Lam H H, Bhardwaj A, O'Connell M T, Hanley D F, Traystman R J, Sofroniew M V
Medical Research Council Cambridge Centre for Brain Repair and Department of Anatomy, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 2PY, United Kingdom.
Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10926-31. doi: 10.1073/pnas.95.18.10926.
In adult forebrain, nerve growth factor (NGF) influences neuronal maintenance and axon sprouting and is neuroprotective in several injury models through mechanisms that are incompletely understood. Most NGF signaling is thought to occur after internalization and retrograde transport of trkA receptor and be mediated through the nucleus. However, NGF expression in hippocampus is rapidly and sensitively regulated by synaptic activity, suggesting that NGF exerts local effects more dynamically than possible through signaling requiring retrograde transport to distant afferent neurons. Interactions have been reported between NGF and nitric oxide (NO). Because NO affects both neural plasticity and degeneration, and trk receptors can mediate signaling within minutes, we hypothesized that NGF might rapidly modulate NO production. Using in vivo microdialysis we measured conversion of L-[14C]arginine to L-[14C]citrulline as an accurate reflection of NO synthase (NOS) activity in adult rat hippocampus. NGF significantly reduced NOS activity to 61% of basal levels within 20 min of onset of delivery and maintained NOS activity at less than 50% of baseline throughout 3 hr of delivery. This effect did not occur with control protein (cytochrome c) and was not mediated by an effect of NGF on glutamate levels. In addition, simultaneous delivery of NGF prevented significant increases in NOS activity triggered by the glutamate receptor agonists N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Rapid suppression by NGF of basal and glutamate-stimulated NOS activity may regulate neuromodulatory functions of NO or protect neurons from NO toxicity and suggests a novel mechanism for rapidly mediating functions of NGF and other neurotrophins.
在成体前脑，神经生长因子（NGF）影响神经元维持和轴突萌发，并在多种损伤模型中通过尚未完全明确的机制发挥神经保护作用。多数NGF信号传导被认为发生在trkA受体内化和逆行运输之后，并通过细胞核介导。然而，海马体中的NGF表达受突触活动快速且灵敏地调节，这表明NGF发挥局部作用的动态性比通过向远处传入神经元逆行运输的信号传导方式可能实现的更高。已有报道称NGF与一氧化氮（NO）之间存在相互作用。由于NO既影响神经可塑性又影响神经变性，且trk受体可在数分钟内介导信号传导，我们推测NGF可能快速调节NO生成。利用体内微透析技术，我们测量了L-[14C]精氨酸向L-[14C]瓜氨酸的转化，以此作为成年大鼠海马体中一氧化氮合酶（NOS）活性的准确反映。在给予NGF后20分钟内，其显著将NOS活性降低至基础水平的61%，并在整个3小时的给药过程中将NOS活性维持在低于基线水平的50%。对照蛋白（细胞色素c）未产生此效应，且NGF对谷氨酸水平的影响并未介导该效应。此外，同时给予NGF可防止由谷氨酸受体激动剂N-甲基-D-天冬氨酸（NMDA）和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）引发的NOS活性显著增加。NGF对基础和谷氨酸刺激的NOS活性的快速抑制可能调节NO的神经调节功能或保护神经元免受NO毒性影响，并提示了一种快速介导NGF和其他神经营养因子功能的新机制。
