title: Ischemic postconditioning relieves cerebral ischemia and reperfusion injury through activating T-LAK cell-originated protein kinase/protein kinase B pathway in rats.
abstract: OBJECTIVE
  Ischemic postconditioning (IPostC) protects against ischemic brain injury. To date, no study has examined the role of T-LAK-cell-originated protein kinase (TOPK) in IPostC-afforded neuroprotection. We explored the molecular mechanism related with TOPK in antioxidant effect of IPostC against ischemia/reperfusion.
  
  
  METHODS
  Focal ischemia was induced in rats by transient middle cerebral artery occlusion. Reactive oxygen species production in the peri-infarct cortex was detected using dihydroethidium. Malondialdehyde, as a marker of lipid peroxidation, and 3-nitrotyrosine, as a marker of protein oxidation, were detected by ELISA. The expression or location of antioxidant proteins and signal molecules TOPK, phosphatase, and tensin homolog, and Akt was analyzed by Western blotting and immunofluorescence.
  
  
  RESULTS
  Our results revealed that IPostC relieved transient middle cerebral artery occlusion-induced oxidative damage by reducing reactive oxygen species, malondialdehyde, and 3-nitrotyrosine accumulation in the peri-infarct cortex and raised levels of antioxidants perioxiredoxin-1, peroxiredoxin-2, and thioredoxin-1. In addition, IPostC increased p-AKT and p-TOPK levels, which colocalized in neural cells. In vitro TOPK knockdown by small interfering RNA decreased the levels of antioxidants peroxiredoxin-1, thioredoxin, and manganese superoxide dismutase activity in PC12 cells. In vivo intracerebroventricular injection of TOPK small interfering RNA reversed IPostC-induced neuroprotection by increasing infarct volume and nitric oxide content and reducing manganese superoxide dismutase activity. Moreover, IPostC-evoked Akt activation was blocked by TOPK small interfering RNA in vivo, but the decreased phosphorylated phosphatase and tensin homolog level in ischemia/reperfusion was not influenced by IPostC or by TOPK small interfering RNA treatment.
  
