Rotundarpene attenuates cholesterol oxidation product-induced apoptosis by suppressing the mitochondrial pathway and the caspase-8- and bid-dependent pathways

Eur J Pharmacol. 2015 Feb 15:749:39-48. doi: 10.1016/j.ejphar.2014.11.048. Epub 2015 Jan 12.

Abstract

The extract of from the barks of Ilex Rotunda Thunb has demonstrated anti-inflammatory and anti-oxidant effects. Nevertheless, the effect of rotundarpene (4-caffeoyl-3-methyl-but-2-ene-1,4-diol) on the neuronal cell death induced by cholesterol oxidation products is unclear. We assessed the preventive effect of rotundarpene on the cholesterol oxidation product-induced apoptosis in neuronal cells using differentiated PC12 cells. 7-Ketocholesterol and 25-hydroxycholesterol induced a decrease in Bid, Bcl-2, Bcl-xL and survivin protein levels, increase in Bax levels, loss of the mitochondrial transmembrane potential, cytochrome c release, activation of caspases (-8, -9 and -3), cleavage of PARP-1 and an increase in the tumor suppressor p53 levels. Rotundarpene attenuated the cholesterol oxidation product-induced changes in the apoptosis-related protein levels, formation of reactive oxygen species, depletion of GSH, nuclear damage and cell death. The results show that rotundarpene may attenuate the cholesterol oxidation product-induced apoptosis in PC12 cells by suppressing the activation of the mitochondrial pathway and the caspase-8- and Bid-dependent pathways. The preventive effect appears to be attributed to its inhibitory effect on the formation of reactive oxygen species and depletion of GSH. Rotundarpene appears to attenuate cholesterol-oxidation product-mediated neuronal degeneration.

Keywords: Apoptosis-related proteins; Cholesterol oxidation product; PC12 cells; Protection; Rotundarpene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • BH3 Interacting Domain Death Agonist Protein / metabolism
  • Caffeic Acids / pharmacology*
  • Caspase 8 / metabolism
  • Cell Survival / drug effects
  • Cholesterol / metabolism
  • Cytochromes c / metabolism
  • Glutathione / metabolism
  • Hemiterpenes / pharmacology*
  • Ketocholesterols
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Neurons / drug effects*
  • Neurons / metabolism
  • Oxidation-Reduction
  • PC12 Cells
  • Rats

Substances

  • BH3 Interacting Domain Death Agonist Protein
  • Bid protein, rat
  • Caffeic Acids
  • Hemiterpenes
  • Ketocholesterols
  • rotundarpene
  • Cytochromes c
  • Cholesterol
  • Casp8 protein, rat
  • Caspase 8
  • Glutathione
  • 7-ketocholesterol