Skip to main content

Emerging Roles of Sirtuins in Ischemic Stroke

Translational Stroke Research volume 8, pages 405–423 (2017)Cite this article

Abstract

Ischemic stroke is one of the leading causes of death worldwide. It is characterized by a sudden disruption of blood flow to the brain causing cell death and damage, which will lead to neurological impairments. In the current state, only one drug is approved to be used in clinical setting and new therapies that confer ischemic neuroprotection are desperately needed. Several targets and pathways have been indicated to be neuroprotective in ischemic stroke, among which the sirtuin family of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases has emerged as important modulators of several processes in the normal physiology and pathological conditions such as stroke. Recent studies have identified some members of the sirtuin family are able to ameliorate the devastating consequences of ischemic stroke by conferring neuroprotection by means of reducing neuronal cell death, oxidative stress, and neuroinflammation whereas some sirtuins are found to be detrimental in the pathophysiology of ischemic stroke. This review summarizes implications of sirtuins in ischemic stroke and the experimental evidences that demonstrate the potential of sirtuin modulators as neuroprotective therapy for ischemic stroke.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2

References

  1. Frye RA. Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. Biochem Biophys Res Commun. 1999;260(1):273–9. doi:10.1006/bbrc.1999.0897.

    CAS  PubMed  Article  Google Scholar 

  2. Brachmann CB, Sherman JM, Devine SE, Cameron EE, Pillus L, Boeke JD. The SIR2 gene family, conserved from bacteria to humans, functions in silencing, cell cycle progression, and chromosome stability. Genes Dev. 1995;9(23):2888–902. doi:10.1101/gad.9.23.2888.

    CAS  PubMed  Article  Google Scholar 

  3. Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000;403(6771):795–800. doi:10.1038/35001622.

    CAS  PubMed  Article  Google Scholar 

  4. Landry J, Sutton A, Tafrov ST, Heller RC, Stebbins J, Pillus L, et al. The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases. Proc Natl Acad Sci U S A. 2000;97(11):5807–11. doi:10.1073/pnas.110148297.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Frye RA. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys Res Commun. 2000;273(2):793–8. doi:10.1006/bbrc.2000.3000.

    CAS  PubMed  Article  Google Scholar 

  6. North BJ, Marshall BL, Borra MT, Denu JM, Verdin E. The human Sir2 ortholog, SIRT2, is an NAD+−dependent tubulin deacetylase. Mol Cell. 2003;11(2):437–44.

    CAS  PubMed  Article  Google Scholar 

  7. Jin Q, Yan T, Ge X, Sun C, Shi X, Zhai Q. Cytoplasm-localized SIRT1 enhances apoptosis. J Cell Physiol. 2007;213(1):88–97. doi:10.1002/jcp.21091.

    CAS  PubMed  Article  Google Scholar 

  8. North BJ, Verdin E. Interphase nucleo-cytoplasmic shuttling and localization of SIRT2 during mitosis. PLoS One. 2007;2(8):e784. doi:10.1371/journal.pone.0000784.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  9. Michishita E, Park JY, Burneskis JM, Barrett JC, Horikawa I. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol Biol Cell. 2005;16(10):4623–35. doi:10.1091/mbc.E05-01-0033.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. Yamakuchi M, Lowenstein CJ. MiR-34, SIRT1 and p53: the feedback loop. Cell Cycle. 2009;8(5):712–5. doi:10.4161/cc.8.5.7753.

    CAS  PubMed  Article  Google Scholar 

  11. Nemoto S, Fergusson MM, Finkel T. Nutrient availability regulates SIRT1 through a forkhead-dependent pathway. Science. 2004;306(5704):2105–8. doi:10.1126/science.1101731.

    CAS  PubMed  Article  Google Scholar 

  12. Chen WY, Wang DH, Yen RC, Luo J, Gu W, Baylin SB. Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Cell. 2005;123(3):437–48. doi:10.1016/j.cell.2005.08.011.

    CAS  PubMed  Article  Google Scholar 

  13. Wang F, Nguyen M, Qin FX-F, Tong Q. SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction. Aging Cell. 2007;6(4):505–14. doi:10.1111/j.1474-9726.2007.00304.x.

    CAS  PubMed  Article  Google Scholar 

  14. Kobayashi Y, Furukawa-Hibi Y, Chen C, Horio Y, Isobe K, Ikeda K, et al. SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress. Int J Mol Med. 2005;16(2):237–43.

    CAS  PubMed  Google Scholar 

  15. Qiao L, Shao J. SIRT1 regulates adiponectin gene expression through Foxo1-C/enhancer-binding protein alpha transcriptional complex. J Biol Chem. 2006;281(52):39915–24. doi:10.1074/jbc.M607215200.

    CAS  PubMed  Article  Google Scholar 

  16. Jing E, Gesta S, Kahn CR. SIRT2 regulates adipocyte differentiation through FoxO1 acetylation/deacetylation. Cell Metab. 2007;6(2):105–14. doi:10.1016/j.cmet.2007.07.003.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature. 2005;434(7029):113–8. doi:10.1038/nature03354.

    CAS  PubMed  Article  Google Scholar 

  18. Krishnan J, Danzer C, Simka T, Ukropec J, Walter KM, Kumpf S, et al. Dietary obesity-associated Hif1α activation in adipocytes restricts fatty acid oxidation and energy expenditure via suppression of the Sirt2-NAD+ system. Genes Dev. 2012;26(3):259–70. doi:10.1101/gad.180406.111.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. Oellerich MF, Potente M. FOXOs and sirtuins in vascular growth, maintenance, and aging. Circ Res. 2012;110(9):1238–51. doi:10.1161/CIRCRESAHA.111.246488.

    CAS  PubMed  Article  Google Scholar 

  20. Vaquero A, Scher M, Lee D, Erdjument-Bromage H, Tempst P, Reinberg D. Human SirT1 interacts with Histone H1 and promotes formation of facultative heterochromatin. Mol Cell Elsevier. 2004;16(1):93–105. doi:10.1016/j.molcel.2004.08.031.

    CAS  Article  Google Scholar 

  21. Dang W, Steffen KK, Perry R, Dorsey JA, Johnson FB, Shilatifard A, et al. Histone H4 lysine 16 acetylation regulates cellular lifespan. Nature. 2009;459(7248):802–7. doi:10.1038/nature08085.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A, et al. Negative control of p53 by Sir2α promotes cell survival under stress. Cell. Elsevier. 2001;107(2):137–48. doi:10.1016/S0092-8674(01)00524-4.

