Bisperoxovandium (pyridin-2-squaramide) targets both PTEN and ERK1/2 to confer neuroprotection

Autor:	Ze-Fen Wang, Hua-Bao Liao, Qi Wan, Zhi-Qiang Li, Zhi-Feng Zhang, Xin Han, Wei-Jing Liao, Juan Chen, Hai-Bing Zhou, Jincao Chen, Ya Zhang, Fang Liu, Rui-Xue Lei, Yang Zhuang
Rok vydání:	2017
Předmět:	0301 basic medicine Pharmacology Programmed cell death viruses Phosphatase biochemical phenomena metabolism and nutrition Biology medicine.disease Virology Neuroprotection Brain ischemia 03 medical and health sciences 030104 developmental biology 0302 clinical medicine In vivo biology.protein medicine Tensin PTEN Protein kinase B 030217 neurology & neurosurgery
Zdroj:	British Journal of Pharmacology. 174:641-656
ISSN:	0007-1188
Popis:	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.
Databáze:	OpenAIRE
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