Abstract
The aim of the present study was to examine the neuroprotective effects of a panel of active components of ginseng and to explore their molecular mechanisms of action in two rotenone (Rot)‑induced models of Parkinson's disease: An in vitro model using the human neuroblastoma cell line SH‑SY5Y and an in vivo model using Drosophila. Ginsenoside Re (Re) was identified as the most potent inhibitor of Rot‑induced cytotoxicity in SH‑SY5Y cells by Cell Counting kit‑8 assay and lactate dehydrogenase release assay. Flow cytometry, Hoechst staining, Rhodamine 123 staining, ATP and cytochrome c release revealed that Re rescue of Rot‑induced mitochondrial dysfunction and inhibition of the mitochondrial apoptotic pathway. Western blot analysis demonstrated that Re alleviated Rot‑induced oxidative stress by activating the nuclear factor erythroid 2‑related factor 2 (Nrf2) anti‑oxidant pathway, and these effects were abolished by RNA interference‑mediated knockdown of Nrf2. Re enhanced phosphorylation of components of the phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (AKT) and extracellular regulated protein kinase (ERK) pathways, and pharmacological inhibition of these pathways reduced Re‑mediated Nrf2 activation and neuroprotection. In the Drosophila model, Immunofluorescence microscopy, reactive oxygen species (ROS), hydrogen peroxide and knockdown analysis revealed that Re reversed Rot‑induced motor deficits and dopaminergic neuron loss while concomitantly alleviating Rot‑induced oxidative damage. The findings of the present study suggest that Re protects neurons against Rot‑induced mitochondrial dysfunction and oxidative damage, at least in part, by inducing Nrf2/heme oxygenase‑1 expression and activation of the dual PI3K/AKT and ERK pathways.