ABSTRACT
Although programmed cell death (PCD) plays an important role in the normal development of the nervous system, in adults PCD leads to the neuronal cell loss associated with various neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, as well as that associated with acute central nervous system (CNS) trauma, including stroke (for review, see Ref. 1). In all of these cases PCD has been linked to oxidative stress and the production of reactive oxygen species (ROS) (for reviews, see Refs. 1-4). One potential mechanism for the generation of ROS in the CNS is via the excitatory amino acid glutamate. Excess glutamate has been linked to the neuronal cell death seen in Alzheimer’s disease and Parkinson’s disease, as well as that seen following acute insults to the CNS (5). Two pathways for glutamate toxicity have been described: excitotoxicity (6), which occurs through activation of ionotropic glutamate receptors, and oxidative glutamate toxicity (7), which is mediated via a series of distur bances to the redox homeostasis of the cell. Evidence for the involvement of the oxidative pathway in glutamate toxicity arose from several discrepancies in stud ies involving ionotropic glutamate receptors, antagonists, and cell death (8-12). This pathway does not involve ionotropic glutamate receptors but rather a
glutamate/cystine antiporter that is required for the delivery of cystine into neu ronal cells (7). Inhibition of cystine uptake by high concentrations of extracellular glutamate leads to an imbalance in cellular cysteine homeostasis and a reduction in cellular glutathione (GSH) levels, which can eventually lead to cell death. A critical role for GSH in protecting neuronal cells from PCD has been suggested by a number of in vitro and in vivo studies. For instance, in Parkinson’s disease patients there is an early and specific decrease in GSH levels that may precede cell death (for review, see Ref. 13). Similarly, the levels of GSH were shown to fall during ischemia (14). In vitro, the inhibition of GSH biosynthesis leads to the degeneration of cultured dopaminergic neurons and increases in their sensitiv ity to various neurotoxic agents (15,16). Thus, the early drop in cellular GSH levels seen in oxidative glutamate toxicity is very similar to changes seen in vivo in neuronal cells responding to both acute and chronic injury.
