Abstract
Reactive oxygen species and oxidative stress are associated with various cell processes, including cell survival and apoptosis. Oxidative stress has been implicated in the pathogenesis of several neurological disorders including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and multiple sclerosis (MS). In the present study, we evaluated the effects of lovastatin chemoprotection against hydrogen peroxide-induced oxidative stress in bone marrow stromal cell-derived neural stem cells (BMSC-derived NSCs) and whether it has protective effects. BMSC-derived NSCs were pretreated with different doses of lovastatin for 48 h and then exposed to 125 μM H2O2 for 30 min. Using MTT, TUNEL assay, and real-time RT-PCR, we evaluated the effects of lovastatin on cell survival, apoptosis, and PGC-1α and Nrf2 expression rates in pretreated BMSC-derived NSCs compared to control groups. Results showed that apoptosis rate in the lovastatin-pretreated BMSC-derived NSCs was significantly decreased compared to the control group. Our findings suggest that lovastatin protects NSCs against oxidative stress-induced cell death, and therefore, it may be used to promote the survival rate of NSCs and can be a candidate for treatment of oxidative stress-mediated neurological diseases.
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Di Carlo M, Giacomazza D, Picone P, Nuzzo D, San Biagio PL (2012) Are oxidative stress and mitochondrial dysfunction the key players in the neurodegenerative diseases? Free Radic Res 46:1327–1338
Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443(7113):787–795
Gilgun-Sherki Y, Melamed E, Offen D (2001) Oxidative stress induced-neurodegenerative diseases: the need for antioxidants that penetrate the blood brain barrier. Neuropharmacology 40(8):959–975
Crunkhorn S (2011) Neurodegenerative disorders: restoring the balance. Nat Rev Drug Discov 10(8):576
Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ (2004) Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Arterioscler Thromb Vasc Biol 24(8):e149–e161
Schachter M (2005) Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol 19:117–125
Huang W, Shang WL, Li DH, Wu WW, Hou SX (2012) Simvastatin protects osteoblast against H2O2-induced oxidative damage via inhibiting the upregulation of Nox4. Mol Cell Biochem 360(1–2):71–77
Laks DR, Masterman-Smith M, Visnyei K, Angenieux B, Orozco NM, Foran I, Yong WH, Vinters HV, Liau LM, Lazareff JA, Mischel PS, Cloughesy TF, Horvath S, Kornblum HI (2009) Neurosphere formation is an independent predictor of clinical outcome in malignant glioma. Stem Cells 27(4):980–987
Yang Q, Mu J, Li Q, Li A, Zeng Z, Yang J, Zhang X, Tang J, Xie P (2008) A simple and efficient method for deriving neurospheres from bone marrow stromal cells. Biochem Biophys Res Commun 372(4):520–524
Radad K, Rausch WD, Gille G (2006) Rotenone induces cell death in primary dopaminergic culture by increasing ROS production and inhibiting mitochondrial respiration. Neurochem Int 49:379–386
Yuan JS, Reed A, Chen F, Stewart CN Jr (2006) Statistical analysis of real-time PCR data. BMC Bioinformatics 7:85
Chen PS, Cheng CL, Kao Yang YH, Yeh PS, Li YH (2013) Impact of early statin therapy in patients with ischemic stroke or transient ischemic attack. Acta Neurol Scand 129:41–48
Ghosh A, Roy A, Matras J, Brahmachari S, Gendelman HE, Pahan K (2009) Simvastatin inhibits the activation of p21ras and prevents the loss of dopaminergic neurons in a mouse model of Parkinson's disease. J Neurosci 29:13543–13556
Roy A, Pahan K (2011) Prospects of statins in Parkinson disease. Neuroscientist 17:244–255
