title: Thioredoxin-1 attenuates post-ischemic neuronal apoptosis via reducing oxidative/nitrative stress.
abstract: 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.
authors.affiliation: Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Y H
authors.initials: YH
authors.lastname: Ma
authors.forename: Ning
authors.initials: N
authors.lastname: Su
authors.forename: X D
authors.initials: XD
authors.lastname: Chao
authors.forename: Y Q
authors.initials: YQ
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Feng
authors.initials: F
authors.lastname: Han
authors.forename: Peng
authors.initials: P
authors.lastname: Luo
authors.forename: Zhou
authors.initials: Z
authors.lastname: Fei
authors.forename: Yan
authors.initials: Y
authors.lastname: Qu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology*; D004789:Enzyme Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009566:Nitrates / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D011994:Recombinant Proteins / Q000494:pharmacology; D013879:Thioredoxins / Q000494:pharmacology* / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D009566:Nitrates; D011994:Recombinant Proteins; D013879:Thioredoxins; D048051:p38 Mitogen-Activated Protein Kinases