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

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.

• Authors: Kei Gunjima, Ryoichi Tomiyama, Ken Takakura, Takashi Yamada, Koji Hashida, Yutaka Nakamura, Tetsuya Konishi, Seiichi Matsugo, Osamu Hori
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 115 Issue 1 Pg. 151-60 (Jan 2014) ISSN: 1097-4644 [Electronic] United States
• PMID: 23959789 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 Wiley Periodicals, Inc.

Chemical References

• 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

Topics

• 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, metabolism)
• Neuroprotective Agents (pharmacology)
• Neurotoxins (toxicity)
• Oxidative Stress (drug effects)
• Oxidopamine (toxicity)
• Parkinson Disease (drug therapy, metabolism)
• Protein Transport (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Reactive Oxygen Species (metabolism)