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 in vitro 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-3 beta (GSK-3 beta). Inhibition of GSK-3 beta 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-3 beta modulation. This study highlights the potential neuroprotective function of PON2 against cerebral ischemia-reperfusion injury.

Automated summary

PON2 plays a crucial role in protecting neurons against oxidative stress induced by cerebral ischemia-reperfusion injury. Upregulation of PON2 improves neuronal viability, reduces apoptosis, and attenuates reactive oxygen species levels under oxidative stress. PON2 achieves this neuroprotective effect by potentiating Nrf2 activation through modulation of GSK-3 beta.