Neuhaus O, Strasser-Fuchs S, Fazekas F, Kieseier BC, Niederwieser G, Hartung HP, Archelos JJ (2002) Statins as immunomodulators: comparison with interferon-beta 1b in MS. Neurology 59(7):990–997
Darlington CL (2005) The potential role for statins in the treatment of multiple sclerosis. Curr Opin Investig Drugs 6:667–671
Silva T, Teixeira J, Remiao F, Borges F (2013) Alzheimer's disease, cholesterol, and statins: the junctions of important metabolic pathways. Angew Chem Int Ed Engl 52:1110–1121
Sparks DL (2011) Alzheimer disease: statins in the treatment of Alzheimer disease. Nat Rev Neurol 7:662–663
Chen J, Zhang C, Jiang H, Li Y, Zhang L, Robin A, Katakowski M, Lu M, Chopp M (2005) Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice. J Cereb Blood Flow Metab 25(2):281–290
Chen J, Zhang ZG, Li Y, Wang Y, Wang L, Jiang H, Zhang C, Lu M, Katakowski M, Feldkamp CS, Chopp M (2003) Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. Ann Neurol 53(6):743–751
Dolga AM, Nijholt IM, Ostroveanu A, Ten Bosch Q, Luiten PG, Eisel UL (2008) Lovastatin induces neuroprotection through tumor necrosis factor receptor 2 signaling pathways. J Alzheimers Dis 13:111–122
Dolga AM, Granic I, Nijholt IM, Nyakas C, van der Zee EA, Luiten PG, Eisel UL (2009) Pretreatment with lovastatin prevents N-methyl-D-aspartate-induced neurodegeneration in the magnocellular nucleus basalis and behavioral dysfunction. J Alzheimers Dis 17(2):327–336
Salins P, Shawesh S, He Y, Dibrov A, Kashour T, Arthur G, Amara F (2007) Lovastatin protects human neurons against Abeta-induced toxicity and causes activation of beta-catenin-TCF/LEF signaling. Neurosci Lett 412(3):211–216
Jin Y, Sui HJ, Dong Y, Ding Q, Qu WH, Yu SX, Jin YX (2012) Atorvastatin enhances neurite outgrowth in cortical neurons in vitro via up-regulating the Akt/mTOR and Akt/GSK-3β signaling pathways. Acta Pharmacol Sin 33(7):861–872
Wu H, Mahmood A, Qu C, Xiong Y, Chopp M (2012) Simvastatin attenuates axonal injury after experimental traumatic brain injury and promotes neurite outgrowth of primary cortical neurons. Brain Res 1486:121–130
Marz P, Otten U, Miserez AR (2007) Statins induce differentiation and cell death in neurons and astroglia. Glia 55:1–12
Xiang Z, Reeves SA (2009) Simvastatin induces cell death in a mouse cerebellar slice culture (CSC) model of developmental myelination. Exp Neurol 215:41–47
Chen SD, Yang DI, Lin TK, Shaw FZ, Liou CW, Chuang YC (2011) Roles of oxidative stress, apoptosis, PGC-1alpha and mitochondrial biogenesis in cerebral ischemia. Int J Mol Sci 12:7199–7215
Gleyzer N, Vercauteren K, Scarpulla RC (2005) Control of mitochondrial transcription specificity factors (TFB1M and TFB2M) by nuclear respiratory factors (NRF-1 and NRF-2) and PGC-1 family coactivators. Mol Cell Biol 25:1354–1366
Uttara B, Singh AV, Zamboni P, Mahajan RT (2009) Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Curr Neuropharmacol 7(1):65–74
Emerit J, Edeas M, Bricaire F (2004) Neurodegenerative diseases and oxidative stress. Biomed Pharmacother 58(1):39–46
Hernández-Saavedra D, McCord JM (2007) Evolution and free radicals. Importance of oxidative stress in human pathology. Rev Med Inst Mex Seguro Soc 45(5):477–484
Ischiropoulos H, Beckman JS (2003) Oxidative stress and nitration in neurodegeneration: cause, effect, or association? J Clin Invest 111:163–169
Yokota T, Igarashi K, Uchihara T, Jishage K, Tomita H, Inaba A, Li Y, Arita M, Suzuki H, Mizusawa H, Arai H (2001) Delayed-onset ataxia in mice lacking alpha-tocopherol transfer protein: model for neuronal degeneration caused by chronic oxidative stress. Proc Natl Acad Sci U S A 98(26):15185–15190