  
  CONCLUSIONS
  Our results suggest that the antioxidative effects of TOPK/Akt might contribute to the neuroprotection of IPostC treatment against transient middle cerebral artery occlusion.
authors.affiliation: From the Cerebrovascular Diseases Research Institute (H.Z., R.W., Z.T., F.Y., Z.G., X.L., X.J., Y.L.) and Department of Neurology (L.G.), Xuanwu Hospital of Capital Medical University, Beijing, China; Cerebralvascular Diseases Research Laboratory, Beijing Geriatric Medical Research Center, Beijing, China (H.Z., R.W., Z.T., F.Y., Z.G., X.L., X.J., Y.L.); and Key Laboratory of Neurodegenerative Diseases of Ministry of Education and Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing, China (H.Z., R.W., Z.T., F.Y., Z.G., X.L., X.J., Y.L.).
authors.forename: Haiping
authors.initials: H
authors.lastname: Zhao
authors.affiliation: From the Cerebrovascular Diseases Research Institute (H.Z., R.W., Z.T., F.Y., Z.G., X.L., X.J., Y.L.) and Department of Neurology (L.G.), Xuanwu Hospital of Capital Medical University, Beijing, China; Cerebralvascular Diseases Research Laboratory, Beijing Geriatric Medical Research Center, Beijing, China (H.Z., R.W., Z.T., F.Y., Z.G., X.L., X.J., Y.L.); and Key Laboratory of Neurodegenerative Diseases of Ministry of Education and Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing, China (H.Z., R.W., Z.T., F.Y., Z.G., X.L., X.J., Y.L.).
authors.forename: Rongliang
authors.initials: R
authors.lastname: Wang
authors.affiliation: From the Cerebrovascular Diseases Research Institute (H.Z., R.W., Z.T., F.Y., Z.G., X.L., X.J., Y.L.) and Department of Neurology (L.G.), Xuanwu Hospital of Capital Medical University, Beijing, China; Cerebralvascular Diseases Research Laboratory, Beijing Geriatric Medical Research Center, Beijing, China (H.Z., R.W., Z.T., F.Y., Z.G., X.L., X.J., Y.L.); and Key Laboratory of Neurodegenerative Diseases of Ministry of Education and Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing, China (H.Z., R.W., Z.T., F.Y., Z.G., X.L., X.J., Y.L.).
authors.forename: Zhen
authors.initials: Z
authors.lastname: Tao
authors.affiliation: From the Cerebrovascular Diseases Research Institute (H.Z., R.W., Z.T., F.Y., Z.G., X.L., X.J., Y.L.) and Department of Neurology (L.G.), Xuanwu Hospital of Capital Medical University, Beijing, China; Cerebralvascular Diseases Research Laboratory, Beijing Geriatric Medical Research Center, Beijing, China (H.Z., R.W., Z.T., F.Y., Z.G., X.L., X.J., Y.L.); and Key Laboratory of Neurodegenerative Diseases of Ministry of Education and Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing, China (H.Z., R.W., Z.T., F.Y., Z.G., X.L., X.J., Y.L.).
authors.forename: Li
authors.initials: L
authors.lastname: Gao
authors.affiliation: From the Cerebrovascular Diseases Research Institute (H.Z., R.W., Z.T., F.Y., Z.G., X.L., X.J., Y.L.) and Department of Neurology (L.G.), Xuanwu Hospital of Capital Medical University, Beijing, China; Cerebralvascular Diseases Research Laboratory, Beijing Geriatric Medical Research Center, Beijing, China (H.Z., R.W., Z.T., F.Y., Z.G., X.L., X.J., Y.L.); and Key Laboratory of Neurodegenerative Diseases of Ministry of Education and Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing, China (H.Z., R.W., Z.T., F.Y., Z.G., X.L., X.J., Y.L.).
authors.forename: Feng
authors.initials: F
authors.lastname: Yan
authors.affiliation: From the Cerebrovascular Diseases Research Institute (H.Z., R.W., Z.T., F.Y., Z.G., X.L., X.J., Y.L.) and Department of Neurology (L.G.), Xuanwu Hospital of Capital Medical University, Beijing, China; Cerebralvascular Diseases Research Laboratory, Beijing Geriatric Medical Research Center, Beijing, China (H.Z., R.W., Z.T., F.Y., Z.G., X.L., X.J., Y.L.); and Key Laboratory of Neurodegenerative Diseases of Ministry of Education and Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing, China (H.Z., R.W., Z.T., F.Y., Z.G., X.L., X.J., Y.L.).
authors.forename: Zhi
authors.initials: Z
authors.lastname: Gao
authors.affiliation: From the Cerebrovascular Diseases Research Institute (H.Z., R.W., Z.T., F.Y., Z.G., X.L., X.J., Y.L.) and Department of Neurology (L.G.), Xuanwu Hospital of Capital Medical University, Beijing, China; Cerebralvascular Diseases Research Laboratory, Beijing Geriatric Medical Research Center, Beijing, China (H.Z., R.W., Z.T., F.Y., Z.G., X.L., X.J., Y.L.); and Key Laboratory of Neurodegenerative Diseases of Ministry of Education and Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing, China (H.Z., R.W., Z.T., F.Y., Z.G., X.L., X.J., Y.L.).
authors.forename: Xiangrong
authors.initials: X
authors.lastname: Liu
authors.affiliation: From the Cerebrovascular Diseases Research Institute (H.Z., R.W., Z.T., F.Y., Z.G., X.L., X.J., Y.L.) and Department of Neurology (L.G.), Xuanwu Hospital of Capital Medical University, Beijing, China; Cerebralvascular Diseases Research Laboratory, Beijing Geriatric Medical Research Center, Beijing, China (H.Z., R.W., Z.T., F.Y., Z.G., X.L., X.J., Y.L.); and Key Laboratory of Neurodegenerative Diseases of Ministry of Education and Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing, China (H.Z., R.W., Z.T., F.Y., Z.G., X.L., X.J., Y.L.). yumin111@ccmu.edu.cn jixm@ccmu.edu.cn.
authors.forename: Xunming
authors.initials: X
authors.lastname: Ji
authors.affiliation: From the Cerebrovascular Diseases Research Institute (H.Z., R.W., Z.T., F.Y., Z.G., X.L., X.J., Y.L.) and Department of Neurology (L.G.), Xuanwu Hospital of Capital Medical University, Beijing, China; Cerebralvascular Diseases Research Laboratory, Beijing Geriatric Medical Research Center, Beijing, China (H.Z., R.W., Z.T., F.Y., Z.G., X.L., X.J., Y.L.); and Key Laboratory of Neurodegenerative Diseases of Ministry of Education and Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing, China (H.Z., R.W., Z.T., F.Y., Z.G., X.L., X.J., Y.L.). yumin111@ccmu.edu.cn jixm@ccmu.edu.cn.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Luo
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism*; D057775:Ischemic Postconditioning; D015227:Lipid Peroxidation / Q000502:physiology; D008315:Malondialdehyde / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D015398:Signal Transduction / Q000502:physiology; D013481:Superoxides / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D013481:Superoxides; D008315:Malondialdehyde; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; C409022:PDZ-binding kinase
keywords: T-LAK cell-originated protein kinase; brain ischemia; ischemic postconditioning; oxidative stress