Novel Prophylactic and Therapeutic Interventions for Stress-Induced Depression

 描述(由申请人提供)： 这项功绩审查拨款申请的总体目标是将多酚表征为抑郁症退伍军人潜在的预防和治疗药物。拟议的研究对退伍军人群体具有重要影响，因为大约30%的退伍军人，特别是那些来自持久自由行动/伊拉克自由行动的退伍军人，受到情绪焦虑障碍的影响，特别是抑郁症。我们最近发现了一种安全且耐受性良好的生物活性多酚制剂，可以有效地将多种(我们确定的16种)生物可用多酚代谢物输送到大脑。此外，我们发现，口服补充该制剂显著提高了反复社会失败应激(RSD)抑郁症小鼠模型对抑郁/焦虑表型的恢复能力。伏核(NAC)中棘神经元(MSN)突触可塑性异常在应激相关抑郁/焦虑的发生发展中起关键作用。我们的研究是为了在体外、原代NAC、MSN强化培养和RSD模型中鉴定能够保持突触可塑性的精选多酚代谢物。我们的证据表明，在NAC MSN中，rac1(一种控制肌动蛋白重塑的GTPase相关蛋白)的下调是抑郁症/焦虑症异常突触重塑的核心，而抑制兴奋性VGLUT2和/或促进抑制性VGAT MSN突触机制也可以增强对抑郁/焦虑的韧性。基于这一证据，在拟议的研究中，我们将首先筛选单个多酚代谢物，以了解它们在MSN浓缩培养中调节rac1、VGLUT2和VGAT的体外剂量反应生物活性。根据体外筛选的结果，我们将优先选择三个最具生物活性的候选药物，并使用多酚前体作为潜在的能够将已识别的代谢物输送到大脑的“前体药物”进行体内剂量发现研究。基于这一结果 通过一系列研究，我们将确定具有足够浓度的多酚前体的最低安全和有效剂量，以吸引NAC中的分子靶标(例如rac1)。在有效性研究中，我们将测试这些通过前体传递的大脑生物活性代谢物是否可以通过正常化应激诱导的病理性神经可塑性重塑和NAC的功能电生理变化来促进对应激诱导的抑郁/焦虑表型的弹性。总而言之，我们建议的研究结果将确定新的预防和治疗药物，可以预防和逆转慢性应激导致的不良适应行为反应。这项拟议的研究还将提供多酚在压力中介抑郁中的有益作用的新机制。这项拟议的研究将为翻译应用安全的多酚“前体药物”提供动力，以促进退伍军人对压力相关疾病的心理弹性，包括抑郁症和焦虑症。

 DESCRIPTION (provided by applicant): The overall goal of this MERIT review grant application is to characterize polyphenols as potential prophylactic as well as therapeutic agents in veterans with depression. The proposed studies have important implications for the veteran population since approximately 30% of veterans, in particular those from Operation Enduring Freedom/Operation Iraqi Freedom, are affected by mood anxiety disorders, especially depression. We recently identified a safe and well-tolerated bioactive polyphenol preparation effective in delivering multiple (16 that we identified) bioavailable polyphenol metabolites to the brain. Moreover, we found that oral supplementation with this preparation significantly promotes resilience to depression/anxiety phenotypes in the repeated social defeat stress (RSDS) mouse model of depression. Synaptic plasticity abnormalities in nucleus accumbens (NAc) medium spiny neurons (MSN) play a key role in the development of stress-related depression/anxiety. Our proposed studies are designed to identify select polyphenol metabolites that can preserve synaptic plasticity in vitro i primary NAc MSN-enriched cultures and in vivo in the RSDS model. Our evidence indicates that down-regulation of Rac1 (a GTPase-related protein that controls actin remodeling) in NAc MSNs is central to aberrant synaptic remodeling in depression/anxiety, and that resilience to depression/anxiety may also be augmented by attenuation of excitatory VGLUT2 and/or promotion of inhibitory VGAT MSN synaptic mechanisms. Based on this evidence, in the proposed studies, we will first screen individual polyphenol metabolites for their in vitro dose-response bioactivities in modulating Rac1, VGLUT2, and VGAT in MSN- enriched cultures. Based on the outcomes of the in vitro screening, we will then prioritize the three most bioactive candidates and conduct dose-finding studies in vivo using polyphenol precursors as potential "pro- drugs" able to deliver the identified metabolites to the brain. Based on the outcomes of this set of studies, we will identify the lowest safe and efficacious doses of polyphenol precursors with sufficient concentration to engage the molecular targets (e.g. Rac1) in the NAc. In efficacy studies, we will then test whether these brain bioavailable bioactive metabolites delivered through precursors may promote resilience to stress-induced depression/anxiety phenotypes by normalizing stress-induced pathological neuroplasticity remodeling and functional electrophysiological changes in the NAc. Collectively, the outcomes from our proposed studies will identify novel prophylactic as well as therapeutic agents that can prevent and reverse the maladaptive behavioral responses that result from chronic stress. The proposed studies will also provide novel mechanisms underlying the beneficial role of polyphenols on stress-mediated depression. The proposed studies will provide the impetus for translational application of safe polyphenol "pro-drugs" to promote psychological resilience to stress-related conditions, including depression and anxiety disorders in veterans.