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3,4‐Dihydroxybenzalacetone Protects Against Parkinson's Disease‐Related Neurotoxin 6‐OHDA Through Akt/Nrf2/Glutathione Pathway

Oxidative stress is implicated in the pathogenesis of various neurodegenerative diseases including Parkinson's disease (PD). 3,4‐Dihydroxybenzalacetone (DBL) is a small catechol‐containing compound isolated from Chaga (Inonotus obliquus [persoon] Pilat), and has been reported to have beneficial bioactivities, including antioxidative, anti‐inflammatory, and anti‐tumorigenic activities, with a relatively low toxicity to normal cells. We, therefore, investigated the neuroprotective activity of DBL against the PD‐related neurotoxin 6‐hydroxydopamine (6‐OHDA). Pretreatment of human neuroblastoma SH‐SY5Y cells with DBL, but not with another Chaga‐derived catechol‐containing compound, caffeic acid, dose‐dependently improved the survival of 6‐OHDA‐treated cells. Although DBL did not reduce 6‐OHDA‐induced reactive oxygen species in the cell‐free system, it promoted the translocation of Nrf2 to the nucleus, activated the transcription of Nrf2‐dependent antioxidative genes, and increased glutathione synthesis in the cells. Buthionine sulfoximine, an inhibitor of glutathione synthesis, but not Sn‐mesoporphyrin IX, a heme oxygenase‐1 inhibitor, or dicoumarol, an NAD(P)H:quinone oxidoreductase 1 inhibitor, abolished the protective effect of DBL against 6‐OHDA. Furthermore, DBL activated stress‐associated kinases such as Akt, ERK, and p38 MAPK, and PI3K or Akt inhibitors, but not ERK, p38, or JNK inhibitors, diminished DBL‐induced glutathione synthesis and protection against 6‐OHDA. These results suggest that DBL activates the Nrf2/glutathione pathway through PI3K/Akt, and improves survival of SH‐SY5Y cells against 6‐OHDA toxicity. J. Cell. Biochem. 115: 151–160, 2014. © 2013 Wiley Periodicals, Inc.