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

Abstract

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 simvastatininduced 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.

Simvastatin overcomes the resistance to serum withdrawal-induced apoptosis of lymphocytes from Alzheimer’s disease patients

“…Moreover, statins inhibit the growth of variant human embryonic stem cells and cancer cells in vitro but not the growth of normal human embryonic stem cells [55]. The results described herein are, however, in contrast with the reported neuroprotective effects of statins in neuronal cells [56][57][58]. These effects of statins, protecting neuron from certain noxious stimuli, involve alteration in the ratio of pro and anti apoptotic proteins and inactivation of caspases [59].…”

Impact of Targeting the Adenine- and Uracil-Rich Element of bcl-2 mRNA with Oligoribonucleotides on Apoptosis, Cell Cycle, and Neuronal Differentiation in SHSY-5Y Cells

“…Particularly attractive is the potential application of bcl-2 ARE asORNs to neurodegenerative conditions, in which induction of high level of Bcl-2 protein has already shown therapeutic values (Lawrence et al, 1996). The recent finding that statins are implied in neuroprotection by a bcl-2-dependent mechanism (Johnson-Anuna et al, 2007) further supports our approach. Authors suggest that transcriptional and post-transcriptional mechanisms can be involved in simvastatin-induced up-regulation of bcl-2.…”

“…Furthermore, stabilizing bcl-2 expression could rescue cells committed to apoptosis by hypoxia/ischemia-related stress (Cao et al, 2002). Recently, simvastatin has been found to protect neurons from excitotoxicity by up-regulating bcl-2 mRNA and protein by a still-to-be-clarified mechanism (Johnson-Anuna et al, 2007).…”

Atorvastatin Protects NSC-34 Motor Neurons Against Oxidative Stress by Activating PI3K, ERK and Free Radical Scavenging

“…Furthermore, statins have been proposed as potential treatments for diverse diseases such as certain types of cancer and neurodegenerative disease [28]. Paradoxically, it has been suggested, in the case of cancer, that statins increase apoptosis and alter levels of Bcl-2 family members [29,30] whereas studies mainly using noncancerous cells report the opposite effects [31,32].…”