    CAS  Google Scholar 

  23. Vaziri H, Dessain SK, Eaton EN, Imai S-I, Frye RA, Pandita TK, et al. hSIR2 SIRT1 functions as an NAD-dependent p53 Deacetylase. Cell Elsevier. 2001;107(2):149–59. doi:10.1016/S0092-8674(01)00527-X.

    CAS  Google Scholar 

  24. Leker RR, Aharonowiz M, Greig NH, Ovadia H. The role of p53-induced apoptosis in cerebral ischemia: effects of the p53 inhibitor pifithrin alpha. Exp Neurol. 2004;187(2):478–86. doi:10.1016/j.expneurol.2004.01.030.

    CAS  PubMed  Article  Google Scholar 

  25. Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 2004;303(5666):2011–5. doi:10.1126/science.1094637.

    CAS  PubMed  Article  Google Scholar 

  26. van der Horst A, Tertoolen LGJ, de Vries-Smits LMM, Frye RA, Medema RH, Burgering BMT. FOXO4 is acetylated upon peroxide stress and Deacetylated by the longevity protein hSir2SIRT1. J Biol Chem. 2004;279(28):28873–9. doi:10.1074/jbc.M401138200.

    PubMed  Article  CAS  Google Scholar 

  27. Santo EE, Stroeken P, Sluis PV, Koster J, Versteeg R, Westerhout EM. FOXO3a is a major target of inactivation by PI3K/AKT signaling in aggressive neuroblastoma. Cancer Res. 2013;73(7):2189–98. doi:10.1158/0008-5472.CAN-12-3767.

    CAS  PubMed  Article  Google Scholar 

  28. Greer EL, Brunet A. FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene. 2005;24(50):7410–25. doi:10.1038/sj.onc.1209086.

    CAS  PubMed  Article  Google Scholar 

  29. Chang F, Lee JT, Navolanic PM, Steelman LS, Shelton JG, Blalock WL, et al. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia. 2003;17(3):590–603. doi:10.1038/sj.leu.2402824.

    CAS  PubMed  Article  Google Scholar 

  30. Motta MC, Divecha N, Lemieux M, Kamel C, Chen D, Gu W, et al. Mammalian SIRT1 represses forkhead transcription factors. Cell. 2004;116(4):551–63.

    CAS  PubMed  Article  Google Scholar 

  31. Puigserver P, Spiegelman BM. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr Rev. 2003;24(1):78–90. doi:10.1210/er.2002-0012.

    CAS  PubMed  Article  Google Scholar 

  32. St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jäger S, et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell. 2006;127(2):397–408. doi:10.1016/j.cell.2006.09.024.

    CAS  PubMed  Article  Google Scholar 

  33. Srivastava S, Haigis MC. Role of sirtuins and calorie restriction in neuroprotection: implications in Alzheimer’s and Parkinson’s diseases. Curr Pharm Des. 2011;17(31):3418–33. doi:10.2174/138161211798072526.

    CAS  PubMed  Article  Google Scholar 

  34. Jin J, Iakova P, Jiang Y, Medrano EE, Timchenko NA. The reduction of SIRT1 in livers of old mice leads to impaired body homeostasis and to inhibition of liver proliferation. Hepatology. 2011;54(3):989–98. doi:10.1002/hep.24471.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. Yang Y, Duan W, Li Y, Jin Z, Yan J, Yu S, et al. Novel role of silent information regulator 1 in myocardial ischemia. Circulation. 2013;128(20):2232–40. doi:10.1161/CIRCULATIONAHA.113.002480.

    PubMed  Article  Google Scholar 

  36. Perrod S, Cockell MM, Laroche T, Renauld H, Ducrest A-L, Bonnard C, et al. A cytosolic NAD-dependent deacetylase, Hst2p, can modulate nucleolar and telomeric silencing in yeast. EMBO J Oxford, UK: Oxford University Press. 2001;20(1–2):197–209. doi:10.1093/emboj/20.1.197.

    CAS  Article  Google Scholar 

  37. Vaquero A, Scher MB, Lee DH, Sutton A, Cheng H-L, Alt FW, et al. SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis. Genes Dev. 2006;20(10):1256–61. doi:10.1101/gad.1412706.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. de Oliveira RM, Sarkander J, Kazantsev AG, Outeiro TF. SIRT2 as a therapeutic target for age-related disorders. Front Pharmacol. 2012;3:82. doi:10.3389/fphar.2012.00082.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  39. Beirowski B, Gustin J, Armour SM, Yamamoto H, Viader A, North BJ, et al. Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein par-3/atypical protein kinase C (aPKC) signaling. Proc Natl Acad Sci U S A. 2011;108(43):E952–61. doi:10.1073/pnas.1104969108.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. Jiang W, Wang S, Xiao M, Lin Y, Zhou L, Lei Q, et al. Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase. Mol Cell. 2011;43(1):33–44. doi:10.1016/j.molcel.2011.04.028.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. Hiratsuka M, Inoue T, Toda T, Kimura N, Shirayoshi Y, Kamitani H, et al. Proteomics-based identification of differentially expressed genes in human gliomas: down-regulation of SIRT2 gene. Biochem Biophys Res Commun. 2003;309(3):558–66. doi:10.1016/j.bbrc.2003.08.029.

    CAS  PubMed  Article  Google Scholar 

  42. Lennerz V, Fatho M, Gentilini C, Frye RA, Lifke A, Ferel D, et al. The response of autologous T cells to a human melanoma is dominated by mutated neoantigens. Proc Natl Acad Sci U S A. 2005;102(44):16013–8. doi:10.1073/pnas.0500090102.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. Kim H-S, Vassilopoulos A, Wang R-H, Lahusen T, Xiao Z, Xu X, et al. SIRT2 maintains genome integrity and suppresses tumorigenesis through regulating APC/C activity. Cancer Cell. 2011;20(4):487–99. doi:10.1016/j.ccr.2011.09.004.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Dan L, Klimenkova O, Klimiankou M, Klusman JH, van den Heuvel-Eibrink MM, Reinhardt D, et al. The role of sirtuin 2 activation by nicotinamide phosphoribosyltransferase in the aberrant proliferation and survival of myeloid leukemia cells. Haematologica. 2012;97(4):551–9. doi:10.3324/haematol.2011.055236.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Xie XQ, Zhang P, Tian B, Chen XQ. Downregulation of NAD-dependent Deacetylase SIRT2 protects mouse brain against ischemic stroke. Mol Neurobiol. 2016; doi:10.1007/s12035-016-0173-z.

