anthocyanins with a stable, fluorinated methyl group. The collective expertise of the Colby group (synthesis of natural product derivatives), Rochet group (characterization of bioactivity of botanical extracts in cellular models of PD), and Ferruzzi/Janle group (analysis of polyphenol bioavailability in rat brain) places us in a strong position to develop and characterize anthocyanin derivatives with enhanced stability, brain bioavailability, and neuroprotective activity. Our central hypothesis is that metabolically stable semisynthetic anthocyanins will increase neuron viability when administered in low doses. Our studies are innovative, because the identification of lead structures from naturally occurring compounds that prevent neuronal death in PD models would be valuable in the development of new treatment strategies for this age-related, neurodegenerative disorder. Also, there are no efficient synthetic methods to replace the labile linkage in these molecules with fluorinated methyl groups. A metabolically stable and biologically active anthocyanin derivative would be a significant lead structure for use in drug development in age-related neurodegeneration. PUBLIC HEALTH RELEVANCE: Parkinson's disease disrupts the lives of an estimated 5 million people worldwide, and current therapies only temporarily relieve symptoms without slowing the underlying neurodegeneration. As our population continues to age, the financial burden associated with Parkinson's disease and other age-related neurodegenerative disorders will become more severe unless ways to prevent, delay, or treat these diseases are implemented. In this project we will seek to develop new molecules that may have value in drug discovery to decrease the risk of Parkinson's disease and other age-related neurodegenerative disorders in humans.

描述（由申请人提供）：帕金森氏病（PD）是一种使人衰弱的，与年龄相关的神经退行性疾病，是由于黑质Nigra中多巴胺神经元丧失而导致的。据信这种神经元死亡涉及：1）线粒体功能丧失； 2）氧化应激； 3）突触前蛋白1-核蛋白的聚集。当前的药物治疗可解决神经元丧失导致的症状，但它们并不能阻止疾病的进展和潜在的持续神经元死亡。因此，存在着发现新疗法以减缓PD和其他与年龄相关的神经退行性疾病的进展的重要生物医学需求。蓝莓，葡萄和黑醋栗等水果是一种称为花青素的多种生物活性，多酚分子的丰富来源。这些天然产物（以糖基化形式存在）是有效的抗氧化剂。先前的研究表明，口服后，大脑中只有糖基化的花青素。然而，在消化过程中，糖部分迅速水解，以产生静脉蛋白酶糖酮（称为花青素），并且必须给予高口服剂量以观察任何生物学作用。在这项研究中，我们将解决在各种植物提取物和代谢稳定的衍生物中发现的花青素是否不能水解糖基，这是药物发现的合理铅结构，以促进帕金森氏病中的神经元生存。我们推动这项工作的关键数据是鉴定PD的原代细胞培养模型中富含花色苷提取物（和两个单独的花色苷）的神经保护作用。给药富含花青素的提取物后，对大鼠和猪进行的其他体内研究导致鉴定出脑组织中同一个个体的花青素之一。此外，我们开发了一种新的合成方法，用稳定的氟化甲基代替花色苷的不稳定糖基链接。 Colby组（自然产品衍生物的合成），Rochet组（PD细胞模型中植物提取物的生物活性表征）和费鲁西/Janle组（大鼠大脑中多酚生物利用度的分析）在我们处于强大的位置和表征脑力衍生型的强度和表征脑力的表征。我们的中心假设是，当低剂量给药时，代谢稳定的半合成花青素会增加神经元的活力。我们的研究具有创新性，因为从天然发生的化合物中鉴定了预防PD模型中神经元死亡的铅结构对于这种与年龄相关的神经退行性疾病的新治疗策略的制定将是有价值的。同样，没有有效的合成方法可以用氟化甲基代替这些分子中不稳定的联系。代谢稳定且具有生物活性的花青素衍生物将是与年龄相关的神经变性中使用的重要铅结构。 公共卫生相关性：帕金森氏病破坏了全球估计有500万人的生活，当前的疗法仅暂时缓解症状而不会减慢基本神经变性。随着我们人口的持续衰老，除非实施预防，延迟或治疗这些疾病，否则与帕金森氏病和其他与年龄相关的神经退行性疾病相关的财务负担将变得更加严重。在这个项目中，我们将寻求开发可能在药物发现中具有价值的新分子，以降低人类帕金森氏病和其他与年龄有关的神经退行性疾病的风险。