title: Targeting thioredoxin-1 with siRNA exacerbates oxidative stress injury after cerebral ischemia/reperfusion in rats.
abstract: Reactive oxygen species and their detrimental effects on the brain after transient ischemia/reperfusion (I/R) have been implicated in the pathogenesis of ischemic reperfusion injury. Thioredoxin-1 (Trx-1) is an endogenous antioxidant protein that has neuroprotective effects. We hypothesized that Trx-1 plays a crucial role in regulating cerebral I/R injury. To be able to test this, 190 Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion (tMCAO) with Trx-1 siRNA (small interference RNA) injected 24 h prior to ischemia. At 24 h after tMCAO, we measured neurological deficits, infarct volume, and brain water content, and found that neurological dysfunction, brain infarct size, and brain edema were worse in the Trx-1 siRNA group than in the control group. Oxidative stress was evaluated by measuring superoxide dismutase activity and malondialdehyde level. The levels of Trx-1 and its cofactor, peroxiredoxin (Prdx), were significantly decreased after Trx-1 down-regulated. However, there is no significant difference in the Prdx mRNA level after administration of Trx-1 siRNA. In contrast, Prdx-SO3 protein levels were significantly increased in the Trx-1 siRNA group. We also investigated the specific role of nuclear factor erythroid 2-related factor 2 (Nrf2) in Trx-1 induction by knocking down Nrf2. Nrf2 siRNA injection decreased Trx-1 mRNA and protein expression. Our results suggest that the exacerbation of brain damage was associated with enhanced cerebral peroxidation in brain tissues. Moreover, these results revealed that Trx-1, which is more likely regulated by Nrf2, exerts a neuroprotective role probably through maintaining the reduction activity of Prdx1-4.
authors.affiliation: Department of Pathophysiology, Chongqing Medical University, Chongqing, People's Republic of China; Institute of Neuroscience, Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, Chongqing Medical University, Chongqing, People's Republic of China; Institute of Neuroscience, Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: K
authors.initials: K
authors.lastname: Zhu
authors.affiliation: Department of Pathology, Chongqing Medical University, Chongqing, People's Republic of China; Institute of Neuroscience, Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pathophysiology, Chongqing Medical University, Chongqing, People's Republic of China; Institute of Neuroscience, Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: X
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Pathology, Chongqing Medical University, Chongqing, People's Republic of China; Institute of Neuroscience, Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Pathology, Chongqing Medical University, Chongqing, People's Republic of China; Institute of Neuroscience, Chongqing Medical University, Chongqing, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pathophysiology, Chongqing Medical University, Chongqing, People's Republic of China; Institute of Neuroscience, Chongqing Medical University, Chongqing, People's Republic of China. Electronic address: zjbingsheng@sina.com.
authors.forename: J
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology*; D001929:Brain Edema / Q000473:pathology / Q000503:physiopathology; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D020244:Infarction, Middle Cerebral Artery; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D054464:Peroxiredoxins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology*; D013482:Superoxide Dismutase / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C495697:Txn1 protein, rat; D008315:Malondialdehyde; D013879:Thioredoxins; D054464:Peroxiredoxins; D013482:Superoxide Dismutase
keywords: nuclear factor erythroid 2-related factor 2; oxidative stress; peroxiredoxin; thioredoxin-1