  46. Krey L, Lühder F, Kusch K, Czech-Zechmeister B, Könnecke B, Fleming Outeiro T, et al. Knockout of silent information regulator 2 (SIRT2) preserves neurological function after experimental stroke in mice. J Cereb Blood Flow Metab. 2015;35(12):2080–8. doi:10.1038/jcbfm.2015.178.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. Hallows WC, Lee S, Denu JM. Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proc Natl Acad Sci U S A. 2006;103(27):10230–5. doi:10.1073/pnas.0604392103.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB, et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature. 2010;464(7285):121–5. doi:10.1038/nature08778.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. Schlicker C, Gertz M, Papatheodorou P, Kachholz B, Becker CFW, Steegborn C. Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5. J Mol Biol. 2008;382(3):790–801. doi:10.1016/j.jmb.2008.07.048.

    CAS  PubMed  Article  Google Scholar 

  50. Shimazu T, Hirschey MD, Hua L, Dittenhafer-Reed KE, Schwer B, Lombard DB, et al. SIRT3 deacetylates mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 and regulates ketone body production. Cell Metab. 2010;12(6):654–61. doi:10.1016/j.cmet.2010.11.003.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. Qiu X, Brown K, Hirschey MD, Verdin E, Chen D. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab. 2010;12(6):662–7. doi:10.1016/j.cmet.2010.11.015.

    CAS  PubMed  Article  Google Scholar 

  52. Yu W, Dittenhafer-Reed KE, Denu JM. SIRT3 protein deacetylates isocitrate dehydrogenase 2 (IDH2) and regulates mitochondrial redox status. J Biol Chem. 2012;287(17):14078–86. doi:10.1074/jbc.M112.355206.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. Hafner AV, Dai J, Gomes AP, Xiao C-Y, Palmeira CM, Rosenzweig A, et al. Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy. Aging (Albany NY). 2010;2(12):914–23. doi:10.18632/aging.100252.

    CAS  Article  Google Scholar 

  54. Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ, et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell. 2006;126(5):941–54. doi:10.1016/j.cell.2006.06.057.

    CAS  PubMed  Article  Google Scholar 

  55. Jeong SM, Xiao C, Finley LWS, Lahusen T, Souza AL, Pierce K, et al. SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism. Cancer Cell. 2013;23(4):450–63. doi:10.1016/j.ccr.2013.02.024.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. Laurent G, de Boer VCJ, Finley LWS, Sweeney M, Lu H, Schug TT, et al. SIRT4 represses peroxisome proliferator-activated receptor α activity to suppress hepatic fat oxidation. Mol Cell Biol. 2013;33(22):4552–61. doi:10.1128/MCB.00087-13.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. Nasrin N, Wu X, Fortier E, Feng Y. Bare’ OC, Chen S, et al. SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells. J Biol Chem. 2010;285(42):31995–2002. doi:10.1074/jbc.M110.124164.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Laurent G, German NJ, Saha AK, de Boer VCJ, Davies M, Koves TR, et al. SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase. Mol Cell. 2013;50(5):686–98. doi:10.1016/j.molcel.2013.05.012.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. Tao Y, Huang C, Huang Y, Hong L, Wang H, Zhou Z, et al. SIRT4 suppresses inflammatory responses in human umbilical vein endothelial cells. Cardiovasc Toxicol. 2015;15(3):217–23. doi:10.1007/s12012-014-9287-6.

    CAS  PubMed  Article  Google Scholar 

  60. Du J, Zhou Y, Su X, Yu JJ, Khan S, Jiang H, et al. Sirt5 is a NAD-dependent protein lysine Demalonylase and Desuccinylase. Science. 2011;334(6057):806–9. doi:10.1126/science.1207861.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. Peng C, Lu Z, Xie Z, Cheng Z, Chen Y, Tan M, et al. The first identification of lysine malonylation substrates and its regulatory enzyme. Mol Cell Proteomics. 2011;10(12):M111.012658. doi:10.1074/mcp.M111.012658.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  62. Nakagawa T, Lomb DJ, Haigis MC, Guarente L. SIRT5 Deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell. 2009;137(3):560–70. doi:10.1016/j.cell.2009.02.026.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. Park J, Chen Y, Tishkoff DX, Peng C, Tan M, Dai L, et al. SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways. Mol Cell. 2013;50(6):919–30. doi:10.1016/j.molcel.2013.06.001.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. Liang F, Wang X, Ow SH, Chen W, Ong WC. Sirtuin 5 is anti-apoptotic and anti-oxidative in cultured SH-EP Neuroblastoma cells. Neurotox Res. 2016; doi:10.1007/s12640-016-9664-y.

  65. Polletta L, Vernucci E, Carnevale I, Arcangeli T, Rotili D, Palmerio S, et al. SIRT5 regulation of ammonia-induced autophagy and mitophagy. Autophagy. 2015;11(2):253–70. doi:10.1080/15548627.2015.1009778.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  66. Guedouari H, Daigle T, Scorrano L, Hebert-Chatelain E. Sirtuin 5 protects mitochondria from fragmentation and degradation during starvation. Biochim. Biophys. Acta - Mol. Cell Res. 2017;1864(1):169–76. doi:10.1016/j.bbamcr.2016.10.015.

    CAS  Google Scholar 

  67. Michishita E, McCord RA, Berber E, Kioi M, Padilla-Nash H, Damian M, et al. SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature. 2008;452(7186):492–6. doi:10.1038/nature06736.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. Michishita E, McCord RA, Boxer LD, Barber MF, Hong T, Gozani O, et al. Cell cycle-dependent deacetylation of telomeric histone H3 lysine K56 by human SIRT6. Cell Cycle. 2009;8(16):2664–6. doi:10.4161/cc.8.16.9367.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR, Gellon L, et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell. 2006;124(2):315–29. doi:10.1016/j.cell.2005.11.044.

    CAS  PubMed  Article  Google Scholar 

  70. McCord RA, Michishita E, Hong T, Berber E, Boxer LD, Kusumoto R, et al. SIRT6 stabilizes DNA-dependent protein kinase at chromatin for DNA double-strand break repair. Aging (Albany NY). 2009;1(1):109–21. doi:10.18632/aging.100011.

