Development of a novel NF-kB antagonist to block cytokine-induced behavioral chan

描述(申请人提供)：这个项目将调查UBS109，一种结构上与印度咖喱香料姜黄素的主要姜黄素相关的水溶性核因子-kB(NF-kB)拮抗剂，在细胞因子诱导的抑郁动物模型中阻断中枢神经系统和行为改变的效果。数据表明，过度的先天免疫(炎症)反应，包括通过核因子-kB通路的信号增加，可能是导致严重抑郁症(MD)的重要因素。MD患者的炎性免疫反应增强，包括应激诱导的NF-kB DNA结合增加，这与应激诱导的促炎细胞因子反应增加相关。此外，炎性细胞因子及其信号通路与MD相关的多个病理生理学领域相互作用，包括单胺代谢、神经内分泌功能、突触可塑性和局部脑代谢。这些观察结果提示，过度炎症和/或促炎信号通路如核因子-kB的活性增强可能在MD的病理生理过程中起重要作用。很大比例的MD患者对传统的抗抑郁药物治疗没有反应，而且治疗耐药的患者被发现表现出更高的炎症反应。因此，对于MD患者，特别是那些具有治疗抵抗力的患者，一种新的治疗方法可能是通过抑制NF-kB来阻断过度的炎症活动。姜黄素已显示出相当大的前景作为抗炎药，阻断核因子-kB，并在炎症性和自身免疫性疾病中显示出初步的疗效。然而，由于吸收差和组织分布有限，姜黄素的生物利用度很低。UBS109就是为了克服这些限制而开发的，它在提高生物利用度的同时显示出更强的核因子-kB拮抗作用。鉴于这一药效学特征，我们假设UBS109将防止脂多糖(LPS)诱导的小鼠脑炎症反应和行为变化。为了验证这一假设，我们将1)研究UBS109和姜黄素对内毒素诱导的成年雄性C57/BL6小鼠外周和中枢核因子-kB DNA结合以及核因子-kB依赖的基因和蛋白表达的影响；2)研究UBS109和姜黄素对内毒素诱导的行为改变的影响及其与核因子-kB途径活性变化的关系。在急性或慢性UBS109或姜黄素(均为递增剂量)存在或不存在的情况下，小鼠将接受脂多糖(30 ug/只)治疗，脑组织和外周的炎症活动(例如，核因子-kB DNA结合增加，细胞因子基因和蛋白表达增加)将连同早期(例如，运动活动减少)和后期(例如，降低对蔗糖的偏好，减少在强迫游泳试验中挣扎)的行为一起进行评估。将进行初步实验，以建立相关的药代动力学特性，为慢性UBS109的给药策略提供依据。总之，这些研究将为UBS109在治疗炎症增加的MD中的使用提供“概念证明”参数。公共卫生相关性：最近的数据表明，炎症可能导致抑郁症的发展，并可能在对传统抗抑郁药物无效的抑郁症患者中发挥作用。这项拟议的研究将探索新型抗炎药UBS109在阻断炎症诱导的抑郁小鼠模型中的行为变化的有效性。UBS109是从天然化合物姜黄素开发而来的，姜黄素是咖喱香料姜黄的一种成分，具有抗炎和抗抑郁特性。

DESCRIPTION (provided by applicant): This project will investigate the efficacy of UBS109, a water soluble nuclear factor kappa B (NF-kB ) antagonist structurally related to curcumin, the principal curcuminoid of the Indian curry spice turmeric, to block CNS and behavioral changes in an animal model of cytokine-induced depression. Data suggest that excessive innate immune (inflammatory) responses, including increased signaling through NF-kB pathways, may be an important contributor to major depression (MD). Increased inflammatory immune responses have been found in patients with MD, including increased stress-induced NF-kB DNA binding, which correlates with increased stress-induced proinflammatory cytokine responses. In addition, inflammatory cytokines and their signaling pathways have been shown to interact with multiple pathophysiologic domains relevant to MD including monoamine metabolism, neuroendocrine function, synaptic plasticity and regional brain metabolism. These observations suggest that excessive inflammation and/or increased activity of proinflammatory signaling pathways such as NF-kB may play an important role in the pathophysiology of MD. A significant percentage of MD patients do not respond to conventional antidepressant therapies, and patients who are treatment resistant have been found to exhibit increased inflammatory responses. Thus, a novel treatment approach for MD patients, especially those with treatment resistance, may be to block excessive inflammatory activity through inhibition of NF-kB. Curcumin has shown considerable promise as an anti-inflammatory agent, blocking NF-kB and exhibiting preliminary efficacy in inflammatory and autoimmune disorders. However, curcumin exhibits poor bioavailability due to poor absorption and limited tissue distribution. UBS109 was developed to overcome these limitations, and exhibits greater NF-kB antagonism in combination with improved bioavailability. Given this pharmacodynamic profile, we hypothesize that UBS109 will prevent lipopolysaccharide (LPS)-induced brain inflammatory responses and behavioral changes in mice. To test this hypothesis, we will 1) investigate the effects of UBS109 versus curcumin on LPS-induced peripheral and central NF-kB DNA-binding and NF-kB -dependent gene and protein expression in adult male C57/BL6 mice and 2) study the effects of UBS109 versus curcumin on LPS-induced behavioral changes and their relationship to changes in NF-kB pathway activity. Mice will be treated with LPS (30 ug/mouse) in the presence or absence of acute or chronic UBS109 or curcumin (each at increasing doses), and inflammatory activity (e.g. increased NF-kB DNA-binding and increased cytokine gene & protein expression) in the brain and periphery will be assessed along with both early (e.g. reduced locomotor activity) and later phase (e.g. reduced sucrose preference, decreased struggling in the forced swim test) behaviors. Preliminary experiments will be conducted to establish relevant pharmacokinetics properties to inform chronic UBS109 dosing strategies. Together, these studies will provide "proof of concept" parameters for use of UBS109 in the treatment of MD with increased inflammation. PUBLIC HEALTH RELEVANCE: Recent data indicate that inflammation may contribute to the development of depression and may play a role in depressed patients who fail to respond to conventional antidepressant medications. The proposed studies will explore the effectiveness of the novel anti-inflammatory drug, UBS109, to block behavioral changes in a mouse model of inflammation-induced depression. UBS109 was developed from the natural compound curcumin, an ingredient of the curry spice, turmeric, which exhibits both anti-inflammatory and antidepressant properties.