3,4-dihydroxybenzalacetone protects against Parkinson's disease-related neurotoxin 6-OHDA through Akt/Nrf2/glutathione pathway

J Cell Biochem. 2014 Jan;115(1):151-60. doi: 10.1002/jcb.24643.


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.


Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Buthionine Sulfoximine / pharmacology
  • Caffeic Acids / pharmacology*
  • Cell Line, Tumor / drug effects
  • Dose-Response Relationship, Drug
  • Glutathione / metabolism*
  • Humans
  • NF-E2-Related Factor 2 / metabolism*
  • Neuroblastoma / drug therapy
  • Neuroblastoma / metabolism
  • Neuroprotective Agents / pharmacology*
  • Neurotoxins / toxicity
  • Oxidative Stress / drug effects
  • Oxidopamine / toxicity*
  • Parkinson Disease / drug therapy*
  • Parkinson Disease / metabolism
  • Protein Transport / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Reactive Oxygen Species / metabolism


  • 3,4-dihydroxybenzalacetone
  • Caffeic Acids
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Neuroprotective Agents
  • Neurotoxins
  • Reactive Oxygen Species
  • Buthionine Sulfoximine
  • Oxidopamine
  • Proto-Oncogene Proteins c-akt
  • Glutathione
  • caffeic acid