Nitroxides as Protectors Against Oxidative Stress

氮氧化物作为氧化应激的保护剂

• 批准号: 10262693
• 负责人: James Mitchell
• 金额: $ 27.78万
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10262693
• 关键词: Animal Model; Animals; Anti-Inflammatory Agents; Antioxidants; CD8-Positive T-Lymphocytes; Cells; Chemicals; Chemoprevention; Clinical; Clinical Trials; Disease; Experimental Autoimmune Encephalomyelitis; Exposure to; FOXP3 gene; Family suidae; Free Radicals; Gene Expression; Goals; Human; Immune; Incidence; Inflammation; Inflammatory; Inflammatory Infiltrate; Interferon Type II; Ionizing radiation; Laboratories; Lead; Mediating; Metabolism; Miniature Swine; Modeling; Molecular; Mucositis; Multiple Sclerosis; Mus; Nerve Degeneration; Neuraxis; Normal tissue morphology; Obesity; Oral; Oxidative Stress; Oxygen; Pathologic; Pathway interactions; Population; Process; Property; Publishing; Radiation; Radiation Protection; Radiation induced damage; Reaction; Reactive Nitrogen Species; Reactive Oxygen Species; Role; Severities; Severity of illness; Signal Pathway; Signal Transduction; Superoxide Dismutase; Symptoms; T-Lymphocyte; TNF gene; Therapeutic; Tissues; Ulcer; axon injury; cancer therapy; carcinogenesis; catalase; cell injury; fractionated radiation; immunoregulation; irradiation; multiple sclerosis treatment; nervous system disorder; oral mucositis; pathogen; tempol

Nitroxides (lead compound, Tempol), which are potent antioxidants, are proving to have broad utility in a number of disease processes and/or conditions that represent excessive oxidative stress. The fact that nitroxides exert activity over such a range of disease conditions speaks to the importance of free radical reactions in tissue. Likewise, it is becoming apparent that free radicals are important in normal molecular signaling pathways and related gene expression. We have published a study that shows Tempol application can provide protection of normal tissues exposed to radiation. Using a miniature pig (minipig) model for irradiation-induced oral mucositis, animals were exposed to daily fractionated radiation (5 x 6 Gy), where the nitroxide Tempol was administered i.p. 10 min before each radiation fraction. Tempol provided protection against radiation-induced mucositis and ulceration. These findings are consistent with mouse studies conducted recently showing comparable radioprotective effects. We believe Tempol is worthy of being evaluated in clinical trials to protect against radiation-induced mucositis. We have published studies evaluating Tempol to reduce the severity and progression of multiple sclerosis (MS). Several reactive oxygen (ROS) and reactive nitrogen species (RNS) are implicated in inflammatory-mediated damage to the central nervous system (CNS) in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). The goal of these studies was to investigate the immunomodulatory effects and therapeutic potential of orally-delivered Tempol in the mouse EAE model. Mice receiving Tempol chow ad libitum for 2 weeks prior to induction of active EAE showed delayed onset and reduced incidence of disease compared to control-fed animals. Reduced disease severity was associated with limited microglial activation and fewer inflammatory infiltrates. Tempol's effects were immunomodulatory, not immunosuppressive: T cells produced less interferon-gamma and tumor necrosis factor-alpha. Tempol administration was associated with an enrichment of CD8+ T cell populations and CD4+FoxP3+ regulatory populations. Tempol treatment also reduced the severity of disease when administered after the induction of disease, and also after the onset of clinical symptoms. The ability of oral Tempol to reduce inflammation and axonal damage and loss demonstrate both anti-inflammatory and protective properties, holds significant promise for the treatment of MS and related neurological disorders.

氮氧自由基（铅化合物，Tempol），这是有效的抗氧化剂，被证明有广泛的用途，在许多疾病的过程和/或条件，代表过度氧化应激。氮氧自由基在如此广泛的疾病条件下发挥活性的事实说明了组织中自由基反应的重要性。同样，自由基在正常分子信号通路和相关基因表达中的重要性也变得越来越明显。我们已经发表了一项研究，表明Tempol应用可以保护暴露于辐射的正常组织。使用辐射诱导的口腔粘膜炎的小型猪（minipig）模型，将动物暴露于每日分次辐射（5 × 6戈伊），其中在每次辐射分次之前10分钟腹膜内施用氮氧化物Tempol。Tempol可防止辐射引起的粘膜炎和溃疡。这些发现与最近进行的小鼠研究一致，显示出相当的辐射防护作用。我们相信Tempol值得在临床试验中进行评估，以防止辐射引起的粘膜炎。我们已经发表了评估Tempol降低多发性硬化症（MS）严重程度和进展的研究。在MS及其动物模型实验性自身免疫性脑脊髓炎（EAE）中，几种活性氧（ROS）和活性氮物质（RNS）参与炎症介导的中枢神经系统（CNS）损伤。这些研究的目的是研究口服Tempol在小鼠EAE模型中的免疫调节作用和治疗潜力。与对照喂养的动物相比，在诱导活动性EAE之前随意接受Tempol食物2周的小鼠显示出延迟的发病和降低的疾病发生率。疾病严重程度的降低与有限的小胶质细胞活化和较少的炎性浸润有关。Tempol的作用是免疫调节，而不是免疫抑制：T细胞产生更少的干扰素-γ和肿瘤坏死因子-α。Tempol给药与CD 8 + T细胞群和CD 4 + FoxP 3+调节群的富集相关。Tempol治疗还降低了疾病的严重程度，当在疾病诱导后给药时，以及在临床症状发作后给药。口服Tempol减少炎症和轴突损伤和损失的能力证明了抗炎和保护特性，为MS和相关神经系统疾病的治疗带来了重大希望。