Deckwerth T L, Johnson E M
Washington University School of Medicine, Department of Molecular Biology and Pharmacology, St. Louis, Missouri 63110.
Ann N Y Acad Sci. 1993 May 28;679:121-31. doi: 10.1111/j.1749-6632.1993.tb18293.x.
Deprivation of sympathetic neurons of their physiological neurotrophic factor, nerve growth factor (NGF), leads to degeneration of soma and neurites, followed by loss of viability. The progression of degeneration and death are dependent upon macromolecular synthesis indicating an active participation of neuronal metabolism. Loss of viability begins only after a considerable delay after onset of NGF deprivation suggesting the presence of a sequence of degenerative events that triggers death. Such a sequence of degenerative events predicts that the activity of neuroprotective agents functioning by different mechanisms will be restricted to particular windows in time. The time-course of commitment to die as measured by the ability of NGF-deprived neurons to respond to NGF with long-term survival precedes the time-course of loss of viability by only a few hours, demonstrating that NGF displays neuroprotective properties for most of the time between onset of deprivation and death. Furthermore, NGF repairs and reverses the degenerative changes caused by prolonged periods of NGF deprivation. Because of these two aspects of NGF action, NGF demonstrates superior properties as a neuroprotective agents. NGF deprivation initiates DNA fragmentation of the neuronal genome into oligonucleosomal fragments in close temporal association with the onset of commitment to die. This is consistent with the idea that DNA fragmentation may be instrumental in causing the commitment to die. Thus, DNA fragmentation may serve as a marker of the physiologically most relevant critical step occurring during degeneration and may indicate the end of the period during which trophic factors are useful as neuroprotective agents. These results may be transferable to neurodegenerative diseases or sequelae of neuronal injury because of similarities in the phenomenology of degeneration and death.
交感神经元若被剥夺其生理性神经营养因子——神经生长因子（NGF），会导致胞体和神经突退化，继而丧失活力。退化和死亡的进程依赖于大分子合成，这表明神经元代谢积极参与其中。活力丧失仅在NGF剥夺开始后的相当一段时间延迟后才开始，这表明存在一系列引发死亡的退化事件。这样一系列的退化事件预示着，通过不同机制发挥作用的神经保护剂的活性将被限制在特定的时间窗口内。以NGF剥夺的神经元对NGF作出长期存活反应的能力来衡量，走向死亡的时间进程仅比活力丧失的时间进程早几个小时，这表明在剥夺开始到死亡之间的大部分时间里，NGF都具有神经保护特性。此外，NGF能修复并逆转由长时间NGF剥夺所引起的退化性变化。由于NGF作用的这两个方面，NGF作为一种神经保护剂展现出卓越的特性。NGF剥夺会引发神经元基因组的DNA断裂成寡核小体片段，且与走向死亡的开始在时间上紧密相关。这与DNA断裂可能有助于导致走向死亡的观点一致。因此，DNA断裂可能作为退化过程中发生的生理上最相关关键步骤的标志物，并且可能表明营养因子作为神经保护剂发挥作用的时期的结束。这些结果可能适用于神经退行性疾病或神经元损伤的后遗症，因为在退化和死亡的现象学上存在相似性。
