title: Recombinant human thioredoxin-1 promotes neurogenesis and facilitates cognitive recovery following cerebral ischemia in mice.
abstract: Cerebral ischemia (CI) can induce loss of hippocampal neurons, causing cognitive dysfunction such as learning and memory deficits. In adult mammals, the hippocampal dentate gyrus contains neural stem cells (NSCs) that continuously generate newborn neurons and integrate into the pre-existing networks throughout life, which may ameliorate cognitive dysfunction following CI. Recent studies have demonstrated that recombinant human thioredoxin-1 (rhTrx-1) could promote proliferation of human adipose tissue-derived mesenchymal stem cells and angiogenesis. To investigate whether rhTrx-1 also regulates hippocampal neurogenesis following CI and its underlying mechanisms, adult mice were subjected to bilateral common carotid arteries occlusion (BCCAO) to induce CI and treated with rhTrx-1 before reperfusion. Mice treated with rhTrx-1 showed shortened escape latencies in Morris water maze by 30 days and improvements in spatial memory demonstrated by probe trial test. Enhanced NSCs proliferation was observed at day 14, indicated by BrdU and Ki67 immunostaining. Doublecortin (DCX)(+) cells were also significantly increased following rhTrx-1 treatment. Despite increases in BrdU(+)/NeuN(+) cells by day 30, the double-labeling to total BrdU(+) ratio was not affected by rhTrx-1 treatment. The promotive effects of rhTrx-1 on NSCs proliferation and differentiation were further confirmed in in vitro assays. Western blot revealed increased ERK1/2 phosphorylation after rhTrx-1 treatment, and the ERK inhibitor U0126 abrogated the effects of rhTrx-1 on NSCs proliferation. These results provide initial evidence that rhTrx-1 effects neurogenesis through the ERK signaling pathway and are beneficial for improving spatial learning and memory in adult mice following global CI.
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, 127th Changle West Road, Xi'an 710032, China.
authors.forename: Li
authors.initials: L
authors.lastname: Tian
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, 127th Changle West Road, Xi'an 710032, China.
authors.forename: Huang
authors.initials: H
authors.lastname: Nie
authors.affiliation: Department of Orthopedic Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, 127th Changle West Road, Xi'an 710032, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Psychosomatic Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Zhengwu
authors.initials: Z
authors.lastname: Peng
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, 127th Changle West Road, Xi'an 710032, China.
authors.forename: Min
authors.initials: M
authors.lastname: Cai
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, 127th Changle West Road, Xi'an 710032, China.
authors.forename: Haidong
authors.initials: H
authors.lastname: Wei
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, 127th Changle West Road, Xi'an 710032, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Qin
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, 127th Changle West Road, Xi'an 710032, China. Electronic address: hldong6@hotmail.com.
authors.forename: Hailong
authors.initials: H
authors.lastname: Dong
authors.affiliation: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, 127th Changle West Road, Xi'an 710032, China. Electronic address: mzkxlz@126.com.
authors.forename: Lize
authors.initials: L
authors.lastname: Xiong
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D049109:Cell Proliferation / Q000187:drug effects; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D000089662:Doublecortin Protein; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D058953:Neural Stem Cells / Q000187:drug effects / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology; D013879:Thioredoxins / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D013879:Thioredoxins
keywords: Cerebral ischemia; ERK signaling pathway; Hippocampus; Learning and memory; Neurogenesis; Recombinant human Trx-1