Control of redox state and redox signaling by neural antioxidant systems

The glutathione/glutathione disulfide (GSH/GSSG) redox pair forms the major redox couple in cells and as such plays a critical role in regulating redox-dependent cellular functions. Not only does GSH act as an antioxidant but it can also modulate the activity of a variety of different proteins. An impairment in GSH status is thought to be the precipitating event in a wide range of neurological disorders. Therefore, understanding how to maintain GSH in the CNS could provide a valuable therapeutic approach. Intracellular GSH levels are regulated by a complex series of pathways that include substrate transport and availability, rates of synthesis and regeneration, GSH utilization, and GSH efflux. To date, the most effective approaches for maintaining GSH levels in the CNS include enhancing cyst(e)ine uptake both directly and indirectly via transcriptional upregulation of system x(c)(-), increasing GSH synthesis via transcriptional upregulation of the rate limiting enzyme in GSH biosynthesis, and decreasing GSH utilization. Among the transcription factors that play critical roles in GSH metabolism are NF-E2-related factor 2 (Nrf2) and activating transcription factor 4 (ATF4). Thus, compounds that can upregulate these transcription factors may be particularly useful in promoting the functional maintenance of the CNS through their effects on GSH metabolism.