PTEN Inhibition Protects Against Experimental Intracerebral Hemorrhage-Induced Brain Injury Through PTEN/E2F1/ß-Catenin Pathway.

ABSTRACT

Intracerebral hemorrhage (ICH) is a subtype of stroke with highest mortality and morbidity. We have previously demonstrated that dipotassium bisperoxo (picolinato) oxovanadate (V), (bpV[pic]) inhibits phosphatase and tensin homolog (PTEN) and activates extracellular signal-regulated kinase (ERK)1/2. In this study, we examined the effect of bpV[pic] in the rat ICH model in vivo and the hemin-induced injury model in rat cortical cultures. The rat model of ICH was created by injecting autologous blood into the striatum, and bpV[pic] was intraperitoneally injected. The effects of bpV[pic] were evaluated by neurological tests, Fluoro-Jade C (FJC) staining, and Nissl staining. We demonstrate that bpV[pic] attenuates ICH-induced brain injury in vivo and hemin-induced neuron injury in vitro. The expression of E2F1 was increased, but ß-catenin expression was decreased after ICH, and the altered expressions of E2F1 and ß-catenin after ICH were blocked by bpV[pic] treatment. Our results further show that bpV[pic] increases ß-catenin expression through downregulating E2F1 in cortical neurons and prevents hemin-induced neuronal damage through E2F1 downregulation and subsequent upregulation of ß-catenin. By testing the effect of PTEN-siRNA, PTEN cDNA, or combined use of ERK1/2 inhibitor and bpV[pic] in cultured cortical neurons after hemin-induced injury, we provide evidence suggesting that PTEN inhibition by bpV[pic] confers neuroprotection through E2F1 and ß-catenin pathway, but the neuroprotective role of ERK1/2 activation by bpV[pic] cannot be excluded.