Thioredoxin-1 attenuates post-ischemic neuronal apoptosis via reducing oxidative/nitrative stress

Recent studies show that Thioredoxin (Trx) possesses a neuronal protective effect and that Trx inactivation is closely related to cerebral ischemia injury. Peroxynitrite (ONOO−) formation may trigger oxidative/nitrative stress and represent a major cytotoxic effect in cerebral ischemia. The present study was conducted to validate whether treatment with recombinant human Trx-1 (rhTrx-1) would attenuate ONOO− generation and oxidative/nitrative stress in focal transient cerebral ischemia. The results showed that intravenously administered rhTrx-1 (10 mg/kg) significantly improved neurological functions and reduced cerebral infarction and apoptotic cell death following cerebral ischemia. Neuronal ONOO− formation was significantly attenuated after rhTrx-1 treatment. Moreover, rhTrx-1 resulted in a significant decrease in antioxidant capacity and p38 mitogen activated protein kinase (MAPK) activity in ischemic brain tissue. Furthermore, the suppression on ONOO− formation by either rhTrx-1 or an ONOO− scavenger uric acid reduced cerebral infarct size in mice subjected to cerebral ischemia. Peroxynitrite donor SIN-1 not only blocked the neuronal protection of rhTrx-1 but also markedly attenuated rhTrx-1-induced antioxidative/antinitrative effect. We concluded that rhTrx-1 exerts an antioxidative/antinitrative effect against cerebral ischemia injury by blocking ONOO− and superoxide anion formation. These results provide the information that thioredoxin is much more likely to succeed as a therapeutic approach to diminish oxidative/nitrative stress-induced neuronal apoptotic cell death in the ischemic brain.

► Trx-1 reduced infarct volume after transient cerebral ischemia.
► Trx-1 improved neurological deficits after transient cerebral ischemia.
► Trx-1 attenuated oxidative/nitrative stress after transient cerebral ischemia.
► Trx-1 reduced ischemia-induced neuronal apoptosis via reducing nitrative stress.