    CAS  Article  Google Scholar 

  71. Mao Z, Hine C, Tian X, Van Meter M, Au M, Vaidya A, et al. SIRT6 promotes DNA repair under stress by activating PARP1. Science. 2011;332(6036):1443–6. doi:10.1126/science.1202723.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. Kanfi Y, Naiman S, Amir G, Peshti V, Zinman G, Nahum L, et al. The sirtuin SIRT6 regulates lifespan in male mice. Nature. 2012;483(7388):218–21. doi:10.1038/nature10815.

    CAS  PubMed  Article  Google Scholar 

  73. Ford E, Voit R, Liszt G, Magin C, Grummt I, Guarente L. Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription. Genes Dev. 2006;20(9):1075–80. doi:10.1101/gad.1399706.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. Vakhrusheva O, Smolka C, Gajawada P, Kostin S, Boettger T, Kubin T, et al. Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice. Circ Res. 2008;102(6):703–10. doi:10.1161/CIRCRESAHA.107.164558.

    CAS  PubMed  Article  Google Scholar 

  75. Tsai Y-C, Greco TM, Boonmee A, Miteva Y, Cristea IM. Functional proteomics establishes the interaction of SIRT7 with chromatin remodeling complexes and expands its role in regulation of RNA polymerase I transcription. Mol Cell Proteomics. 2012;11(5):60–76. doi:10.1074/mcp.A111.015156.

    CAS  PubMed  Article  Google Scholar 

  76. Barber MF, Michishita E, Xi Y, Tasselli L, Kioi M, Moqtaderi Z, et al. SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation. Nature. 2012;487(7405):114–8. doi:10.1038/nature11043.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Sidorova-Darmos E, Wither RG, Shulyakova N, Fisher C, Ratnam M, Aarts M, et al. Differential expression of sirtuin family members in the developing, adult, and aged rat brain. Front Aging Neurosci. 2014;6:333. doi:10.3389/fnagi.2014.00333.

    PubMed  PubMed Central  Article  Google Scholar 

  78. Sakamoto J, Miura T, Shimamoto K, Horio Y. Predominant expression of Sir2alpha, an NAD-dependent histone deacetylase, in the embryonic mouse heart and brain. FEBS Lett. 2004;556(1–3):281–6.

    CAS  PubMed  Article  Google Scholar 

  79. Hisahara S, Chiba S, Matsumoto H, Tanno M, Yagi H, Shimohama S, et al. Histone deacetylase SIRT1 modulates neuronal differentiation by its nuclear translocation. Proc Natl Acad Sci U S A. 2008;105(40):15599–604. doi:10.1073/pnas.0800612105.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. Ramadori G, Lee CE, Bookout AL, Lee S, Williams KW, Anderson J, et al. Brain SIRT1: anatomical distribution and regulation by energy availability. J Neurosci. 2008;28(40):9989–96. doi:10.1523/JNEUROSCI.3257-08.2008.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. Prozorovski T, Schulze-Topphoff U, Glumm R, Baumgart J, Schröter F, Ninnemann O, et al. Sirt1 contributes critically to the redox-dependent fate of neural progenitors. Nat Cell Biol. 2008;10(4):385–94. doi:10.1038/ncb1700.

    CAS  PubMed  Article  Google Scholar 

  82. Chen J, Zhou Y, Mueller-Steiner S, Chen L-F, Kwon H, Yi S, et al. SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling. J Biol Chem. 2005;280(48):40364–74. doi:10.1074/jbc.M509329200.

    CAS  PubMed  Article  Google Scholar 

  83. Körner S, Böselt S, Thau N, Rath KJ, Dengler R, Petri S. Differential sirtuin expression patterns in amyotrophic lateral sclerosis (ALS) postmortem tissue: neuroprotective or neurotoxic properties of sirtuins in ALS? Neurodegener Dis. 2013;11(3):141–52. doi:10.1159/000338048.

    PubMed  Article  CAS  Google Scholar 

  84. Park HR, Kong KH, Yu BP, Mattson MP, Lee J. Resveratrol inhibits the proliferation of neural progenitor cells and hippocampal neurogenesis. J Biol Chem. 2012;287(51):42588–600. doi:10.1074/jbc.M112.406413.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. Ma C-Y, Yao M, Zhai Q, Jiao J, Yuan X, Poo M. SIRT1 suppresses self-renewal of adult hippocampal neural stem cells. Development. 2014;141(24):4697–709. doi:10.1242/dev.117937.

    CAS  PubMed  Article  Google Scholar 

  86. Michán S, Li Y, Chou MM-H, Parrella E, Ge H, Long JM, et al. SIRT1 is essential for normal cognitive function and synaptic plasticity. J Neurosci. 2010;30(29):9695–707. doi:10.1523/JNEUROSCI.0027-10.2010.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  87. Gao J, Wang W-Y, Mao Y-W, Gräff J, Guan J-S, Pan L, et al. A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature. 2010;466(7310):1105–9. doi:10.1038/nature09271.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. Maxwell MM, Tomkinson EM, Nobles J, Wizeman JW, Amore AM, Quinti L, et al. The Sirtuin 2 microtubule deacetylase is an abundant neuronal protein that accumulates in the aging CNS. Hum Mol Genet. 2011;20(20):3986–96. doi:10.1093/hmg/ddr326.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. Braidy N, Poljak A, Grant R, Jayasena T, Mansour H, Chan-Ling T, et al. Differential expression of sirtuins in the aging rat brain. Front Cell Neurosci. 2015;9:167. doi:10.3389/fncel.2015.00167.

    PubMed  PubMed Central  Article  Google Scholar 

  90. Oh CS, Lee E, Lee YS, Shin DH. SIRT2 protein expression in normal and aged rat brain. J Korean Geriatr Soc. 2012;16(1):27. doi:10.4235/jkgs.2012.16.1.27.

    Article  Google Scholar 

  91. Suzuki K, Koike T. Resveratrol abolishes resistance to axonal degeneration in slow Wallerian degeneration (WldS) mice: activation of SIRT2, an NAD-dependent tubulin deacetylase. Biochem Biophys Res Commun. 2007;359(3):665–71. doi:10.1016/j.bbrc.2007.05.164.

    CAS  PubMed  Article  Google Scholar 

  92. Creppe C, Malinouskaya L, Volvert M-L, Gillard M, Close P, Malaise O, et al. Elongator controls the migration and differentiation of cortical neurons through acetylation of alpha-tubulin. Cell. 2009;136(3):551–64. doi:10.1016/j.cell.2008.11.043.

