Glutathione (GSH), an abundant tripeptidyl molecule, plays pivotal roles in protecting cells against oxidative
stress-induced cellular damage and in detoxifying xenobiotics and drug metabolism. GSH is now entering a
new era of therapeutic applications. Decreased GSH levels are associated with the common features of aging as
well as of a wide range of pathological conditions, including neurodegenerative disorders. Notably, GSH depletion
and/or alterations in its metabolism appear to be crucial in the onset of Parkinson’s disease. Despite the fact that
GSH is required for cell survival, the molecular mechanism that links GSH depletion to cell death remains poorly
understood. Recently, considerable attention has been focused on a newly defined type of cell death: irondependent
cell death, also referred to as “ferroptosis”. The iron chelator deferoxamine nearly abolishes ferroptosis induced by inhibiting
GSH synthesis or cystine uptake by the xCT transporter. Deferoxamine preferentially abrogates the intralysosomal accumulation of iron
and inhibits oxidative stress-induced lysosomal membrane permeabilization and cell death. The use of GSH and a prodrug derived from it
can be useful, since the dysfunction of the GSH redox system appears to cause a variety of diseases including neurodegenerative disorders.
However, the effectiveness of GSH as a therapeutic agent is limited because of its low bioavailability. We also review trials that
have been designed to cope with this difficulty; e.g. the use of precursors such as N-acetyl cysteine and chemical modification such as
Keywords: Oxidative stress, glutathione, cysteine, N-acetylcysteine, cell death.
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