A nitric oxide(NO)-based metabonomic approach to investigate tobacco addiction

基于一氧化氮 (NO) 的代谢组学方法研究烟草成瘾

• 批准号: 7021937
• 负责人: MARTIN FEELISCH
• 金额: $ 13.21万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7021937
• 关键词: brain; nicotine; nitric oxide; oxidative stress; smoking; tissues; tobacco; tobacco abuse

DESCRIPTION (provided by applicant): The interaction of nicotine with specific receptors in the brain is known to trigger the release of a number of neurotransmitters, including nitric oxide (NO). While the latter has been established to play an important role in the development of addiction to tobacco products, the underlying molecular pathways remain unclear. Current pharmacological methods for countering the release of NO include inhibition of NO formation and NO scavenging. However, neither one is a viable option for the treatment of nicotine addiction due to the central role endogenous NO plays in cell homeostasis and signaling, and to the deleterious consequences of a systemic reduction in NO availability. Moreover, NO is a constituent of tobacco smoke, and little is known about its actions on downstream effector mechanisms of nicotine. Nicotine metabolism is associated with the formation of redox-active byproducts that can cause oxidative stress through formation of reactive oxygen species (ROS). Because the latter are known to interact strongly with NO, it is likely that nicotine-induced ROS production globally affects the fate and biological actions of NO in the brain and other organs, leading to local nitrosation, nitration and oxidation of biomolecules with profound alterations in protein function and activity. The central hypothesis of this proposal is that local tissue redox poise and nicotine-induced ROS formation are key determinants of the metabolic fate of NO that triggers or facilitates the development of addiction (Stage I). If true, modulation of these determinants may provide a novel targeted approach for suppressing this nicotine-related NO pathway without the adverse effects associated with a global reduction in NO bioavailability (Stage II). To examine this hypothesis, the effects of NO, nicotine and cigarette smoke will be investigated in rodent models of oxidative stress with and w/o antioxidant supplementation or NO pretreatment using a novel metabonomic approach for simultaneous in vivo quantification of free and protein-bound nitroso, nitro and nitrosyl species as well as nitrite and nitrate. In addition, regional changes in cGMP levels, nicotine metabolites and oxidant biomarkers will be measured. Results from these studies are expected to offer an unprecedented insight into the interplay of ROS with NO and important NO-delivery forms in vivo, providing the "building blocks" and conceptual framework for a Stage II application that focuses on novel, targeted intervention strategies in tobacco-related addiction. Tobacco use is a major, worldwide health problem which claims >3 million lives each year. Although the research efforts and public health education in recent years have helped reducing the smoking prevalence in developed countries tobacco use remains the largest single cause of preventable death in the United States and elsewhere. The tragic consequences of nicotine addiction stress the importance of unraveling the molecular mechanisms involved.

描述（由申请人提供）：已知尼古丁与大脑中特定受体的相互作用可触发许多神经递质的释放，包括一氧化氮（NO）。虽然后者已被确定在烟草制品成瘾的发展中发挥重要作用，但潜在的分子途径仍不清楚。目前对抗NO释放的药理学方法包括抑制NO形成和清除NO。然而，由于内源性NO在细胞稳态和信号传导中起着核心作用，以及全身NO可用性降低的有害后果，这两种方法都不是治疗尼古丁成瘾的可行选择。此外，一氧化氮是烟草烟雾的一种成分，其对尼古丁下游效应机制的作用尚不清楚。尼古丁代谢与氧化还原活性副产物的形成有关，氧化还原活性副产物可通过形成活性氧（ROS）引起氧化应激。由于已知后者与NO有强烈的相互作用，因此尼古丁诱导的ROS的产生很可能在全球范围内影响NO在大脑和其他器官中的命运和生物作用，导致生物分子的局部亚硝化、硝化和氧化，从而深刻改变蛋白质的功能和活性。该提案的中心假设是，局部组织氧化还原平衡和尼古丁诱导的ROS形成是触发或促进成瘾发展的NO代谢命运的关键决定因素（阶段1）。如果这是真的，那么调节这些决定因素可能会提供一种新的靶向方法来抑制这种与尼古丁相关的NO途径，而不会产生与NO生物利用度整体降低相关的副作用（第二阶段）。为了验证这一假设，我们将在啮齿类动物氧化应激模型中研究NO、尼古丁和香烟烟雾对氧化应激的影响，使用一种新的代谢组学方法，同时定量体内游离和蛋白质结合的亚硝基、硝基和亚硝基物种以及亚硝酸盐和硝酸盐。此外，还将测量cGMP水平、尼古丁代谢物和氧化剂生物标志物的区域变化。这些研究的结果有望为ROS与NO和体内重要NO递送形式的相互作用提供前所未有的见解，为专注于烟草相关成瘾的新型靶向干预策略的II期应用提供“构建块”和概念框架。烟草使用是一个世界性的重大健康问题，每年夺去300万人的生命。尽管近年来的研究工作和公共卫生教育有助于减少发达国家的吸烟率，但烟草使用仍然是美国和其他地方可预防死亡的最大单一原因。尼古丁成瘾的悲剧性后果强调了揭示相关分子机制的重要性。