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是一种水结构上与姜黄素（Indian Curry Spice姜黄的主要姜黄素）结构相关的拮抗剂Kappa B（NF-KB）拮抗剂，以阻止CNS和行为变化的细胞座动物模型抑制抑郁症的动物模型。数据表明，过度先天免疫（炎症）反应，包括通过NF-KB途径增加的信号传导，可能是重大抑郁症（MD）的重要原因。在MD患者中发现了增加的炎症免疫反应，包括胁迫诱导的NF-KB DNA结合增加，这与应激诱导的促炎性细胞因子反应的增加相关。此外，炎性细胞因子及其信号通路已被证明与与MD有关的多个病理生理结构域相互作用，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，促炎和/或增加促炎信号通路（如NF-KB）的活性可能在MD的病理生理学中起重要作用。很大一部分的MD患者对常规抗抑郁药没有反应，并且已经发现耐药性的患者表现出增加的炎症反应。因此，一种针对MD患者的新型治疗方法，尤其是患有治疗耐药性的患者，可能是通过抑制NF-KB来阻止过度的炎症活性。姜黄素作为一种抗炎剂表现出很大的希望，阻止了NF-KB并在炎症和自身免疫性疾病中表现出初步疗效。然而，姜黄素由于吸收不良和组织分布有限而表现出较差的生物利用度。 UBS109的开发是为了克服这些局限性，并表现出更大的NF-KB拮抗作用以及改善的生物利用度。鉴于这种药效学的特征，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。为了检验这一假设，我们将1）研究UBS109与姜黄素对LPS诱导的外围和NF-KB中央NF-KB DNA结合以及NF-KB依赖性基因和蛋白质表达对成年男性C57/BL6小鼠的影响以及2）研究UBS1109对LPS curcumin对LPS诱导的行为变化的影响。在存在或不存在急性或慢性UBS109或姜黄素（每种剂量增加的剂量）和炎症活性（例如，NF-KB DNA结合以及细胞因子基因和蛋白质表达增加的大脑和外周的持续性（E. e.g. redot）（E.G. REDOR）中，将用LPS（30 ug/鼠标）处理小鼠（每种剂量增加）和炎症活性（例如，NF-KB DNA结合以及增加的细胞因子基因和蛋白质表达）将在早期（E.G. REDOR中评估）（E. redot），将其用于炎症活性（例如，NF-KB DNA结合的增加，NF-kb DNA结合的增加，增加了NF-KB DNA结合以及增加的NF-kb DNA结合，增加了NF-KB DNA结合以及增加的NF-KB DNA结合和增加），偏爱，在强制游泳测试中挣扎的行为减少。将进行初步实验，以建立相关的药代动力学特性，以告知慢性UBS109剂量策略。总之，这些研究将提供“概念证明”参数，用于使用UBS109在炎症增加的MD治疗中。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反应的抑郁症患者中发挥作用。拟议的研究将探讨新型抗炎药UBS109的有效性，以阻止炎症引起的抑郁症的小鼠模型中的行为变化。 UBS109是由天然化合物姜黄素（咖喱香料，姜黄的成分）开发的，姜黄姜黄具有抗炎和抗抑郁剂的特性。