Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.399310
Title: The role of cellular glutathione concentration in dictating astrocytic and neuronal susceptibility to oxidative stress
Author: Gegg, Matthew Edward
ISNI:       0000 0001 3493 4491
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2002
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Abstract:
The availability of the antioxidant glutathione (GSH) within astrocytes and neurones has been suggested to protect the mitochondrial electron transport chain (ETC) from inactivation by reactive oxygen and nitrogen species. Since perturbed glutathione metabolism, increased production of reactive nitrogen species, and impaired mitochondrial function have been implicated in several neurological disorders, the effect of oxidative stress on GSH metabolism in astrocytes and neurones, and the consequences this has on ETC function and cell viability has been investigated. When cultured alone, neurones were more susceptible to ETC damage and cell death, compared to astrocytes, following exposure to the nitric oxide (NO) donor DETA-NO, or 3-hydroxy-4-pentenoic acid, a drug previously reported to specifically deplete mitochondrial GSH in liver. A reason for this maybe that the activity of glutamate-cysteine ligase, the rate-limiting enzyme in GSH synthesis, was increased in astrocytes but not neurones following treatment, and resulted in elevated GSH levels. The rate of GSH efflux and the activity of y- glutamyltranspeptidase (y-GT), an ectoenzyme that metabolises GSH to cysteinylglycine (CysGly), were also increased in astrocytes exposed to NO. The supply of CysGly from astrocytes has previously been shown to increase GSH levels in neurones when cocultured with astrocytes. This thesis has shown that the elevation of neuronal GSH levels relied on the release of GSH from astrocytes only, and does not appear to require a concomitant increase in neuronal GCL activity. Therefore, the increased release of GSH from astrocytes, and the activity of y-GT upon NO exposure, may increase the supply of CysGly to neurones in coculture and in vivo, and therefore give them greater protection. Interestingly, neurones can increase GCL activity when cultured with astrocytes that did not release GSH. In summary, GSH metabolism in both astrocytes and neurones can be modulated upon oxidative stress as a possible protective mechanism.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.399310  DOI: Not available
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