Loss of PHLDA1 has a protective role in OGD/R-injured neurons via regulation of the GSK-3β/Nrf2 pathway

Abstract

Pleckstrin homology-like domain, family A, member 1 (PHLDA1) is a multifunctional protein that plays a role in diverse pathological conditions. However, whether PHLDA1 participates in cerebral ischemia-reperfusion injury has not been reported. The goals of the present work were to assess the possible relationship between PHLDA1 and cerebral ischemia-reperfusion injury. Hippocampal neurons were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to simulate cerebral ischemia-reperfusion injury in vitro, which led to significant increases in the expression of PHLDA1. Cellular functional studies showed that the knockdown of PHLDA1 produced a protective role in OGD/R-injured neurons via the down-regulation of neuronal apoptosis, oxidative stress and proinflammatory cytokine release. On the contrary, the overexpression of PHLDA1 rendered neurons more vulnerable to OGD/R injury. In-depth research revealed that the inhibition of PHLDA1 resulted in the enhancement of nuclear factor erythroid 2 like 2 (Nrf2) signaling in OGD/R-injured neurons. The reactivation of glycogen synthase kinase 3β (GSK-3β) abolished the PHLDA1-inhibition-mediated activation of Nrf2 signaling. Moreover, the restraint of Nrf2 signaling diminished the PHLDA1-knockdown-induced neuroprotective effects in OGD/R-injured neurons. In summary, the data of our work show that the loss of PHLDA1 protects against OGD/R injury via potentiating Nrf2 signaling via the regulation of GSK-3β. This work underscores a potential role of PHLDA1 in cerebral ischemia-reperfusion injury and proposes PHLDA1 as an attractive target for the development of neuroprotective therapy.