Nitroxides as Protectors Against Oxidative Stress

氮氧化物(先导化合物，Tempoll)是一种有效的抗氧化剂，已被证明在许多疾病过程和/或代表过度氧化应激的条件下具有广泛的用途。事实是，氮氧化物在这样一系列疾病条件下发挥作用，说明了组织中自由基反应的重要性。同样，很明显，自由基在正常的分子信号通路和相关基因表达中也是重要的。我们已经发表了一项研究，表明应用坦普尔可以保护暴露在辐射中的正常组织。采用小型猪(小型猪)放射性口腔粘膜炎模型，每日分次照射(5×6GY)，给予氮氧化物坦普尔。每一次照射前10分钟。坦波尔对辐射引起的粘膜炎和溃疡具有保护作用。这些发现与最近进行的小鼠研究显示出类似的辐射防护作用是一致的。我们认为，坦波尔值得在临床试验中进行评估，以防止放射性粘膜炎。我们已经发表了评估Tempoll以降低多发性硬化症(MS)的严重性和进展的研究。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(RNS)参与了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坦波尔对小鼠EAE模型的免疫调节作用和治疗潜力。与对照组相比，在诱发活动期EAE之前，接受坦波尔自由进食2周的小鼠表现出发病延迟和发病率降低。疾病严重程度的降低与小胶质细胞的有限激活和较少的炎症浸润物有关。坦波尔的作用是免疫调节，而不是免疫抑制：T细胞产生较少的干扰素-伽马和肿瘤坏死因子-α。坦普尔的应用与CD8T细胞群和CD4FoxP3调节群的丰富有关。在疾病诱导后和临床症状出现后给药，坦波尔治疗也可以降低疾病的严重程度。口服坦波尔能够减少炎症和轴突损伤和丢失，显示出抗炎和保护特性，为治疗多发性硬化症和相关的神经疾病带来了巨大的希望。我们应邀在《氮氧化物：合成、性质和应用》一书中写了一章关于坦波尔的生物效应；伦敦：皇家化学学会，519-550,2021年。

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. We were invited to write a chapter on the biological effects of Tempol in the book entitled Nitroxides: Synthesis, Properties, and Applications; London: Royal Society of Chemistry, 519-550, 2021.