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

BDPP 治疗应激相关疾病的临床药理学和靶点验证

基本信息

批准号：
10671054
负责人：
James Warren Murrough
金额：
$ 39.44万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10671054
关键词：
Acids Acute Address Animals Anti-Inflammatory Agents Anxiety Behavior Behavioral Biological Biological Availability Biological Models Blood Botanical dietary supplements Botanicals Central Nervous System Clinical Clinical Pharmacology Clinical Trials Dietary Polyphenol Dose Double-Blind Method Drug Kinetics Eligibility Determination Exhibits Functional disorder Future Grapes Health Human IL-6 inhibitor Immune Impairment Individual Inflammation Mediators Inflammatory Interleukin-6 Intervention Juice Knowledge Laboratories Lead Leukocytes Link Literature Major Depressive Disorder Mental Depression Mental Health Mental disorders Modeling Oral Oral Administration Outcome Pathologic Patients Peripheral Pharmacodynamics Phenotype Placebo Control Placebos Plants Plasma Predisposition Preparation Production Property Psychological Models Psychological Stress Randomized Refractory Regulation Research Design Research Project Grants Risk Factors Rodent Safety Signal Transduction Statistical Methods Stress Supplementation Synaptic plasticity Testing Therapeutic Uses Trier Social Stress Test Up-Regulation Validation Work Xenobiotic Metabolism acute stress burden of illness cytokine depressive symptoms dietary experimental study falls gastrointestinal gastrointestinal bacteria grape seed healthy volunteer inflammatory marker opportunity cost patient subsets polyphenol pre-clinical prevent promote resilience psychologic research clinical testing resilience response stress related disorder therapeutic target trans-resveratrol translational potential treatment duration treatment-resistant depression

项目摘要

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.

项目总结/文摘