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

项目概要/摘要 压力是全球多种最流行的精神健康疾病的主要危险因素，包括 重度抑郁症（MDD）。目前的治疗方法不足以满足日益增长的需求 疾病负担和机会成本。此外，当前的治疗模式未能缓解潜在的 病理生理学和很大比例的患者变得难以治疗。目的 研究项目 2 是研究一种经过充分表征的富含多酚的植物补充剂是否可以 提供一种替代方法来抑制压力的病理影响，从而增加个体的 易患某些精神疾病。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函数。特别是，选择 炎症介质，例如白细胞介素 (IL)-6，最近被认为是关键的机制 压力引起的焦虑和抑郁的影响因素。支持这一原则的是临床 观察结果表明，一部分患有难治性抑郁症的患者表现出增加 血浆中IL-6的表达。我们在压力诱发抑郁症的模型系统中展示了特定的 我们的植物补充剂的生物可利用代谢物可抑制应激诱导的 IL-6 产生 白细胞，并进一步提供对压力引起的心理障碍的恢复能力。因此，第一个 研究项目 2 的目标是彻底了解我们的药物动力学和稳态特性 植物补充剂，以确认被发现调节 IL-6 表达的生物活性化合物 啮齿类动物也具有生物利用度，并在人体中达到生物活性浓度。我们将进行双盲， 在健康志愿者中使用低剂量进行随机、安慰剂对照（未经治疗的对照）剂量范围研究， 中剂量和高剂量 BDPP，基于我们对动物的研究和科学文献。 项目 2 然后研究我们的植物补充剂的代谢物与表达之间的关联 健康受试者中炎症细胞因子的变化。我们提出的实验将描述 BDPP 是否 代谢物可防止特里尔社会压力测试中 IL-6 的上调：经过充分验证的模型 心理压力。此外，通过整合多元自适应回归样条（MARS）统计 我们可以确定哪种代谢物或代谢物组合可能负责的方法 在临床环境中抑制 IL-6 以应对压力。研究项目 2 的目标将告知 未来的临床试验，提供有关最佳产品剂量、治疗时机、结果标志物的指导 生物利用度；将验证抑制 IL-6 表达的代谢物是否以生物活性浓度存在 血浆，并确定 BDPP 的抗炎特性是否在应激模型系统中观察到 诱发的抑郁症可以在压力的临床模型中重现。

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.