Protective Effects of Fisetin Against 6-OHDA-Induced Apoptosis by Activation of PI3K-Akt Signaling in Human Neuroblastoma SH-SY5Y Cells

Neurochem Res. 2018 Feb;43(2):488-499. doi: 10.1007/s11064-017-2445-z. Epub 2017 Dec 4.

Abstract

6-Hydroxydopamine (6-OHDA) induces the production of reactive oxygen species (ROS) that are associated with various neurodegenerative diseases such as Parkinson's disease. 3,3',4',7-Tetrahydroxyflavone (fisetin), a plant flavonoid has a variety of physiological effects such as antioxidant activity. In this study, we investigated the molecular mechanism of the neuroprotective effects of fisetin against 6-OHDA-induced cell death in human neuroblastoma SH-SY5Y cells. 6-OHDA-mediated cell toxicity was reduced in a fisetin concentration-dependent manner. 6-OHDA-mediated elevation of the expression of the oxidative stress-related genes such as hemeoxygenase-1, NAD(P)H dehydrogenase quinone 1, NF-E2-related factor 2, and γ-glutamate-cysteine ligase modifier was suppressed by fisetin. Fisetin also lowered the ratio of the proapoptotic Bax protein and the antiapoptotic Bcl-2 protein in SH-SY5Y cells. Moreover, fisetin effectively suppressed 6-OHDA-mediated activation of caspase-3 and caspase-9, which leads to the cell death, while, 6-OHDA-induced caspase-3/7 activity was lowered. Furthermore, fisetin activated the PI3K-Akt signaling, which inhibits the caspase cascade, and fisetin-mediated inhibition of 6-OHDA-induced cell death was negated by the co-treatment with an Akt inhibitor. These results indicate that fisetin protects 6-OHDA-induced cell death by activating PI3K-Akt signaling in human neuronal SH-SY5Y cells. This is the first report that the PI3K-Akt signaling is involved in the fisetin-protected ROS-mediated neuronal cell death.

Keywords: 6-OHDA; Caspase; Fisetin; PI3K-Akt; SH-SY5Y cells.

MeSH terms

  • Apoptosis / drug effects*
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Flavonoids / chemistry
  • Flavonoids / pharmacology*
  • Humans
  • Neuroblastoma / drug therapy*
  • Neuroblastoma / metabolism
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology
  • Oxidative Stress / drug effects
  • Oxidopamine / pharmacology*
  • Phosphatidylinositol 3-Kinases / drug effects
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects

Substances

  • Flavonoids
  • Neuroprotective Agents
  • Reactive Oxygen Species
  • Oxidopamine
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • fisetin