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

描述（由申请人提供）：本项目将研究UBS 109（一种结构上与姜黄素（印度咖喱香料姜黄的主要类姜黄素）相关的水溶性核因子κ B（NF-κ B）拮抗剂）在姜黄素诱导的抑郁症动物模型中阻断CNS和行为变化的疗效。数据表明，过度的先天免疫（炎症）反应，包括通过NF-κ B途径增加的信号传导，可能是重度抑郁症（MD）的重要因素。在MD患者中发现了增加的炎性免疫应答，包括增加的应激诱导的NF-κ B DNA结合，其与增加的应激诱导的促炎细胞因子应答相关。此外，炎性细胞因子及其信号通路已被证明与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。这些观察结果表明，过度炎症和/或增加的活性的促炎信号通路，如NF-κ B可能在MD的病理生理学中发挥重要作用。很大比例的MD患者对传统的抗抑郁治疗没有反应，并且已经发现治疗抵抗的患者表现出增加的炎症反应。因此，一种新的治疗MD患者的方法，特别是那些治疗抵抗，可能是通过抑制NF-κ B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剂，阻断NF-κ B，并表现出初步的疗效，在炎症和自身免疫性疾病。然而，姜黄素由于吸收差和有限的组织分布而表现出差的生物利用度。开发UBS 109以克服这些局限性，并表现出更强的NF-κ B拮抗作用以及改善的生物利用度。鉴于这种药效学特征，我们假设UBS 109将预防脂多糖（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UBS 109与姜黄素对成年雄性C57/BL 6小鼠中LPS诱导的外周和中枢NF-kB DNA结合以及NF-kB依赖性基因和蛋白表达的影响，2）研究UBS 109与姜黄素对LPS诱导的行为变化的影响及其与NF-kB通路活性变化的关系。小鼠将用LPS处理（30 ug/小鼠），存在或不存在急性或慢性UBS 109或姜黄素（每种剂量递增）和炎症活性将沿着两种早期免疫反应，评估脑和外周中的NF-κ B DNA结合增加和细胞因子基因和蛋白表达增加。（例如减少的自发活动）和后期（例如减少的蔗糖偏好，在强迫游泳测试中减少的挣扎）行为。将进行初步实验以建立相关的药代动力学特性，从而为长期UBS 109给药策略提供信息。总之，这些研究将为UBS 109治疗炎症增加的MD提供“概念验证”参数。公共卫生相关性：最近的数据表明，炎症可能有助于抑郁症的发展，并可能在对常规抗抑郁药物无效的抑郁症患者中发挥作用。拟议的研究将探索新型抗炎药UBS 109在炎症诱导的抑郁症小鼠模型中阻断行为变化的有效性。UBS 109是从天然化合物姜黄素中开发出来的，姜黄素是咖喱香料姜黄的一种成分，具有抗炎和抗抑郁的特性。

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.