Induction of apoptosis in the CNS during development by the combination of hyperoxia and inhibition of glutathione synthesis

Giulio Taglialatela, J. Regino Perez-Polo, David K. Rassin

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47 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)936-942
Number of pages7
JournalFree Radical Biology and Medicine
Volume25
Issue number8
DOIs
StatePublished - Nov 15 1998

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Keywords

  • Apoptosis
  • Buthionine sulfoximine
  • Cysteine
  • Early development
  • Glutathione
  • Hyperoxia
  • Nerve growth factor

ASJC Scopus subject areas

  • Medicine(all)
  • Toxicology
  • Clinical Biochemistry

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