Acidosis Potentiates Oxidative Neuronal Death by Multiple Mechanisms

• Published in: Journal of neurochemistry 1999-10, Vol.73 (4), p.1549-1556
• Main Authors: Ying, Weihai, Han, Shan‐Kuo, Miller, Johann W., Swanson, Raymond A.
• Format: Article
• Language: English
• Subjects: Acidosis; Ageing, cell death; Amidines - pharmacology; Animals; Animals, Newborn; Biological and medical sciences; Cell Death - drug effects; Cell physiology; Cells, Cultured; Chelating Agents - pharmacology; Deferoxamine - pharmacology; Ethylenediamines - pharmacology; Fundamental and applied biological sciences. Psychology; glutathione peroxidase; Glutathione Peroxidase - metabolism; Glutathione Reductase - metabolism; glutathione transferase; Glutathione Transferase - metabolism; Hydrogen Peroxide - toxicity; Hydrogen-Ion Concentration; Iron; Mice; Mice, Inbred ICR; Models, Neurological; Molecular and cellular biology; Neuronal death; Neurons - cytology; Neurons - drug effects; Neurons - physiology; Oxidation-Reduction; Oxidative stress; Peroxide
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.1999.0731549.x

: Both acidosis and oxidative stress contribute to ischemic brain injury. The present study examines interactions between acidosis and oxidative stress in murine cortical cultures. Acidosis (pH 6.2) was found to potentiate markedly neuronal death induced by H2O2 exposure. To determine if this effect was mediated by decreased antioxidant capacity at low pH, the activities of several antioxidant enzymes were measured. Acidosis was found to reduce the activities of glutathione peroxidase and glutathione S‐transferase by 50‐60% (p < 0.001) and the activity of glutathione reductase by 20% (p < 0.01) in lysates of the cortical cultures. Like acidosis, direct inhibition of glutathione peroxidase with mercaptosuccinate also potentiated H2O2 toxicity. Because acidosis may accelerate hydroxyl radical production by the Fenton reaction, the effect of iron chelators was also examined. Both desferrioxamine and N,N,N′,N′‐tetrakis(2‐pyridylmethyl)ethylenediamine, two structurally different iron chelators, significantly reduced H2O2‐induced neuronal death under both pH 7.2 and pH 6.2 conditions. These results suggest that the increased cell death produced by severe acidosis during cerebral ischemia may result in part from excerbation of oxidative injury. This exacerbation may result from both impaired antioxidant enzyme functions and increased intracellular free iron levels.