Stone, Rebecca; (2002) Glutathione release from astrocytes; Characterization and implications for neurodegeneration. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Reduced glutathione (GSH) plays a major intracellular role in the protection against oxidizing species. Within the brain, the neuronal GSH concentration may be dependent on the release of this antioxidant from neighbouring cells such as astrocytes. The aim of this thesis was to investigate the characteristics of GSH release from astrocytes, using primary rat astrocyte cultures or glial cell line cultures. GSH release from astrocytes was positively linear with respect to time and cell density. GSH was released predominantly in the reduced form, and the increase in GSH concentration was not due to extracellular reduction of oxidized glutathione (GSSG). This suggested that the preservation of released GSH with time and cell density was due to the presence of an astrocyte-released factor preventing the oxidation of released GSH. The astrocyte-released factor had similar characteristics to the extracellular isoform of superoxide dismutase (EcSOD), previously shown to be released by astrocytes. The molecular mass of the factor was determined to be between 50-100 kDa, which is comparable to the molecular mass previously determined for EcSOD in rats. In addition, SOD activity was determined in medium previously exposed to astrocytes. Excessive generation of nitric oxide (NO∙) and GSH depletion have been proposed to contribute towards neurodegeneration. It was therefore investigated, whether GSH release by astrocytes was affected by NO∙ exposure. The ability of astrocytes to release GSH was preserved after exposure to NO∙, and after the induction of NO∙ synthesis. Thus GSH release by astrocytes was maintained in the presence of NO∙. In summary, the release of an EcSOD-like factor by astrocytes preserves GSH released by astrocytes. This may be important in limiting neuronal damage from astrocyte-derived oxidizing species such as NO∙.

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