title: Bisperoxovandium (pyridin-2-squaramide) targets both PTEN and ERK1/2 to confer neuroprotection.
abstract: We and others have shown that inhibiting phosphatase and tensin homolog deleted on chromosome 10 (PTEN) or activating ERK1/2 confer neuroprotection. As bisperoxovanadium compounds are well-established inhibitors of PTEN, we designed bisperoxovandium (pyridin-2-squaramide) [bpV(pis)] and determined whether and how bpV(pis) exerts a neuroprotective effect in cerebral ischaemia-reperfusion injury.
  
  
  
  Malachite green-based phosphatase assay was used to measure PTEN activity. A western blot assay was used to measure the phosphorylation level of Akt and ERK1/2 (p-Akt and p-ERK1/2). Oxygen-glucose deprivation (OGD) was used to injure cultured cortical neurons. Cell death and viability were assessed by LDH and MTT assays. To verify the effects of bpV(pis) in vivo, Sprague-Dawley rats were subjected to middle cerebral artery occlusion, and brain infarct volume was measured and neurological function tests performed.
  
  
  
  bpV(pis) inhibited PTEN activity and increased p-Akt in SH-SY5Y cells but not in PTEN-deleted U251 cells. bpV(pis) also elevated p-ERK1/2 in both SH-SY5Y and U251 cells. These data indicate that bpV(pis) enhances Akt activation through PTEN inhibition but increases ERK1/2 activation independently of PTEN signalling. bpV(pis) prevented OGD-induced neuronal death in vitro and reduced brain infarct volume and promoted functional recovery in stroke animals. This neuroprotective effect of bpV(pis) was blocked by inhibiting Akt and/or ERK1/2.
  
  
  
  bpV(pis) confers neuroprotection in OGD-induced injury in vitro and in cerebral ischaemia in vivo by suppressing PTEN and activating ERK1/2. Thus, bpV(pis) is a bi-target neuroprotectant that may be developed as a drug candidate for stroke treatment.
authors.affiliation: Department of Physiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences, Wuhan University School of Medicine, Wuhan, China.|Department of Physiology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China.
authors.forename: Zhi-Feng
authors.initials: ZF
authors.lastname: Zhang
authors.affiliation: Department of Physiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences, Wuhan University School of Medicine, Wuhan, China.|Department of Neurology, the Central Hospital of Wuhan, Tongji Medical College of Huazhong University of Science & Technology, Wuhan, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Chen
authors.affiliation: School of Pharmacy, Wuhan University, Wuhan, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Physiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences, Wuhan University School of Medicine, Wuhan, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Physiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences, Wuhan University School of Medicine, Wuhan, China.
authors.forename: Hua-Bao
authors.initials: HB
authors.lastname: Liao
authors.affiliation: Department of Physiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences, Wuhan University School of Medicine, Wuhan, China.
authors.forename: Rui-Xue
authors.initials: RX
authors.lastname: Lei
authors.affiliation: Department of Physiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences, Wuhan University School of Medicine, Wuhan, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhuang
authors.affiliation: Department of Physiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences, Wuhan University School of Medicine, Wuhan, China.
authors.forename: Ze-Fen
authors.initials: ZF
authors.lastname: Wang
authors.affiliation: Brain Centre, Zhongnan Hospital, Wuhan University School of Medicine, Wuhan, China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Brain Centre, Zhongnan Hospital, Wuhan University School of Medicine, Wuhan, China.
authors.forename: Jin-Cao
authors.initials: JC
authors.lastname: Chen
authors.affiliation: Brain Centre, Zhongnan Hospital, Wuhan University School of Medicine, Wuhan, China.
authors.forename: Wei-Jing
authors.initials: WJ
authors.lastname: Liao
authors.affiliation: School of Pharmacy, Wuhan University, Wuhan, China.
authors.forename: Hai-Bing
authors.initials: HB
authors.lastname: Zhou
authors.affiliation: Campbell Research Institute, Centre for Addiction and Mental Health, and Departments of Psychiatry, University of Toronto, Toronto, ON, Canada.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Physiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences, Wuhan University School of Medicine, Wuhan, China.|Brain Centre, Zhongnan Hospital, Wuhan University School of Medicine, Wuhan, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wan
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D017968:Vanadium Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D017968:Vanadium Compounds; C472777:bisperoxovanadium; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D005947:Glucose; D010100:Oxygen