Puerarin suppresses MPP+/MPTP-induced oxidative stress through an Nrf2-dependent mechanism

Abstract

In this study, we hypothesized that anti-parkinsonian effect of puerarin is attributable to its antioxidant properties via Nrf2-dependent glutathione (GSH) biosynthesis mechanism. Experimentally, we found that puerarin attenuated 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative stress through elevating biosynthetic capacity of GSH in PC12 cells. Mechanistically, puerarin suppressed Fyn phosphorylation by GSK-3β-dependent mechanism in MPP+-challenged PC12 cells. Furthermore, puerarin induced accumulation of Nrf2 in the nucleus via inhibiting its nuclear exclusion. In parallel, puerarin up-regulated antioxidant response element (ARE)-driven catalytic subunits from glutamate cysteine ligase (GCLc) expression at levels of transcription and translation. Most interestingly, pharmacological inhibitor of GSK-3β or Fyn shRNA blocked puerarin-induced Nrf2 activation in MPP+-challenged PC12 cells. Concomitantly, puerarin ameliorated motor deficits and inhibited oxidative stress in the ventral midbrain in MPTP-intoxicated wild-type (WT) mice, but failed to attenuate MPTP neurotoxicity and up-regulate GCLc gene in Nrf2-knockout (Nrf2−/−) mice, suggesting that anti-parkinsonian effect of puerarin was dependent on Nrf2. Additionally, puerarin regulated Fyn and GSK-3β phosphorylation in the ventral midbrain in MPTP-intoxicated WT mice. Collectively, the results of the study provide molecular insights into the potential therapeutic action of puerarin in Parkinson's disease, suggesting that puerarin may be a promising candidate for the treatment of Parkinson's disease.