title: 3,4-dihydroxybenzalacetone protects against Parkinson's disease-related neurotoxin 6-OHDA through Akt/Nrf2/glutathione pathway.
abstract: 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
  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.
authors: School of Natural System Bioengineering Course, College of Science and Engineering, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors: Kei
authors: K
authors: Gunjima
authors: Ryoichi
authors: R
authors: Tomiyama
authors: Ken
authors: K
authors: Takakura
authors: Takashi
authors: T
authors: Yamada
authors: Koji
authors: K
authors: Hashida
authors: Yutaka
authors: Y
authors: Nakamura
authors: Tetsuya
authors: T
authors: Konishi
authors: Seiichi
authors: S
authors: Matsugo
authors: Osamu
authors: O
authors: Hori
mesh_terms: D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002109:Caffeic Acids / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D016627:Oxidopamine / Q000633:toxicity*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C546059:3,4-dihydroxybenzalacetone; D002109:Caffeic Acids; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D018696:Neuroprotective Agents; D009498:Neurotoxins; D017382:Reactive Oxygen Species; D019328:Buthionine Sulfoximine; D016627:Oxidopamine; D051057:Proto-Oncogene Proteins c-akt; D005978:Glutathione; C040048:caffeic acid
keywords: GLUTATHIONE; NEURONAL DEATH; PARKINSON'S DISEASE