Simvastatin protects neurons from cytotoxicity by up-regulating Bcl-2 mRNA and protein

J Neurochem. 2007 Apr;101(1):77-86. doi: 10.1111/j.1471-4159.2006.04375.x. Epub 2007 Jan 4.


Statins are most commonly prescribed to reduce hypercholesterolemia; however, recent studies have shown that statins have additional benefits, including neuroprotection. Until now, the mechanism underlying statin-induced neuroprotection has been poorly understood. Recent in vivo studies from our lab reported the novel finding that simvastatin increased expression levels of a gene encoding for a major cell survival protein, bcl-2 [Johnson-Anuna et al., J. Pharmacol. Exp. Ther.312 (2005) 786]. The purpose of the present experiments was to determine if simvastatin could protect neurons from excitotoxicity by altering Bcl-2 levels. Neurons were pre-treated with simvastatin and challenged with a compound known to reduce Bcl-2 levels and induce cell death. Simvastatin pre-treatment resulted in a significant reduction in cytotoxicity (lactate dehydrogenase release and caspase 3 activation) following challenge compared with unchallenged neurons. In addition, chronic simvastatin treatment significantly increased Bcl-2 mRNA and protein levels while challenge resulted in a significant reduction in Bcl-2 protein abundance. G3139, an antisense oligonucleotide directed against Bcl-2, abolished the protective effects of simvastatin and eliminated simvastatin-induced up-regulation of Bcl-2 protein. These findings suggest that neuroprotection by simvastatin is dependent on the drug's previously unexplored and important effect of up-regulating Bcl-2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caspase 3 / drug effects
  • Caspase 3 / metabolism
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cell Line, Tumor
  • Cytoprotection / drug effects*
  • Cytoprotection / physiology
  • Cytotoxins / antagonists & inhibitors
  • Humans
  • L-Lactate Dehydrogenase / drug effects
  • L-Lactate Dehydrogenase / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Nerve Degeneration / physiopathology
  • Nerve Degeneration / prevention & control*
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • Oligodeoxyribonucleotides, Antisense / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Simvastatin / pharmacology*
  • Simvastatin / therapeutic use
  • Thionucleotides / pharmacology
  • Up-Regulation / drug effects
  • Up-Regulation / physiology


  • Cytotoxins
  • Neuroprotective Agents
  • Oligodeoxyribonucleotides, Antisense
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger
  • Thionucleotides
  • oblimersen
  • Simvastatin
  • L-Lactate Dehydrogenase
  • Caspase 3