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Bisperoxovandium (pyridin‐2‐squaramide) targets both PTEN and ERK1/2 to confer neuroprotection
Author(s) -
Zhang ZhiFeng,
Chen Juan,
Han Xin,
Zhang Ya,
Liao HuaBao,
Lei RuiXue,
Zhuang Yang,
Wang ZeFen,
Li Zhiqiang,
Chen JinCao,
Liao WeiJing,
Zhou HaiBing,
Liu Fang,
Wan Qi
Publication year - 2017
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13727
Subject(s) - pten , tensin , neuroprotection , protein kinase b , pi3k/akt/mtor pathway , phosphatase , biology , viability assay , pharmacology , cancer research , chemistry , apoptosis , medicine , phosphorylation , microbiology and biotechnology , signal transduction , biochemistry
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.