Glutathione Deficit in Schizophrenia: Replenishment of Glutathione Levels in Neurons and Astrocytes Models

In schizophrenia patients, a decrease in glutathione levels ([GSH]) in cerebrospinal fluid and prefrontal cortex was observed, as well as a decrease in the expression of a gene coding for glutamyl-cysteine ligase (GCL), the limiting enzyme of GSH synthesis. As a redox regulator, GSH plays an important role in protecting cells against oxidative stress. In rat models with a GSH deficit, anomalies analogous to those of patients were observed, such as a decrease in spine number in prefrontal cortex and an alteration of NMDA responses. We aim to find substances that could increase [GSH] in cortical cells and to study the underlying mechanisms. GSH-ethyl-ester (GSHEE) succeeded in replenishing [GSH] in cultured neurons and astrocytes depleted in GSH by BSO, an inhibitor of GCL. GSHEE also abolished dopamine-induced decrease of NMDA-mediated calcium response observed in BSO-treated neurons. Gamma-glutamylcysteine- ethyl-ester (GCEE) increased [GSH] mostly in astrocytes. These results show that GSHEE and GCEE re-establish physiological [GSH] in brain cells by bypassing the limiting step of GSH synthesis. Curcumin (polyphenol), tert-butylhydroquinone (tBHQ; quinone), quercetin (flavonoid) and FK506 (immunosuppressant) were tested for their capacity to boost GSH synthesis. Curcumin was the most efficient. It increased [GSH] by 50 and 100% in non BSO-treated neurons and astrocytes, respectively, and increased GCL activity by more than 100% in astrocytes. In neurons, low concentrations of tBHQ (10-20_M) increased [GSH] by 20% while high [tBHQ] and quercetin led to cell death. In astrocytes, both substances increased [GSH] and GCL activity at rather high concentrations (100_M). FK506 was inefficient in both cell types. These results indicate that neurons and astrocytes are not responding similarly to some of the tested substances, suggesting that the mechanisms regulating GSH synthesis and the susceptibility to oxidative stress might differ in the two cell types.