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

项目概要/摘要 压力是全球范围内许多最普遍的心理健康疾病的主要风险因素，包括 重度抑郁症（MDD）。目前的治疗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减轻潜在的 病理生理学和显著百分比的患者变得难以治疗。的目的 研究项目2是调查一种特征良好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， 易患某些精神疾病。新出现的证据表明， 对应激的敏感性是中枢和外周免疫活性的函数。特别是，选择 炎症介质，如白细胞介素（IL）-6，最近被认为是关键机制， 压力引起的焦虑和抑郁的促成因素。支持这一原则的是临床 观察结果显示，一部分难治性抑郁症患者表现出增加的 血浆中IL-6的表达。我们在一个压力诱导抑郁的模型系统中表明， 我们的植物补充剂的生物可利用的代谢物抑制应激诱导的IL-6的产生， 白细胞，并进一步提供对应激诱导的心理损伤的恢复力。因此第一 研究项目2的目的是彻底研究我们的药物的药代动力学和稳态特性。 植物补充剂，以证实发现调节IL-6表达的生物活性化合物， 啮齿类动物也是生物可利用的，并在人体内达到生物活性浓度。我们将进行双盲测试， 在健康志愿者中进行的随机化、安慰剂对照（未治疗对照）、剂量范围探索研究，使用低剂量， 中等剂量和高剂量的BDPP，基于我们的动物研究和科学文献。 项目2然后研究我们的植物补充剂的代谢产物和表达之间的关联， 健康受试者的炎症细胞因子。然后，我们提出的实验将表征BDPP是否 代谢产物阻止IL-6在Trier社会压力测试中的上调：一个经过充分验证的 心理压力此外，通过整合多元自适应回归样条（MARS）统计， 方法，我们可以确定哪种代谢物，或代谢物的组合，可能负责 在临床环境中响应于应激而抑制IL-6。研究项目2的目标将告知 通过提供最佳产品剂量、治疗时机、 生物利用度;将验证抑制IL-6表达的代谢物以生物活性浓度存在， 血浆，并确定是否在应激模型系统中观察到BDPP的抗炎特性- 诱发性抑郁症可以在临床应激模型中重现。

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.