Clinical Pharmacology and Target Validation of BDPP for Stress-Related Disorders

项目摘要/摘要 压力是世界上许多最常见的精神健康疾病的主要风险因素，包括 抑郁症(MDD)。目前的治疗方法不能满足日益增长的 疾病负担和机会成本。此外，目前的治疗模式未能缓解潜在的 病理生理学和相当大比例的患者对治疗变得难以治疗。目的 研究项目2是调查一种具有良好特性的富含多酚的植物补充剂是否可以 提供了一种替代方法来抑制压力的病理影响，这种压力会增加个人的 易患上某些精神疾病。新出现的证据表明， 对压力的敏感性是中枢和外周免疫活动的一种功能。特别是，选择 炎症介质，如白介素6，最近被认为是关键的机制 应激性焦虑和抑郁的促成因素。支持这一原则的是临床 观察表明，部分难治性抑郁症患者的比例增加 IL-6在血浆中的表达。我们在应激诱导抑郁的模型系统中展示了特定的 我们植物补充剂的生物可用代谢物抑制应激诱导的IL-6的产生 此外，还可提供对应激引起的心理损伤的恢复能力。因此，第一个 研究项目2的目标将是彻底研究我们的药物动力学和稳态特性。 植物补充剂，以证实已发现的调节IL-6表达的生物活性化合物 啮齿动物也是可生物利用的，并在人类体内达到生物活性浓度。我们将进行双盲， 健康志愿者的随机、安慰剂对照(未治疗对照)剂量范围研究，使用低剂量， 中剂量和高剂量的BDPP，基于我们对动物的研究和科学文献。 项目2然后调查我们的植物补充剂的代谢物和表达之间的联系。 炎性细胞因子在健康受试者中的表达。然后，我们提议的实验将表征BDPP 代谢物抑制IL-6在Trier社会压力测试中的上调：一个有效的模型 心理压力。此外，通过积分多元自适应回归样条法(MARS)统计量 方法我们可以确定哪种代谢物或代谢物的组合可能与 在临床环境中抑制IL-6以应对压力。研究项目2的目标将为 通过提供关于最佳产品剂量、治疗时机、结果标志的指导，进行未来的临床试验 生物利用度；将验证抑制IL-6表达的代谢物在 血浆，并确定在应激模型系统中观察到的BDPP的抗炎特性 诱导性抑郁可以用应激的临床模型来概括。

Project Summary/Abstract Stress is a leading risk factor for a multitude of the most prevalent mental health illnesses worldwide, including major depressive disorder (MDD). Current treatments fall short of what is required to meet the ever increasing disease burden and opportunity cost. In addition, current treatment paradigms fail to alleviate underlying pathophysiologies and a significant percentage of patients become refractory to treatment. The purpose of Research Project 2 is to investigate whether a well-characterized polyphenol enrich botanical supplement can provide an alternative approach to suppress the pathological effects of stress that increase an individual's susceptibility to developing certain psychiatric disorders. Emerging evidence has demonstrated that susceptibility to stress is a function of both central and peripheral immune activity. In particular, select inflammatory mediators, such as interleukin (IL)-6, have recently been recognized as key mechanistic contributory factors of stress-induced anxiety and depression. Supporting this principle are clinical observations that show that a subset of patients with treatment-resistant depression exhibit increased expression of IL-6 in the plasma. We show in a model system of stress-induced depression that specific bioavailable metabolites of our botanical supplement suppress stress-induced production of IL-6 from leukocytes and, further, provide resilience to stress-induced psychological impairment. Therefore, the first objective of Research Project 2 will be to thoroughly the pharmacokinetic and steady state properties of our botanical supplement to confirm that the bioactive compounds that were found to modulate IL-6 expression in rodents are also bioavailable and reach a bioactive concentration in humans. We will conduct a double blind, randomized, placebo-controlled (untreated control), dose ranging study in healthy volunteers using a low dose, intermediate dose, and high dose of BDPP, based upon our work with animals and from the scientific literature. Project 2 then investigate the association between metabolites of our botanical supplement and the expression of inflammatory cytokines in healthy subjects. Our proposed experiments will then characterize whether BDPP metabolites prevent upregulation of IL-6 in response to the Trier Social Stress Test: a well-validated model of psychological stress. Moreover, by integrating a multivariate adaptive regression splines (MARS) statistical method we can determine which metabolite, or combination of metabolites, may be responsible for suppressing IL-6 in a clinical setting in response to stress. Objectives from Research Project 2 will inform a future clinical trial by providing guidance on the optimal product dose, treatment timing, outcome markers of bioavailability; will verify metabolites that suppress IL-6 expression are present at bioactive concentrations in plasma, and establish whether anti-inflammatory properties of BDPP observed in model systems of stress- induced depression can be recapitulated in a clinical model of stress.