Decreased brain content of thiol antioxidant glutathione (GSH) is regarded as an indicator of excessive oxidative stress, which, in turn, is recognized as a contributing factor to the development and progression of several age-related neurodegenerative diseases. Brain GSH is mainly produced by astroglia and their metabolic coupling with neurons allows the latter cells to maintain a sufficient antioxidant defense under physiological conditions. Neurons, however, are very sensitive to GSH depletion; hence any impairment in astrocyte-neuron GSH metabolic interactions, as it may occur in brain pathologies, would render neurons more susceptible to oxidative injuries. This also implies that agents capable of elevating brain GSH level could prove useful as neuroprotectants. In this chapter, we review data that supports these suppositions, generated using human NT2/N neurons and NT2/A astrocytes obtained by differentiation of NT2/D1 cells. Indeed, the results showed that astrocytes rendered neurons more resistant to toxic injuries and supported neuronal survival even in the presence of low GSH levels. They could not, however, support the neurons under chronic GSH depletion.
We also tested curcumin, a naturally occurring polyphenol with anti-inflammatory and antioxidant properties, for its ability to alter the GSH levels in NT2/N and NT2/A cells. Since curcumin is insoluble in aqueous media it is difficult to establish convincingly its efficacy. Here we have applied a solubilizing method developed in our laboratory (US patent No. 6,045,826 and 7,645,816; Ubisol technology licensed to Zymes LLC) to produce a water-soluble nano-micellar complex between PSS (polyoxyethanyl -sitosteryl sebacate) and curcumin (WS-Cur) which can be readily tested under any experimental conditions. The data showed that a 24 h treatment with WS-Cur increased GSH levels in both cell types and that this treatment was neuroprotective. Our results add to the growing body of evidence indicating that agents capable of modulating GSH, such as WS-Cur, might prove highly beneficial in the management of oxidative stress-induced neurodegeneration. Furthermore, strategies aimed at modulating and restoring astrocyte function, for example, by increasing GSH, might present new opportunities for repairing and restoring brain function.