Neural stem cells neuroprotection by simvastatin via autophagy induction and apoptosis inhibition.

ABSTRACT

OBJECTIVE: This study was conducted to investigate the effects of Simvastatin (SIM), a member of statin family, on the cellular antioxidant system, autophagy and apoptosis in NSCs exposed to hydrogen peroxide. BACKGROUND: Reduction in cellular oxidative stress increases the survival of neural stem cells (NSCs) after transplantation into the damaged area of the affected central nervous system. MATERIAL AND METHODS: NSCs derived from bone marrow stromal cells (BMSCs) were exposed to H2O2 (100 µM) for 48 hours after pretreatment with SIM (2 µM). Next, the expressions of the master antioxidant transcription factor, Nrf2/nuclear factor erythroid 2 (NFE2)-related factor 2, autophagy-related proteins (microtubule-associated proteins 1A/1B light chain 3B known as LC3I and LC3II and also p62/Sequestosome), and apoptosis (Bcl-2/ B-cell lymphoma 2 and Bax/BCL2 associated X protein) were analyzed. RESULTS: SIM caused Nrf2 over-activation (more localizations in the cellular nucleus), reduction in reactive oxygen species (ROS), induction of autophagy (decrease in p62 expression and increase in LC3II/LC3I ratio) and inhibition of apoptosis (decrease in Bax protein and increase in Bcl-2) in NSCs exposed to H2O2-induced oxidative stress, thereby prolonging the cell viability within 48 hours at low concentration (2 µM). CONCLUSION: SIM protects NSCs against H2O2-induced apoptosis in a pleiotropic signaling manner (Fig. 7, Ref. 35).