Enhancing S-nitrosoglutathione reductase decreases S-nitrosylation of ERO1α and reduces neuronal death in secondary traumatic brain injury.

Traumatic brain injury (TBI) has the highest incidence of all common neurological disorders, along with high mortality and disability rates. Pathological conversion of excess nitric oxide (NO) to S-nitrosoglutathion (GSNO) after TBI leads to high S-nitrosylation of intracellular proteins, causing nitrative stress. GSNO reductase (GSNOR) plays an important role by regulating GSNO and SNO-proteins (PSNOs) and as a redox regulator of the nervous system. However, the effect of GSNOR on protein S-nitrosylation in secondary brain injury after TBI is not clear. In vivo TBI model was established in male C57BL/6 mice via controlled cortical impact (CCI). Neuron-targeted GSNOR-overexpression adeno-associated virus (AAV) was constructed and administered to mice by stereotactic cortical injection. The results showed that NO, GSNO, neuronal protein S-nitrosylation and neuronal death increased after TBI, while the level and activity of GSNOR decreased. Overexpression of GSNOR by AAV decreased GSNO and NO and improved short-term neurobehavioral outcomes in mice. GSNOR overexpression can reduce endoplasmic reticulum stress and neuronal death by reducing the S-nitrosylation of ERO1α via H2O2 generation and plays a neuroprotective role. In conclusion, our results suggest that GSNOR regulating S-nitrosylation of ERO1α may participate in neuronal death, and overexpression of GSNOR in neurons after experimental brain injury alleviates secondary brain injury. Our research provides a potential therapeutic approach for the treatment of TBI.