    CAS  PubMed  Article  Google Scholar 

  93. Ferreira A, Cáceres A. The expression of acetylated microtubules during axonal and dendritic growth in cerebellar macroneurons which develop in vitro. Brain Res Dev Brain Res. 1989;49(2):205–13.

    CAS  PubMed  Article  Google Scholar 

  94. Taylor DM, Balabadra U, Xiang Z, Woodman B, Meade S, Amore A, et al. A brain-permeable small molecule reduces neuronal cholesterol by inhibiting activity of sirtuin 2 deacetylase. ACS Chem Biol. 2011;6(6):540–6. doi:10.1021/cb100376q.

    CAS  PubMed  Article  Google Scholar 

  95. Pais TF, Szegő ÉM, Marques O, Miller-Fleming L, Antas P, Guerreiro P, et al. The NAD-dependent deacetylase sirtuin 2 is a suppressor of microglial activation and brain inflammation. EMBO J. 2013;32(19):2603–16. doi:10.1038/emboj.2013.200.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. Zeng L, Yang Y, Hu Y, Sun Y, Du Z, Xie Z, et al. Age-related decrease in the mitochondrial sirtuin deacetylase Sirt3 expression associated with ROS accumulation in the auditory cortex of the mimetic aging rat model. PLoS One. 2014;9(2):e88019. doi:10.1371/journal.pone.0088019.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  97. Di Loreto S, Falone S, D’Alessandro A, Santini S, Sebastiani P, Cacchio M, et al. Regular and moderate exercise initiated in middle age prevents age-related amyloidogenesis and preserves synaptic and neuroprotective signaling in mouse brain cortex. Exp Gerontol. 2014;57:57–65. doi:10.1016/j.exger.2014.05.006.

    PubMed  Article  CAS  Google Scholar 

  98. Song W, Song Y, Kincaid B, Bossy B, Bossy-Wetzel E. Mutant SOD1G93A triggers mitochondrial fragmentation in spinal cord motor neurons: neuroprotection by SIRT3 and PGC-1α. Neurobiol Dis. 2013;51:72–81. doi:10.1016/j.nbd.2012.07.004.

    CAS  PubMed  Article  Google Scholar 

  99. Someya S, Yu W, Hallows WC, Xu J, Vann JM, Leeuwenburgh C, et al. Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction. Cell. 2010;143(5):802–12. doi:10.1016/j.cell.2010.10.002.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. Cheng A, Yang Y, Zhou Y, Maharana C, Lu D, Peng W, et al. Mitochondrial SIRT3 mediates adaptive responses of neurons to exercise and metabolic and excitatory challenges. Cell Metab. 2016;23(1):128–42. doi:10.1016/j.cmet.2015.10.013.

    CAS  PubMed  Article  Google Scholar 

  101. Komlos D, Mann KD, Zhuo Y, Ricupero CL, Hart RP, Liu AY-C, et al. Glutamate dehydrogenase 1 and SIRT4 regulate glial development. Glia. 2013;61(3):394–408. doi:10.1002/glia.22442.

    PubMed  Article  Google Scholar 

  102. Rardin MJ, He W, Nishida Y, Newman JC, Carrico C, Danielson SR, et al. SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks. Cell Metab. 2013;18(6):920–33. doi:10.1016/j.cmet.2013.11.013.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. Favero G, Rezzani R, Rodella LF. Sirtuin 6 nuclear localization at cortical brain level of young diabetic mice: an immunohistochemical study. Acta Histochem. 2014;116(1):272–7. doi:10.1016/j.acthis.2013.08.006.

    CAS  PubMed  Article  Google Scholar 

  104. Schwer B, Schumacher B, Lombard DB, Xiao C, Kurtev MV, Gao J, et al. Neural sirtuin 6 (Sirt6) ablation attenuates somatic growth and causes obesity. Proc Natl Acad Sci U S A. 2010;107(50):21790–4. doi:10.1073/pnas.1016306107.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the global burden of disease study 2010. Lancet (London, England). 2012;380(9859):2095–128. doi:10.1016/S0140-6736(12)61728-0.

    Article  Google Scholar 

  106. Doyle KP, Simon RP, Stenzel-Poore MP. Mechanisms of ischemic brain damage. Neuropharmacology. 2008;55(3):310–8. doi:10.1016/j.neuropharm.2008.01.005.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. Bansal S, Sangha KS, Khatri P. Drug treatment of acute ischemic stroke. Am J Cardiovasc Drugs. 2013;13(1):57–69. doi:10.1007/s40256-013-0007-6.

    CAS  PubMed  Article  Google Scholar 

  108. Lipton P. Ischemic cell death in brain neurons. Physiol Rev. 1999;79(4):1431–568.

    CAS  PubMed  Google Scholar 

  109. Moskowitz MA, Lo EH, Iadecola C. The science of stroke: mechanisms in search of treatments. Neuron. 2010;67(2):181–98. doi:10.1016/j.neuron.2010.07.002.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. Hernández-Jiménez M, Hurtado O, Cuartero MI, Ballesteros I, Moraga A, Pradillo JM, et al. Silent information regulator 1 protects the brain against cerebral ischemic damage. Stroke. 2013;44(8):2333–7. doi:10.1161/STROKEAHA.113.001715.

    PubMed  Article  CAS  Google Scholar 

  111. Hattori Y, Okamoto Y, Maki T, Yamamoto Y, Oishi N, Yamahara K, et al. Silent information regulator 2 homolog 1 counters cerebral hypoperfusion injury by deacetylating endothelial nitric oxide synthase. Stroke. 2014;45(11):3403–11. doi:10.1161/STROKEAHA.114.006265.

    CAS  PubMed  Article  Google Scholar 

  112. Hattori Y, Okamoto Y, Nagatsuka K, Takahashi R, Kalaria RN, Kinoshita M, et al. SIRT1 attenuates severe ischemic damage by preserving cerebral blood flow. Neuroreport. 2015;26(3):113–7. doi:10.1097/WNR.0000000000000308.

    CAS  PubMed  Article  Google Scholar 

  113. Wang T, Gu J, Wu P-F, Wang F, Xiong Z, Yang Y-J, et al. Protection by tetrahydroxystilbene glucoside against cerebral ischemia: involvement of JNK, SIRT1, and NF-kappaB pathways and inhibition of intracellular ROS/RNS generation. Free Radic Biol Med. 2009;47(3):229–40. doi:10.1016/j.freeradbiomed.2009.02.027.

