Paraoxonase 2 protects against oxygen-glucose deprivation/reoxygenation-induced neuronal injury by enhancing Nrf2 activation via GSK-3β modulation.

Paraoxonase 2 (PON2) is a powerful antioxidant that mediates cell survival under oxidative stress; however, its protection neurons against cerebral ischemia-reperfusion injury-induced oxidative stress remains unclear. This study aimed to determine the precise regulating role of PON2 in neuronal survival under oxidative stress. An model of cerebral ischemia-reperfusion injury was used to assess the effect of PON2 on oxidative stress induced by oxygen-glucose deprivation/reoxygenation (OGD/R). Results showed that PON2 expression in neurons was decreased due to OGD/R exposure. A series of functional experiments revealed that upregulated PON2 improved OGD/R-impaired viability and attenuated OGD/R-induced increases in apoptosis and reactive oxygen species in neurons. Decreased PON2 expression enhanced neuronal sensitivity to OGD/R-induced injury. Overexpressed PON2 markedly enhanced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) in the nucleus and increased the levels of Nrf2-mediated transcriptional activity. Furthermore, PON2 enhanced the Nrf2 activation by modulating glycogen synthase kinase-3β (GSK-3β). Inhibition of GSK-3β substantially abrogated the PON2 knockdown-mediated suppression of Nrf2 activity. Notably, Nrf2 inhibition partially reversed the neuroprotective effects of PON2 overexpression in OGD/R-exposed neurons. These findings indicate that PON2 alleviates OGD/R-induced apoptosis and oxidative stress in neurons by potentiating Nrf2 activation via GSK-3β modulation. This study highlights the potential neuroprotective function of PON2 against cerebral ischemia-reperfusion injury.