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Inhibition of Astrocyte Glutamate Uptake by Reactive Oxygen Species: Role of Antioxidant Enzymes

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Abstract

Background

The recent literature suggests that free radicals and reactive oxygen species may account for many pathologies, including those of the nervous system.

Materials and Methods

The influence of various reactive oxygen species on the rate of glutamate uptake by astrocytes was investigated on monolayers of primary cultures of mouse cortical astrocytes.

Results

Hydrogen peroxide and peroxynitrite inhibited glutamate uptake in a concentration-dependent manner. Addition of copper ions and ascorbate increased the potency and the efficacy of the hydrogen peroxide effect, supporting the potential neurotoxicity of the hydroxyl radical. The free radical scavenger dimethylthiourea effectively eliminated the inhibitory potential of a mixture containing hydrogen peroxide, copper sulphate, and ascorbate on the rate of glutamate transport into astrocytes The inhibitory effect of hydrogen peroxide on glutamate uptake was not altered by the inhibition of glutathione peroxidase, whereas the inhibition of catalase by sodium azide clearly potentiated this effect. Superoxide and nitric oxide had no effect by themselves on the rate of glutamate uptake by astrocytes. The absence of an effect of nitric oxide is not due to an inability of astrocytes to respond to this substance, since the same cultures did respond to nitric oxide with a sustained increase in cytoplasmic free calcium.

Conclusion

These results confirm that reactive oxygen species have a potential neurotoxicity by means of impairing glutamate transport into astrocytes, and they suggest that preventing the accumulation of hydrogen peroxide in the extracellular space of the brain, especially during conditions that favor hydroxyl radical formation, could be therapeutic.

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Acknowledgments

This work was supported in part by MH47680 (F.E.B., N.Y., D.L.G.), Deutscher Akademischer Austauschdienst (T.F.W.H.), and Swiss National Fund (O.S.).

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Author notes

  1. Olivier Sorg

    Present address: Institut de Physiologic Faculté de Médecine, CH-1005, Lausanne, Switzerland

Authors and Affiliations

  1. Department of Neuropharmacology, The Scripps Research Institute, 10550 North Torrey Pines Rd., Mail Code SBR-1, La Jolla, California, 92037, USA

    Olivier Sorg, Thomas F. W. Horn, Naichen Yu, Donna L. Gruol & Floyd E. Bloom

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  1. Olivier Sorg
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Correspondence to Floyd E. Bloom.

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Sorg, O., Horn, T.F.W., Yu, N. et al. Inhibition of Astrocyte Glutamate Uptake by Reactive Oxygen Species: Role of Antioxidant Enzymes. Mol Med 3, 431–440 (1997). https://doi.org/10.1007/BF03401690

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