Potential roles of PI3K/Akt and Nrf2-Keap1 pathways in regulating hormesis of Z-ligustilide in PC12 cells against oxygen and glucose deprivation

Many phytochemicals may ameliorate neurological disorders through a hormetic mechanism. The aim of this study was to characterize the hormetic role of Z-ligustilide in PC12 cells against oxygen glucose deprivation (OGD) induced cell death. We examined the interactions of Z-ligustilide with the pro-survival signals mediated by phosphatidylinositol 3-kinase (PI3K) and transcription factor nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) pathways. We also investigated the effect of Z-ligustilide on the intracellular redox signaling system involving reactive oxygen species (ROS) and glutathione (GSH). Z-ligustilide not only triggered stress response by causing ROS formation and transient GSH depletion, but also activated survival-promoting signals via cross-talking of PI3K and Nrf2 pathways. A key finding was that Z-ligustilide preconditioning protected PC12 cells from OGD-induced injury either at a low concentration for a prolonged period of time or at a high concentration for a short period of time. Presumably, mild preconditioning stimulated moderate ROS production, but effectively activated hormetic signals and induced stress responsive genes. In contrast, higher concentrations of Z-ligustilide could be toxic over a prolonged period of time due to massive ROS production. These results suggest that the effect of Z-ligustilide may be regulated by a biphasic hormetic mechanism involving initial induction of oxidative stress and subsequent activation of stress response gene expression.