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Obstetrics - Respiratory Medicine

Oxidative Stress in the Developing Brain: Effects of Postnatal Glucocorticoid Therapy and Antioxidants in the Rat
Published: Wednesday, June 15, 2011
Author: Emily J. Camm et al.

by Emily J. Camm, Deodata Tijsseling, Hans G. Richter, Alexandra Adler, Jeremy A. Hansell, Jan B. Derks, Christine M. Cross, Dino A. Giussani

In premature infants, glucocorticoids ameliorate chronic lung disease, but have adverse effects on long-term neurological function. Glucocorticoid excess promotes free radical overproduction. We hypothesised that the adverse effects of postnatal glucocorticoid therapy on the developing brain are secondary to oxidative stress and that antioxidant treatment would diminish unwanted effects. Male rat pups received a clinically-relevant tapering course of dexamethasone (DEX; 0.5, 0.3, and 0.1, with or without antioxidant vitamins C and E (DEXCE; 200 and 100, respectively), on postnatal days 1–6 (P1–6). Controls received saline or saline with vitamins. At weaning, relative to controls, DEX decreased total brain volume (704.4±34.7 mm3 vs. 564.0±20.0 mm3), the soma volume of neurons in the CA1 (1172.6±30.4 µm3 vs. 1002.4±11.8 µm3) and in the dentate gyrus (525.9±27.2 µm3 vs. 421.5±24.6 µm3) of the hippocampus, and induced oxidative stress in the cortex (protein expression: heat shock protein 70 [Hsp70]: +68%; 4-hydroxynonenal [4-HNE]: +118% and nitrotyrosine [NT]: +20%). Dexamethasone in combination with vitamins resulted in improvements in total brain volume (637.5±43.1 mm3), and soma volume of neurons in the CA1 (1157.5±42.4 µm3) and the dentate gyrus (536.1±27.2 µm3). Hsp70 protein expression was unaltered in the cortex (+9%), however, 4-HNE (+95%) and NT (+24%) protein expression remained upregulated. Treatment of neonates with vitamins alone induced oxidative stress in the cortex (Hsp70: +67%; 4-HNE: +73%; NT: +22%) and in the hippocampus (NT: +35%). Combined glucocorticoid and antioxidant therapy in premature infants may be safer for the developing brain than glucocorticoids alone in the treatment of chronic lung disease. However, antioxidant therapy in healthy offspring is not recommended.