Floyd Robert A, Hensley Kenneth, Forster Michael J, Kelleher-Anderson Judith A, Wood Paul L
Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA.
Ann N Y Acad Sci. 2002 Apr;959:321-9. doi: 10.1111/j.1749-6632.2002.tb02103.x.
Specific nitrones have been used for more than 30 years in analytical chemistry and biochemistry to trap and stabilize free radicals for the purpose of their identification and characterization. PBN (alpha-phenyl-tert-butyl nitrone), one of the more widely used nitrones for this purpose, has been shown to have potent pharmacologic activities in models of a number of aging-related diseases, most notably the neurodegenerative diseases of stroke and Alzheimer's disease. Studies in cell and animal models strongly suggest that PBN has potent antiaging activity. A novel nitrone, CPI-1429, has been shown to extend the life span of mice when administration was started in older animals. It has also shown efficacy in the prevention of memory dysfunction associated with normal aging in a mouse model. Mechanistic studies have shown that the neuroprotective activity of nitrones is not due to mass-action free radical-trapping activity, but due to cessation of enhanced signal transduction processes associated with neuroinflammatory processes known to be enhanced in several neurodegenerative conditions. Enhanced neuroinflammatory processes produce higher levels of neurotoxins, which cause death or dysfunction of neurons. Therefore, quelling of these processes is considered to have a beneficial effect allowing proper neuronal functioning. The possible antiaging activity of nitrones may reside in their ability to quell enhanced production of reactive oxygen species associated with age-related conditions. On the basis of novel ideas about the action of secretory products formed by senescent cells on bystander cells, it is postulated that nitrones will mitigate these processes and that this may be the mechanism of their antiaging activity.
特定的硝酮已在分析化学和生物化学领域使用了30多年，用于捕获和稳定自由基，以便对其进行鉴定和表征。PBN（α-苯基叔丁基硝酮）是用于此目的的应用较为广泛的硝酮之一，已在多种与衰老相关疾病的模型中显示出具有强大的药理活性，最显著的是中风和阿尔茨海默病等神经退行性疾病。细胞和动物模型研究强烈表明PBN具有强大的抗衰老活性。一种新型硝酮CPI-1429，在老年动物开始给药时已显示可延长小鼠寿命。它在预防小鼠模型中与正常衰老相关的记忆功能障碍方面也显示出疗效。机制研究表明，硝酮的神经保护活性并非由于大量自由基捕获活性，而是由于与已知在几种神经退行性疾病中增强的神经炎症过程相关的增强信号转导过程的停止。增强的神经炎症过程会产生更高水平的神经毒素，导致神经元死亡或功能障碍。因此，抑制这些过程被认为具有有益效果，可使神经元正常发挥功能。硝酮可能的抗衰老活性可能在于它们抑制与年龄相关疾病相关的活性氧过度产生的能力。基于关于衰老细胞形成的分泌产物对旁邻细胞作用的新观点，推测硝酮将减轻这些过程并可能是其抗衰老活性的机制。
