Abstract
Recently, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) have nuclear localization and nuclear exclusion signals and shuttle between the cytoplasm and the nucleus. Thus, we hypothesised that astragaloside IV (AS-IV) induction nuclear import of Nrf2 and ferulic acid (FA) inhibition nuclear export of Nrf2 contribute to synergistic antioxidant effects of combination of FA and AS-IV (FA/AS-IV). Here, we have demonstrated that FA/AS-IV enhances neurite outgrowth of PC12 cells challenged with lead acetate (PbAc) via antioxidant properties in a synergistic manner. Concomitantly, FA/AS-IV significantly promotes Nrf2 activation and induces "phase-II'' enzymes during PbAc toxicity, compared with either FA or AS-IV alone. Interestingly, FA but not AS-IV activates the extracellular signal-regulated kinases 1 and 2 (ERK1/2), leading to an increase in both de novo synthesis of Nrf2 and nuclear import of Nrf2. Simultaneously, AS-IV but not FA suppresses Fyn phosphorylation via Akt-mediated inhibition of GSK-3β, which inhibited nuclear export of Nrf2. Importantly, dual activation of both ERK1/2 and Akt by FA/AS-IV in PC12 cells challenged with PbAc is mediated by independent mechanisms, which are supported by pharmacological inhibitors. Collectively, these results support the notion that the FA/AS-IV may be promising in therapy for lead developmental neurotoxicity. This combination deserves further study in vivo.