Effects of neonatal hypoxia on brain development in the rat: immediate and long-term biochemical alterations in discrete regions.

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.

Duke Scholars

Author Theodore Alan Slotkin Pharmacology & Cancer Biology