    CAS  PubMed  Article  Google Scholar 

  114. Fu B, Zhang J, Zhang X, Zhang C, Li Y, Zhang Y, et al. Alpha-lipoic acid upregulates SIRT1-dependent PGC-1α expression and protects mouse brain against focal ischemia. Neuroscience. 2014;281:251–7. doi:10.1016/j.neuroscience.2014.09.058.

    CAS  PubMed  Article  Google Scholar 

  115. Dioum EM, Chen R, Alexander MS, Zhang Q, Hogg RT, Gerard RD, et al. Regulation of hypoxia-inducible factor 2alpha signaling by the stress-responsive deacetylase sirtuin 1. Science. 2009;324(5932):1289–93. doi:10.1126/science.1169956.

    CAS  PubMed  Article  Google Scholar 

  116. Lim J-H, Lee Y-M, Chun Y-S, Chen J, Kim J-E, Park J-W. Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. Mol Cell. 2010;38(6):864–78. doi:10.1016/j.molcel.2010.05.023.

    CAS  PubMed  Article  Google Scholar 

  117. Wang P, Xu T-Y, Guan Y-F, Tian W-W, Viollet B, Rui Y-C, et al. Nicotinamide phosphoribosyltransferase protects against ischemic stroke through SIRT1-dependent adenosine monophosphate-activated kinase pathway. Ann Neurol. 2011;69(2):360–74. doi:10.1002/ana.22236.

    CAS  PubMed  Article  Google Scholar 

  118. Hu Q, Manaenko A, Bian H, Guo Z, Huang J-L, Guo Z-N, et al. Hyperbaric oxygen reduces infarction volume and hemorrhagic transformation through ATP/NAD(+)/Sirt1 pathway in Hyperglycemic middle cerebral artery occlusion rats. Stroke. 2017; doi:10.1161/STROKEAHA.116.015753.

  119. Guo J-M, Shu H, Wang L, Xu J-J, Niu X-C, Zhang L. SIRT1-dependent AMPK pathway in the protection of estrogen against ischemic brain injury. CNS Neurosci. Ther. 2017;23(4):360–9. doi:10.1111/cns.12686.

    CAS  PubMed  Article  Google Scholar 

  120. Nie H, Hong Y, Lu X, Zhang J, Chen H, Li Y, et al. SIRT2 mediates oxidative stress-induced apoptosis of differentiated PC12 cells. Neuroreport. 2014; doi:10.1097/WNR.0000000000000192.

  121. Wang Q, Li L, Li CY, Pei Z, Zhou M, Li N. SIRT3 protects cells from hypoxia via PGC-1α- and MnSOD-dependent pathways. Neuroscience. 2015;286:109–21. doi:10.1016/j.neuroscience.2014.11.045.

    CAS  PubMed  Article  Google Scholar 

  122. Yin J, Han P, Tang Z, Liu Q, Shi J. Sirtuin 3 mediates neuroprotection of ketones against ischemic stroke. J Cereb Blood Flow Metab. 2015;35(11):1783–9. doi:10.1038/jcbfm.2015.123.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. Jacobs KM, Pennington JD, Bisht KS, Aykin-Burns N, Kim H-S, Mishra M, et al. SIRT3 interacts with the daf-16 homolog FOXO3a in the mitochondria, as well as increases FOXO3a dependent gene expression. Int J Biol Sci. 2008;4(5):291–9. doi:10.7150/ijbs.4.291.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  124. Peserico A, Chiacchiera F, Grossi V, Matrone A, Latorre D, Simonatto M, et al. A novel AMPK-dependent FoxO3A-SIRT3 intramitochondrial complex sensing glucose levels. Cell Mol Life Sci. 2013;70(11):2015–29. doi:10.1007/s00018-012-1244-6.

    CAS  PubMed  Article  Google Scholar 

  125. Novgorodov SA, Riley CL, Keffler JA, Yu J, Kindy MS, Macklin WB, et al. SIRT3 Deacetylates Ceramide Synthases: IMPLICATIONS FOR MITOCHONDRIAL DYSFUNCTION AND BRAIN INJURY. J Biol Chem. 2016;291(4):1957–73. doi:10.1074/jbc.M115.668228.

    CAS  PubMed  Article  Google Scholar 

  126. Shih J, Liu L, Mason A, Higashimori H, Donmez G. Loss of SIRT4 decreases GLT-1-dependent glutamate uptake and increases sensitivity to kainic acid. J Neurochem. 2014;131(5):573–81. doi:10.1111/jnc.12942.

    CAS  PubMed  Article  Google Scholar 

  127. Chu K, Lee S-T, Sinn D-I, Ko S-Y, Kim E-H, Kim J-M, et al. Pharmacological induction of ischemic Tolerance by glutamate transporter-1 (EAAT2) Upregulation. Stroke. 2007;38(1):177–82. doi:10.1161/01.STR.0000252091.36912.65.

    CAS  PubMed  Article  Google Scholar 

  128. Weller ML, Stone IM, Goss A, Rau T, Rova C, Poulsen DJ. Selective overexpression of excitatory amino acid transporter 2 (EAAT2) in astrocytes enhances neuroprotection from moderate but not severe hypoxia-ischemia. Neuroscience. 2008;155(4):1204–11. doi:10.1016/j.neuroscience.2008.05.059.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. Harvey BK, Airavaara M, Hinzman J, Wires EM, Chiocco MJ, Howard DB, et al. Targeted over-expression of glutamate transporter 1 (GLT-1) reduces ischemic brain injury in a rat model of stroke. PLoS One. 2011;6(8):e22135. doi:10.1371/journal.pone.0022135.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. Morris-Blanco KC, Dave KR, Saul I, Koronowski KB, Stradecki HM, Perez-Pinzon MA. Protein Kinase C epsilon promotes cerebral ischemic Tolerance via Modulation of mitochondrial Sirt5. Sci Rep. 2016;6:29790. doi:10.1038/srep29790.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. Di Y, He Y-L, Zhao T, Huang X, Wu K-W, Liu S-H, et al. Methylene blue reduces acute cerebral ischemic injury via the induction of Mitophagy. Mol Med. 2015;21:420–9. doi:10.2119/molmed.2015.00038.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. Zhang X, Yan H, Yuan Y, Gao J, Shen Z, Cheng Y, et al. Cerebral ischemia-reperfusion-induced autophagy protects against neuronal injury by mitochondrial clearance. Autophagy. 2013;9(9):1321–33. doi:10.4161/auto.25132.