Sayre LM, Smith MA, Perry G (2001) Chemistry and biochemistry of oxidative stress in neurodegenerative disease. Curr Med Chem 8(7):721–738
Butterfield DA, Kanski J (2001) Brain protein oxidation in age-related neurodegenerative disorders that are associated with aggregated proteins. Mech Ageing Dev 122(9):945–962
Wang W, Wong CW (2010) Statins enhance peroxisome proliferator-activated receptor gamma coactivator-1alpha activity to regulate energy metabolism. J Mol Med (Berl) 88(3):309–317
Lin J, Puigserver P, Donovan J, Tarr P, Spiegelman BM (2002) Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta), a novel PGC-1-related transcription coactivator associated with host cell factor. J Biol Chem 277(3):1645–1648
Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC, Spiegelman BM (1999) Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98:115–124
Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, Igarashi K, Yamamoto M (2004) Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol 24(16):7130–7139
Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 13(1):76–86
Kaspar JW, Niture SK, Jaiswal AK (2009) Nrf2:INrf2 (Keap1) signaling in oxidative stress. Free Radic Biol Med 47:1304–1309
Xu Y, Duan C, Kuang Z, Hao Y, Jeffries JL, Lau GW (2013) Pseudomonas aeruginosa pyocyanin activates NRF2-ARE-mediated transcriptional response via the ROS-EGFR-PI3K-AKT/MEK-ERK MAP kinase signaling in pulmonary epithelial cells. PLoS One 8:e72528
Niture SK, Jaiswal AK (2012) Nrf2 protein up-regulates antiapoptotic protein Bcl-2 and prevents cellular apoptosis. J Biol Chem 287(13):9873–9886
Chen W, Jiang T, Wang H, Tao S, Lau A, Fang D, Zhang DD (2012) Does Nrf2 contribute to p53-mediated control of cell survival and death? Antioxid Redox Signal 17(12):1670–1675
Niture SK, Jaiswal AK (2013) Nrf2-induced antiapoptotic Bcl-xL protein enhances cell survival and drug resistance. Free Radic Biol Med 57:119–131
Vargas MR, Johnson DA, Sirkis DW, Messing A, Johnson JA (2008) Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis. J Neurosci 28:13574–13581
Tufekci KU, Civi Bayin E, Genc S, Genc K (2011) The Nrf2/ARE pathway: a promising target to counteract mitochondrial dysfunction in Parkinson's disease. Park Dis 2011:314082
Kwak MK, Itoh K, Yamamoto M, Kensler TW (2002) Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter. Mol Cell Biol 22:2883–2892
Moi P, Chan K, Asunis I, Cao A, Kan YW (1994) Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci U S A 91(21):9926–9930
Macari ER, Schaeffer EK, West RJ, Lowrey CH (2013) Simvastatin and t-butylhydroquinone suppress KLF1 and BCL11A gene expression and additively increase fetal hemoglobin in primary human erythroid cells. Blood 121(5):830–839
Habeos IG, Ziros PG, Chartoumpekis D, Psyrogiannis A, Kyriazopoulou V, Papavassiliou AG (2008) Simvastatin activates Keap1/Nrf2 signaling in rat liver. J Mol Med (Berl) 86(11):1279–1285
Acknowledgments
The project was funded by Ardabil Branch, Islamic Azad University, Ardabil, Iran. Also, we are grateful to Dr. Saeid Hashemin for his help in carrying out our project.
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The authors declare that they have no conflict of interest.
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Abdanipour, A., Tiraihi, T., Noori-Zadeh, A. et al. Evaluation of Lovastatin Effects on Expression of Anti-apoptotic Nrf2 and PGC-1α Genes in Neural Stem Cells Treated with Hydrogen Peroxide. Mol Neurobiol 49, 1364–1372 (2014). https://doi.org/10.1007/s12035-013-8613-5
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DOI: https://doi.org/10.1007/s12035-013-8613-5