PMID- 28127755 OWN - NLM STAT- MEDLINE DCOM- 20171027 LR - 20210109 IS - 1476-5381 (Electronic) IS - 0007-1188 (Print) IS - 0007-1188 (Linking) VI - 174 IP - 8 DP - 2017 Apr TI - Bisperoxovandium (pyridin-2-squaramide) targets both PTEN and ERK1/2 to confer neuroprotection. PG - 641-656 LID - 10.1111/bph.13727 [doi] AB - BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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. CONCLUSIONS AND IMPLICATIONS: 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. CI - (c) 2017 The British Pharmacological Society. FAU - Zhang, Zhi-Feng AU - Zhang ZF AD - Department of Physiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences, Wuhan University School of Medicine, Wuhan, China. AD - Department of Physiology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China. FAU - Chen, Juan AU - Chen J AD - Department of Physiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences, Wuhan University School of Medicine, Wuhan, China. AD - Department of Neurology, the Central Hospital of Wuhan, Tongji Medical College of Huazhong University of Science & Technology, Wuhan, China. FAU - Han, Xin AU - Han X AD - School of Pharmacy, Wuhan University, Wuhan, China. FAU - Zhang, Ya AU - Zhang Y AD - Department of Physiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences, Wuhan University School of Medicine, Wuhan, China. FAU - Liao, Hua-Bao AU - Liao HB AD - Department of Physiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences, Wuhan University School of Medicine, Wuhan, China. FAU - Lei, Rui-Xue AU - Lei RX AD - Department of Physiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences, Wuhan University School of Medicine, Wuhan, China. FAU - Zhuang, Yang AU - Zhuang Y AD - Department of Physiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences, Wuhan University School of Medicine, Wuhan, China. FAU - Wang, Ze-Fen AU - Wang ZF AD - Department of Physiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences, Wuhan University School of Medicine, Wuhan, China. FAU - Li, Zhiqiang AU - Li Z AD - Brain Centre, Zhongnan Hospital, Wuhan University School of Medicine, Wuhan, China. FAU - Chen, Jin-Cao AU - Chen JC AD - Brain Centre, Zhongnan Hospital, Wuhan University School of Medicine, Wuhan, China. FAU - Liao, Wei-Jing AU - Liao WJ AD - Brain Centre, Zhongnan Hospital, Wuhan University School of Medicine, Wuhan, China. FAU - Zhou, Hai-Bing AU - Zhou HB AD - School of Pharmacy, Wuhan University, Wuhan, China. FAU - Liu, Fang AU - Liu F AD - Campbell Research Institute, Centre for Addiction and Mental Health, and Departments of Psychiatry, University of Toronto, Toronto, ON, Canada. FAU - Wan, Qi AU - Wan Q AD - Department of Physiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences, Wuhan University School of Medicine, Wuhan, China. AD - Brain Centre, Zhongnan Hospital, Wuhan University School of Medicine, Wuhan, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170227 PL - England TA - Br J Pharmacol JT - British journal of pharmacology JID - 7502536 RN - 0 (Enzyme Inhibitors) RN - 0 (Neuroprotective Agents) RN - 0 (Vanadium Compounds) RN - 0 (bisperoxovanadium) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) RN - EC 3.1.3.67 (PTEN Phosphohydrolase) RN - EC 3.1.3.67 (PTEN protein, human) RN - IY9XDZ35W2 (Glucose) RN - S88TT14065 (Oxygen) SB - IM MH - Animals MH - Brain Ischemia/*drug therapy/pathology MH - Cell Death/drug effects MH - Disease Models, Animal MH - Dose-Response Relationship, Drug MH - Enzyme Inhibitors/chemical synthesis/chemistry/*pharmacology MH - Glucose/metabolism MH - Humans MH - Mitogen-Activated Protein Kinase 1/*metabolism MH - Mitogen-Activated Protein Kinase 3/*metabolism MH - Neurons/drug effects/pathology MH - Neuroprotective Agents/chemical synthesis/chemistry/*pharmacology MH - Oxygen/metabolism MH - PTEN Phosphohydrolase/*metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Structure-Activity Relationship MH - Tumor Cells, Cultured MH - Vanadium Compounds/chemical synthesis/chemistry/*pharmacology PMC - PMC5368051 EDAT- 2017/01/28 06:00 MHDA- 2017/10/28 06:00 PMCR- 2018/04/01 CRDT- 2017/01/28 06:00 PHST- 2016/07/24 00:00 [received] PHST- 2017/01/18 00:00 [revised] PHST- 2017/01/21 00:00 [accepted] PHST- 2017/01/28 06:00 [pubmed] PHST- 2017/10/28 06:00 [medline] PHST- 2017/01/28 06:00 [entrez] PHST- 2018/04/01 00:00 [pmc-release] AID - BPH13727 [pii] AID - 10.1111/bph.13727 [doi] PST - ppublish SO - Br J Pharmacol. 2017 Apr;174(8):641-656. doi: 10.1111/bph.13727. Epub 2017 Feb 27.