ERK 1/2 Activation Mediates the Neuroprotective Effect of BpV(pic) in Focal Cerebral Ischemia–Reperfusion Injury

Abstract

Bisperoxovanadium (pyridine-2-carboxyl) [bpV(pic)] is a commercially available PTEN inhibitor. Previous studies from us and others have shown that bpV(pic) confers neuroprotection in cerebral ischemia injury. We set up to determine whether ERK 1/2 activation plays a role in bpV(pic)-induced neuroprotective effect in cerebral ischemia injury. We found that the phosphorylation levels of Akt (p-AKT) and ERK1/2 (p-ERK 1/2) were down-regulated after cerebral ischemia–reperfusion injury. The injection of bpV(pic) after injury not only increased the level of p-AKT but also the level of p-ERK 1/2. While the inhibition of PTEN mediated the up-regulatation of p-AKT and p-ERK 1/2 by bpV(pic). Interestingly, the ERK 1/2 activation induced by bpV(pic) was also independent of the inhibition of PTEN. Our results indicate that bpV(pic) protects against OGD-induced neuronal death and promotes the functional recovery of stroke animals through PTEN inhibition and ERK 1/2 activation, respectively. This study suggests that the effect of bpV(pic) on ERK 1/2 signaling should be considered while using bpV(pic) as a PTEN inhibitor.Electronic supplementary materialThe online version of this article (10.1007/s11064-018-2558-z) contains supplementary material, which is available to authorized users.

Selectivity, efficacy and toxicity studies of UCCB01-144, a dimeric neuroprotective PSD-95 inhibitor

“…Here, we observed that the amount of p-ERK, which is upstream to pro-survival CREB (Hardingham, 2006;Hu et al, 2000;Lai et al, 2014), was higher in UCCB01-144treated animals compared to that in saline-and Tat-NR2B9c-treated groups. Likewise, other studies of cerebral ischemia report that p-ERK upregulation correlates with the efficacy of various neuroprotectants (Sawe et al, 2008), such as a bisperoxovanadium phosphatase and tensin homolog (PTEN) inhibitor (Liu et al, 2018), leptin (Zhang and Chen, 2008), and combination treatment with progesterone and vitamin D (Atif et al, 2013). By pharmacological inhibition of ERK1/2, the neuroprotective effects of the PTEN inhibitor and leptin was shown to be mediated by ERK1/2.…”

<p>The neuroprotective effect of bisperoxovandium (pyridin-2-squaramide) in intracerebral hemorrhage</p>

“…It has been reported that different vanadium compounds inhibit PTEN and also activate AKT and ERK1/2 21. The neuroprotective effects of bisperoxovandium on cerebral ischemia through ERK1/2 and AKT activations were shown by our group, and also others 22,23. To develop a new compound that may have more effective neuroprotection, we have designed and synthesized a new compound, bpV(pis), which inhibits the activity of PTEN and enhances ERK1/2 activation 20.…”

A novel squaramide compound alleviates cognitive deficits through activation of Akt and Erk1/2 in a rat model of vascular dementia

“…Some compounds derivatized from squaramide are known to be characteristically highly activated, exhibit strong stability, low cost and easy synthesis. Additionally, it has been reported that phosphatase and tension homolog deleted on chromosome ten (PTEN) inhibition induces neuroprotection in ischemic stroke (Liu et al, 2010(Liu et al, , 2018 and bisperoxovanadium compounds not only inhibit phosphatase activity of PTEN (Schmid et al, 2004), but also increases the protein kinase activity of Akt (Stambolic et al, 1998). Hence, the novel squaramide compound, bpV(pis), was designed and synthesized including the two compounds of pyridine-2-squaramide and V2O5.…”

“…Erk1/2 is activated by a series of phosphorylation cascades of the MAPK/ERK pathway. Increasing evidence shows that Erk1/2, to some extent, enhances neuronal survival and reduces neuronal apoptosis in an animal model of VD (Chan, 2004;Chen et al, 2018a;Hu et al, 2017;Lin et al, 2015;Wang et al, 2014;Zhang et al, 2018). Hence, PI3K/Akt and MAPK/ERK pathways may become promising targets for the development of treatments for VD.…”