    CAS  PubMed  Article  Google Scholar 

  133. Zuo W, Zhang S, Xia C-Y, Guo X-F, He W-B, Chen N-H. Mitochondria autophagy is induced after hypoxic/ischemic stress in a Drp1 dependent manner: the role of inhibition of Drp1 in ischemic brain damage. Neuropharmacology. 2014;86:103–15. doi:10.1016/j.neuropharm.2014.07.002.

    CAS  PubMed  Article  Google Scholar 

  134. Shi R-Y, Zhu S-H, Li V, Gibson SB, Xu X-S, Kong J-M. BNIP3 interacting with LC3 triggers excessive mitophagy in delayed neuronal death in stroke. CNS Neurosci. Ther. 2014;20(12):1045–55. doi:10.1111/cns.12325.

    CAS  PubMed  Article  Google Scholar 

  135. Kumari S, Anderson L, Farmer S, Mehta SL, Li PA. Hyperglycemia alters mitochondrial fission and fusion proteins in mice subjected to cerebral ischemia and reperfusion. Transl Stroke Res. 2012;3(2):296–304. doi:10.1007/s12975-012-0158-9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  136. Baek S-H, Noh AR, Kim K-A, Akram M, Shin Y-J, Kim E-S, et al. Modulation of mitochondrial function and autophagy mediates carnosine neuroprotection against ischemic brain damage. Stroke. 2014;45(8):2438–43. doi:10.1161/STROKEAHA.114.005183.

    PubMed  PubMed Central  Article  Google Scholar 

  137. Jin J, Albertz J, Guo Z, Peng Q, Rudow G, Troncoso JC, et al. Neuroprotective effects of PPAR-γ agonist rosiglitazone in N171-82Q mouse model of Huntington’s disease. J Neurochem. 2013;125(3):410–9. doi:10.1111/jnc.12190.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  138. Dong C, Della-Morte D, Wang L, Cabral D, Beecham A, McClendon MS, et al. Association of the sirtuin and mitochondrial uncoupling protein genes with carotid plaque. PLoS One. 2011;6(11):e27157. doi:10.1371/journal.pone.0027157.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  139. Lee O-H, Kim J, Kim J-M, Lee H, Kim EH, Bae S-K, et al. Decreased expression of sirtuin 6 is associated with release of high mobility group box-1 after cerebral ischemia. Biochem Biophys Res Commun. 2013;438(2):388–94. doi:10.1016/j.bbrc.2013.07.085.

    CAS  PubMed  Article  Google Scholar 

  140. Hu Y, Li R, Yang H, Luo H, Chen Z. Sirtuin 6 is essential for sodium sulfide-mediated cytoprotective effect in ischemia/reperfusion-stimulated brain endothelial cells. J Stroke Cerebrovasc Dis. 2015;24(3):601–9. doi:10.1016/j.jstrokecerebrovasdis.2014.10.006.

    PubMed  Article  Google Scholar 

  141. Shao J, Yang X, Liu T, Zhang T, Xie QR, Xia W. Autophagy induction by SIRT6 is involved in oxidative stress-induced neuronal damage. Protein Cell. 2016;7(4):281–90. doi:10.1007/s13238-016-0257-6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. Zhang S, Chen P, Huang Z, Hu X, Chen M, Hu S, et al. Sirt7 promotes gastric cancer growth and inhibits apoptosis by epigenetically inhibiting miR-34a. Sci Rep. 2015;5:9787. doi:10.1038/srep09787.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  143. Wong Y-H, Wu C-C, Lai H-Y, Jheng B-R, Weng H-Y, Chang T-H, et al. Identification of network-based biomarkers of cardioembolic stroke using a systems biology approach with time series data. BMC Syst Biol. 2015;9(Suppl 6):S4. doi:10.1186/1752-0509-9-S6-S4.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  144. Hubbi ME, Hu H. Kshitiz, Gilkes DM, Semenza GL. Sirtuin-7 inhibits the activity of hypoxia-inducible factors. J Biol Chem. 2013;288(29):20768–75. doi:10.1074/jbc.M113.476903.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  145. Raval AP, Dave KR, Pérez-Pinzón MA. Resveratrol mimics ischemic preconditioning in the brain. J Cereb Blood Flow Metab. 2006;26(9):1141–7. doi:10.1038/sj.jcbfm.9600262.

    CAS  PubMed  Article  Google Scholar 

  146. Yang Y, Jiang S, Dong Y, Fan C, Zhao L, Yang X, et al. Melatonin prevents cell death and mitochondrial dysfunction via a SIRT1-dependent mechanism during ischemic-stroke in mice. J Pineal Res. 2015;58(1):61–70. doi:10.1111/jpi.12193.

    CAS  PubMed  Article  Google Scholar 

  147. Dong W, Li N, Gao D, Zhen H, Zhang X, Li F. Resveratrol attenuates ischemic brain damage in the delayed phase after stroke and induces messenger RNA and protein express for angiogenic factors. J Vasc Surg. 2008;48(3):709–14. doi:10.1016/j.jvs.2008.04.007.

    PubMed  Article  Google Scholar 

  148. Koronowski KB, Dave KR, Saul I, Camarena V, Thompson JW, Neumann JT, et al. Resveratrol preconditioning induces a novel extended window of ischemic Tolerance in the mouse brain. Stroke. 2015;46(8):2293–8. doi:10.1161/STROKEAHA.115.009876.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  149. Zhu H, Wang Z, Zhu X, Wu X, Li E, Xu Y. Icariin protects against brain injury by enhancing SIRT1-dependent PGC-1alpha expression in experimental stroke. Neuropharmacology. 2010;59(1–2):70–6. doi:10.1016/j.neuropharm.2010.03.017.

    CAS  PubMed  Article  Google Scholar 

  150. Chen X, Wales P, Quinti L, Zuo F, Moniot S, Herisson F, et al. The sirtuin-2 inhibitor AK7 is neuroprotective in models of parkinson’s disease but not amyotrophic lateral sclerosis and cerebral ischemia. PLoS One. 2015;10(1):1–15. doi:10.1371/journal.pone.0116919.

    Google Scholar 

  151. Narayan N, Lee IH, Borenstein R, Sun J, Wong R, Tong G, et al. The NAD-dependent deacetylase SIRT2 is required for programmed necrosis. Nature. 2012;492(7428):199–204. doi:10.1038/nature11700.

