2-Ethoxy-4,5-diphenyl-1,3-oxazine-6-one activates the Nrf2/HO-1 axis and protects against oxidative stress-induced neuronal death

Eur J Pharmacol. 2011 May 11;658(2-3):84-90. doi: 10.1016/j.ejphar.2011.02.028. Epub 2011 Mar 1.

Abstract

Apoptosis or programmed cell death has been suggested as an important mode of neurodegeneration in Alzheimer's disease pathogenesis. The present study explored the neuroprotective effect of 2-ethoxy-4,5-diphenyl-1,3-oxazine-6-one (EDPOO) against H(2)O(2)-induced cell death in rat pheochromocytoma (PC12) cells. We found that H(2)O(2) triggered a range of cellular cascades which leads to cell death, whereas pretreatment of the cells with this oxazine derivative attenuated the extent of apoptosis, as assessed by MTT assay, acridine orange/ethidium bromide staining and caspase-3 expression assay. We further showed that EDPOO exerts its neuroprotective effect by enhancing Hsp-70 level, stabilizing Nrf2 and upregulation of HO-1 and γ-GCS. Moreover, this oxazine derivative regulated cellular redox status via antioxidant enzyme upregulation. The neuroprotective effect of this compound may provide a new potential application for the treatment of neurodegenerative diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Apoptosis / drug effects
  • Caspase 3 / metabolism
  • Cell Death / drug effects*
  • Enzyme Activation / drug effects
  • Enzyme Induction / drug effects
  • Gene Expression Regulation / drug effects
  • Glutamate-Cysteine Ligase / metabolism
  • HSP70 Heat-Shock Proteins / metabolism
  • Heme Oxygenase-1 / biosynthesis
  • Heme Oxygenase-1 / metabolism*
  • Hydrogen Peroxide / pharmacology
  • Lipid Peroxidation / drug effects
  • NF-E2-Related Factor 2 / metabolism*
  • Neurons / cytology*
  • Neurons / drug effects*
  • Neurons / enzymology
  • Neurons / metabolism
  • Oxazines / pharmacology*
  • Oxidative Stress / drug effects*
  • PC12 Cells
  • Protein Stability / drug effects
  • Rats

Substances

  • 2-ethoxy-4,5-diphenyl-1,3-oxazine-6-one
  • Antioxidants
  • HSP70 Heat-Shock Proteins
  • NF-E2-Related Factor 2
  • Oxazines
  • Hydrogen Peroxide
  • Heme Oxygenase-1
  • Caspase 3
  • Glutamate-Cysteine Ligase