Taglialatela G, Perez-Polo J R, Rassin D K
The Department of Human Biological Chemistry, The University of Texas Medical Branch at Galveston, USA.
Free Radic Biol Med. 1998 Nov 15;25(8):936-42. doi: 10.1016/s0891-5849(98)00131-2.
Apoptosis in the central nervous system (in contrast to necrosis) is an endogenous cell suicide mechanism triggered in response to biological factors and genotoxic stimuli often resulting from oxidative stress. Excessive neural apoptosis may result in longterm brain dysfunction. A significant proportion of prematurely born infants are exposed to high oxygen and nutritional regimens deficient in antioxidant precursors. Such infants frequently display cognitive deficits when studied in later childhood. Studies in cell culture have characterized a close relationship between oxidative stress, glutathione availability and cell death. Here, we assessed this relationship in rat brain, as a model approximation of the situation that occurs in human infants. Two day old rats were exposed to an atmosphere of 95% oxygen and treated with buthionine sulfoximine (BSO), a glutathione synthesis inhibitor. Control groups consisted of rat-pups kept in air, air plus BSO, or oxygen alone. At the end of 5 days of treatment, brains were harvested, dissected and nerve growth factor protein (NGF), glutathione, and extent of apoptosis were measured. Hyperoxia induced a decrease in NGF protein while BSO induced a decrease in glutathione concentrations. Animals treated with both hyperoxia and BSO had a dramatic increase in the extent of brain apoptosis detected. We conclude from these studies that the brains of animals exposed to both oxidative stress and limited antioxidant protection are liable to pro-apoptotic changes. Increased cell death via apoptosis reflecting changes in neurotrophin and glutathione homeostasis may represent the mechanism responsible for the induction of the longterm cognitive deficits observed in some preterm infants.
中枢神经系统中的细胞凋亡（与坏死不同）是一种内源性细胞自杀机制，由生物因素和通常由氧化应激引起的基因毒性刺激所触发。过度的神经细胞凋亡可能导致长期的脑功能障碍。相当一部分早产婴儿会暴露于高氧环境以及缺乏抗氧化前体的营养方案中。这些婴儿在童年后期接受研究时经常表现出认知缺陷。细胞培养研究已经明确了氧化应激、谷胱甘肽可用性与细胞死亡之间的密切关系。在此，我们以大鼠脑作为人类婴儿情况的模型近似物，评估了这种关系。将两天大的大鼠暴露于95%氧气的环境中，并用谷胱甘肽合成抑制剂丁硫氨酸亚砜胺（BSO）进行处理。对照组由饲养在空气中的幼鼠、空气加BSO或仅氧气环境中的幼鼠组成。在处理5天后，收获大脑，进行解剖并测量神经生长因子蛋白（NGF）、谷胱甘肽以及细胞凋亡程度。高氧诱导NGF蛋白减少，而BSO诱导谷胱甘肽浓度降低。同时接受高氧和BSO处理的动物检测到的脑细胞凋亡程度显著增加。我们从这些研究中得出结论，暴露于氧化应激和有限抗氧化保护的动物大脑容易发生促凋亡变化。通过细胞凋亡导致的细胞死亡增加反映了神经营养因子和谷胱甘肽稳态的变化，这可能代表了在一些早产儿中观察到的长期认知缺陷诱导机制。
