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OBJECTIVE To investigate the neuroprotective role of naringenin and delineate its mechanism of action against 6-hydroxydopamine(6-OHDA)-induced neurotoxicity in models of Parkinsons disease (PD) both in vitro and in vivo.METHODS Using the dopaminergic (DA) toxin 6-OHDA to model PD in SH-SY5Y cells and in C57B1/6 mice, we determined whether naringenin protects against 6-OHDA-induced neurotoxicity via activating Nrf2/ARE signaling pathway.RESULTS Naringenin treatment resulted in increase in nuclear factor E2-related factor 2 (Nrf2) protein levels and subsequent activation of antioxidant response element (ARE) pathway genes in SH-SY5Y cells and in mice.Exposure of SH-SY5Y cells to naringenin provides protection against 6-OHDA-induced oxidative insults.The neuroprotective effect of naringenin against 6-OHDA neurotoxicity was dependent on Nrf2,since treatment with Nrf2 siRNA failed to block against 6-OHDA neurotoxicity and induce Nrf2-dependent cytoprotective genes in SH-SY5Y cells.Oral administration of naringenin resulted in significant protection against 6-OHDA-induced nigrostriatal dopaminergic neurodegeneration and oxidative damage in mice.CONCLUSION Our results indicate that activation of Nrf2/ARE signaling by naringenin is strongly associated with its neuroprotective effects against 6-OHDA neurotoxicity and suggest that targeting the Nrf2/ARE pathway is a promising approach for therapeutic intervention in PD.