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

开发新型 NF-kB 拮抗剂来阻断细胞因子诱导的行为变化

• 批准号: 7916801
• 负责人: THADDEUS PACE
• 金额: $ 20.49万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7916801
• 关键词: Acute; Adult; Aftercare; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antidepressive Agents; Autoimmune Diseases; Behavior; Behavior assessment; Behavioral; Biological Availability; Biology; Blood Circulation; Brain; Chemicals; Chronic; Clinical; Consumption; Curcumin; Cytokine Gene; Cytokine Signaling; DNA Binding; Data; Depressed mood; Development; Disease; Dose; Drug Kinetics; Drug or chemical Tissue Distribution; Early treatment; Effectiveness; Enzymes; Exhibits; Functional disorder; Gene Proteins; Half-Life; Hippocampus (Brain); Hypothalamic structure; Immune; Immune response; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Inflammatory Response Pathway; Interleukin-6; Interleukins; Laboratories; Lipopolysaccharides; Major Depressive Disorder; Malignant Neoplasms; Mass Spectrum Analysis; Measurable; Measures; Mental Depression; Metabolism; Motor Activity; Mus; NF-kappa B; Neuraxis; Neurosecretory Systems; Nuclear; Pathway interactions; Patients; Performance; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phosphotransferases; Plasma; Play; Prefrontal Cortex; Property; Research Personnel; Resistance; Role; Saline; Severities; Signal Pathway; Signal Transduction; Social Interaction; Solutions; Spices; Spleen; Stress; Sucrose; Swimming; Synaptic plasticity; Testing; Time; Tissues; Toxic effect; Translations; Tumeric; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Water; Work; absorption; analog; attenuation; behavior test; brain metabolism; compare effectiveness; cytokine; depressive symptoms; design; improved; inhibitor/antagonist; male; monoamine; mouse model; novel; open field behavior; preference; prevent; protein expression; public health relevance; research study; response

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.

描述（由申请人提供）：该项目将研究 UBS109 的功效，UBS109 是一种水溶性核因子 kappa B (NF-kB ) 拮抗剂，其结构与姜黄素（印度咖喱香料姜黄的主要类姜黄素）相关，在细胞因子诱导的抑郁症动物模型中阻断 CNS 和行为变化的功效。数据表明，过度的先天免疫（炎症）反应，包括通过 NF-kB 通路信号传导的增加，可能是导致重度抑郁症 (MD) 的重要因素。 MD 患者的炎症免疫反应增加，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，炎症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、突触可塑性和区域脑代谢。这些观察结果表明，过度炎症和/或促炎信号通路（例如 NF-kB）活性增加可能在 MD 的病理生理学中发挥重要作用。相当大比例的MD患者对传统的抗抑郁疗法没有反应，并且发现对治疗有抵抗力的患者表现出炎症反应增加。因此，对于 MD 患者，尤其是那些具有治疗抵抗性的患者，一种新的治疗方法可能是通过抑制 NF-kB 来阻止过度的炎症活动。姜黄素作为一种抗炎剂显示出相当大的前景，可以阻断 NF-kB，并在炎症和自身免疫性疾病中显示出初步疗效。然而，由于吸收差和组织分布有限，姜黄素的生物利用度较差。 UBS109 的开发是为了克服这些限制，并表现出更强的 NF-kB 拮抗作用和更高的生物利用度。鉴于这种药效学特征，我们假设 UBS109 将预防脂多糖 (LPS) 诱导的小鼠脑部炎症反应和行为变化。为了检验这一假设，我们将 1) 研究 UBS109 与姜黄素对成年雄性 C57/BL6 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 UBS109 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。将在存在或不存在急性或慢性UBS109或姜黄素（每种剂量递增）的情况下用LPS（30微克/小鼠）治疗小鼠，并评估大脑和外周的炎症活性（例如NF-kB DNA结合增加和细胞因子基因和蛋白质表达增加）以及早期（例如运动活性降低）和后期（例如蔗糖减少） 偏好，减少强迫游泳测试中的挣扎）行为。将进行初步实验以确定相关的药代动力学特性，为 UBS109 的长期给药策略提供信息。总之，这些研究将为 UBS109 治疗炎症加重的 MD 提供“概念验证”参数。公共卫生相关性：最近的数据表明，炎症可能会导致抑郁症的发展，并且可能在对传统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 UBS109 阻止炎症引起的抑郁症小鼠模型行为变化的有效性。 UBS109 由天然化合物姜黄素开发而成，姜黄素是咖喱香料姜黄的成分，具有抗炎和抗抑郁特性。