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

描述（由申请人提供）：帕金森病（PD）是一种使人衰弱的、与年龄相关的神经退行性疾病，由黑质中多巴胺神经元的丧失引起。这种神经元死亡被认为涉及：1）线粒体功能丧失; 2）氧化应激;和3）突触前蛋白1-突触核蛋白的聚集。目前的药物治疗解决了由神经元损失引起的症状，但它们不能阻止疾病的进展和潜在的持续神经元死亡。因此，迫切需要发现新的治疗方法来减缓PD和其他年龄相关的神经退行性疾病的进展。水果，如蓝莓，葡萄和黑醋栗是一个丰富的生物活性，多酚分子称为花青素类的不同类别的来源。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，口服给药后，大脑中只存在糖基化的花青素;然而，糖部分在消化过程中迅速水解，产生花青素苷元（称为花青素），必须给予高口服剂量才能观察到任何生物学效应。在这项研究中，我们将讨论在各种植物提取物和代谢稳定的衍生物中发现的花青素，其中糖基不能水解，是否是药物发现的合理先导结构，以促进帕金森氏病的神经元存活。我们推动这项工作的关键数据是在PD的原代细胞培养模型中鉴定富含花青素的提取物（和两种单独的花青素）的神经保护作用。在给予富含花青素的提取物后，在大鼠和猪中进行的其他体内研究导致在脑组织中鉴定出相同的单个花青素之一。此外，我们还开发了一种新的合成方法，用稳定的氟化甲基取代花青素中不稳定的糖基键。科尔比小组（天然产物衍生物的合成）、罗切特小组（PD细胞模型中植物提取物生物活性的表征）和费鲁齐/詹勒小组（大鼠大脑中多酚生物利用度的分析）的集体专业知识使我们处于有利地位，可以开发和表征具有增强稳定性、大脑生物利用度和神经保护活性的花青素衍生物。我们的中心假设是，代谢稳定的半合成花青素将增加神经元的活力时，在低剂量给药。我们的研究是创新的，因为从自然发生的化合物中识别出预防PD模型中神经元死亡的先导结构，对于开发这种年龄相关的神经退行性疾病的新治疗策略将是有价值的。此外，没有有效的合成方法来用氟化甲基取代这些分子中的不稳定键。代谢稳定且具有生物活性的花青素苷衍生物将是用于年龄相关性神经变性药物开发的重要先导结构。 公共卫生相关性：帕金森病扰乱了全球约500万人的生活，目前的治疗只能暂时缓解症状，而不会减缓潜在的神经退行性变。随着我们的人口继续老龄化，与帕金森病和其他与年龄相关的神经退行性疾病相关的经济负担将变得更加严重，除非采取预防，延迟或治疗这些疾病的方法。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，以降低帕金森病和其他与年龄相关的人类神经退行性疾病的风险。

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.