Slotkin T A, Cowdery T S, Orband L, Pachman S, Whitmore W L
Brain Res. 1986 May 21;374(1):63-74. doi: 10.1016/0006-8993(86)90395-1.
To evaluate the sensitivity of immature brain tissue to hypoxic insult, neonatal rats were exposed to 7% O2 for 2 h at critical stages of development (1, 8, 15, 23 days of postnatal age); the immediate and long-term impact of hypoxia was then assessed in cerebellum, cerebral cortex and midbrain through measurement of ornithine decarboxylase (ODC) activity, a biochemical determinant of cellular injury and subsequent maturation, and through measurements of protein synthesis, growth and synaptosomal uptake of norepinephrine (an index of noradrenergic synaptogenesis). In one-day-old rats, hypoxia caused stimulation of protein synthesis and short-term suppression of ODC activity which persisted for several hours after termination of low O2 exposure; over the ensuing days, there was a prolonged elevation of enzyme activity and a subsequent, regionally selective increase in synaptosomal uptake of norepinephrine without changes in brain growth. In contrast, hypoxia in 8-day-old rats produced signs of metabolic injury, with a short-term elevation of ODC throughout the brain and reduced protein synthetic rates, eventual shortfalls in brain regional growth and no net increase in synaptosomal uptake. The effects of hypoxia on brain regional growth in 8-day-old animals appeared to represent an age-specific effect, as low as O2 conditions in older animals did not affect growth (animals made hypoxic at 15 or 23 days), but did produce an eventual reduction in synaptosomal uptake (hypoxia at 15 days). Differences between one-day-old and 8-day-old rats were also apparent in cerebral responses simply to a 2-h separation from the dam under normoxic conditions. These results support the view that cellular development and synaptogenesis are compromised when neonatal brain tissue is exposed to hypoxic conditions, and that there are critical periods of sensitivity in which processes undergoing rapid maturational change are particularly vulnerable.
为评估未成熟脑组织对缺氧损伤的敏感性，在发育的关键阶段（出生后1、8、15、23天）将新生大鼠暴露于7%氧气环境中2小时；然后通过测量鸟氨酸脱羧酶（ODC）活性（细胞损伤及后续成熟的生化指标）、蛋白质合成、生长以及去甲肾上腺素的突触体摄取（去甲肾上腺素能突触发生的指标），评估缺氧对小脑、大脑皮层和中脑的即时和长期影响。在1日龄大鼠中，缺氧导致蛋白质合成受刺激以及ODC活性短期受抑制，在低氧暴露终止后这种抑制持续数小时；在随后的几天里，酶活性持续升高，随后去甲肾上腺素的突触体摄取出现区域选择性增加，而脑生长无变化。相比之下，8日龄大鼠缺氧产生代谢损伤迹象，全脑ODC短期升高，蛋白质合成速率降低，最终脑区生长不足，突触体摄取无净增加。缺氧对8日龄动物脑区生长的影响似乎代表了一种年龄特异性效应，因为年龄较大动物（15或23日龄时缺氧）处于低氧条件下不影响生长，但确实最终导致突触体摄取减少（15日龄时缺氧）。在常氧条件下，1日龄和8日龄大鼠仅与母鼠分离2小时后的脑反应差异也很明显。这些结果支持这样一种观点，即新生脑组织暴露于缺氧条件下时，细胞发育和突触发生会受到损害，并且存在关键的敏感时期，在此期间经历快速成熟变化的过程特别脆弱。
