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Bisperoxovandium (pyridin-2-squaramide) targets both PTEN and ERK1/2 to confer neuroprotection
Zhi-Feng Zhang1,2, Juan Chen1,3, Xin Han4
1Department of Physiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences, Wuhan University School of Medicine, Wuhan, China.
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.
Insights
A novel compound, bpV(pis), protects brain cells from injury by inhibiting PTEN and activating ERK1/2. This dual action makes bpV(pis) a promising drug candidate for treating stroke and cerebral ischemia.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Inhibiting phosphatase and tensin homolog deleted on chromosome 10 (PTEN) or activating ERK1/2 confers neuroprotection.
- Bisperoxovanadium compounds are known PTEN inhibitors.
Purpose of the Study:
- To design and evaluate the neuroprotective effects of a novel bisperoxovanadium compound, bpV(pis), in cerebral ischemia-reperfusion injury.
- To elucidate the mechanisms underlying bpV(pis)-mediated neuroprotection.
Main Methods:
- PTEN activity was measured using a phosphatase assay.
- Western blot was used to assess Akt and ERK1/2 phosphorylation.
- In vitro neuroprotection was evaluated using oxygen-glucose deprivation (OGD) in cultured neurons.
- In vivo studies involved middle cerebral artery occlusion in rats to assess infarct volume and neurological function.
Main Results:
- bpV(pis) inhibited PTEN activity and increased Akt phosphorylation in a PTEN-dependent manner.
- bpV(pis) increased ERK1/2 phosphorylation independently of PTEN.
- bpV(pis) reduced OGD-induced neuronal death in vitro and decreased brain infarct volume and improved functional recovery in vivo.
- The neuroprotective effects were blocked by inhibiting Akt and/or ERK1/2.
Conclusions:
- bpV(pis) confers neuroprotection by suppressing PTEN and activating ERK1/2, acting as a bi-target neuroprotectant.
- bpV(pis) shows potential as a therapeutic drug candidate for stroke treatment.
