Glutathione is a crucial guardian of protein integrity in the brain upon nitric oxide imbalance.

GSH is mostly considered a non-enzymatic antioxidant that serves for modulating the redox status of protein thiols, detoxification and direct scavenging activity of oxyradicals. Within the cells, GSH has also the role to buffer the flux of nitric oxide (NO), which in the nervous system is physiologically produced being an important neuromodulator and neurotransmitter. However, this role of GSH in modulating NO toxicity is often considered of secondary importance. Recently, we confuted such assumption as we demonstrated that GSH depletion triggers a severe NO imbalance, which is the primary cause of neuronal death. Here we report that even a slight and non-toxic decrease of GSH in brain mice causes protein nitration that is reversed by inhibiting NO production. This evidence indicates that NO imbalance and the associated nitrosative hallmarks observed in neurodegenerative diseases as well as in health ageing are likely the consequence of the progressive decline of GSH.