    CAS  PubMed  Article  Google Scholar 

  152. Newton K, Hildebrand JM, Shen Z, Rodriguez D, Alvarez-Diaz S, Petersen S, et al. Is SIRT2 required for necroptosis? Nature. 2014;506(7489):E4–6. doi:10.1038/nature13024.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  153. Wei L, Zhou Y, Dai Q, Qiao C, Zhao L, Hui H, et al. Oroxylin a induces dissociation of hexokinase II from the mitochondria and inhibits glycolysis by SIRT3-mediated deacetylation of cyclophilin D in breast carcinoma. Cell Death Dis. 2013;4:e601. doi:10.1038/cddis.2013.131.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. Huang W-H, Lee A-R, Yang C-H. Antioxidative and anti-inflammatory activities of polyhydroxyflavonoids of Scutellaria Baicalensis GEORGI. Biosci Biotechnol Biochem. 2006;70(10):2371–80. doi:10.1271/bbb.50698.

    CAS  PubMed  Article  Google Scholar 

  155. Kim DH, Jeon SJ, Son KH, Jung JW, Lee S, Yoon BH, et al. The ameliorating effect of oroxylin a on scopolamine-induced memory impairment in mice. Neurobiol Learn Mem. 2007;87(4):536–46. doi:10.1016/j.nlm.2006.11.005.

    CAS  PubMed  Article  Google Scholar 

  156. Jiwajinda S, Santisopasri V, Murakami A, Kim O-K, Kim HW, Ohigashi H. Suppressive effects of edible Thai plants on superoxide and nitric oxide generation. Asian Pac J Cancer Prev. 2002;3(3):215–23.

    PubMed  Google Scholar 

  157. Cardinale A, de Stefano MC, Mollinari C, Racaniello M, Garaci E, Merlo D. Biochemical characterization of sirtuin 6 in the brain and its involvement in oxidative stress response. Neurochem Res. 2015;40(1):59–69. doi:10.1007/s11064-014-1465-1.

    CAS  PubMed  Article  Google Scholar 

  158. Wang R, Tang Y, Feng B, Ye C, Fang L, Zhang L, et al. Changes in hippocampal synapses and learning-memory abilities in age-increasing rats and effects of tetrahydroxystilbene glucoside in aged rats. Neuroscience. 2007;149(4):739–46. doi:10.1016/j.neuroscience.2007.07.065.

    CAS  PubMed  Article  Google Scholar 

  159. Zhang L, Xing Y, Ye C-F, Ai H-X, Wei H-F, Li L. Learning-memory deficit with aging in APP transgenic mice of Alzheimer’s disease and intervention by using tetrahydroxystilbene glucoside. Behav Brain Res. 2006;173(2):246–54. doi:10.1016/j.bbr.2006.06.034.

    CAS  PubMed  Article  Google Scholar 

  160. Zhang X-S, Wu Q, Wu L-Y, Ye Z-N, Jiang T-W, Li W, et al. Sirtuin 1 activation protects against early brain injury after experimental subarachnoid hemorrhage in rats. Cell Death Dis. 2016;7(10):e2416. doi:10.1038/cddis.2016.292.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. Toklu HZ, Hakan T, Biber N, Solakoğlu S, Oğünç AV, Sener G. The protective effect of alpha lipoic acid against traumatic brain injury in rats. Free Radic Res. 2009;43(7):658–67. doi:10.1080/10715760902988843.

    CAS  PubMed  Article  Google Scholar 

  162. Chen Y-J, Zheng H-Y, Huang X-X, Han S-X, Zhang D-S, Ni J-Z, et al. Neuroprotective effects of Icariin on brain metabolism, mitochondrial functions, and cognition in triple-transgenic Alzheimer’s disease mice. CNS Neurosci Ther. 2016;22(1):63–73. doi:10.1111/cns.12473.

    CAS  PubMed  Article  Google Scholar 

  163. Cardinali DP, Brusco LI, Liberczuk C, Furio AM. The use of melatonin in Alzheimer’s disease. Neuro Endocrinol. Lett. 2002;23(Suppl 1):20–3.

  164. Zhao Y-N, Li W-F, Li F, Zhang Z, Dai Y-D, Xu A-L, et al. Resveratrol improves learning and memory in normally aged mice through microRNA-CREB pathway. Biochem Biophys Res Commun. 2013;435(4):597–602. doi:10.1016/j.bbrc.2013.05.025.

  165. Ho DJ, Calingasan NY, Wille E, Dumont M, Beal MF. Resveratrol protects against peripheral deficits in a mouse model of Huntington’s disease. Exp Neurol. 2010;225(1):74–84. doi:10.1016/j.expneurol.2010.05.006.

    CAS  PubMed  Article  Google Scholar 

  166. Gueguen C, Palmier B, Plotkine M, Marchand-Leroux C, Besson VC. Neurological and histological consequences induced by in vivo cerebral oxidative stress: evidence for beneficial effects of SRT1720, a sirtuin 1 activator, and sirtuin 1-mediated neuroprotective effects of poly(ADP-ribose) polymerase inhibition. PLoS One. 2014;9(2):e87367. doi:10.1371/journal.pone.0087367.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  167. Gräff J, Kahn M, Samiei A, Gao J, Ota KT, Rei D, et al. A dietary regimen of caloric restriction or pharmacological activation of SIRT1 to delay the onset of neurodegeneration. J Neurosci. 2013;33(21):8951–60. doi:10.1523/JNEUROSCI.5657-12.2013.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  168. Smith MR, Syed A, Lukacsovich T, Purcell J, Barbaro BA, Worthge SA, et al. A potent and selective Sirtuin 1 inhibitor alleviates pathology in multiple animal and cell models of Huntington’s disease. Hum Mol Genet. 2014;23(11):2995–3007. doi:10.1093/hmg/ddu010.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  169. Liu D, Gharavi R, Pitta M, Gleichmann M, Mattson MP. Nicotinamide prevents NAD+ depletion and protects neurons against excitotoxicity and cerebral ischemia: NAD+ consumption by SIRT1 may endanger energetically compromised neurons. NeuroMolecular Med. 2009;11(1):28–42. doi:10.1007/s12017-009-8058-1.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  170. Schulz JB, Henshaw DR, Matthews RT, Beal MF. Coenzyme Q10 and nicotinamide and a free radical spin trap protect against MPTP neurotoxicity. Exp Neurol. 1995;132(2):279–83.

    CAS  PubMed  Article  Google Scholar 

  171. Green KN, Steffan JS, Martinez-Coria H, Sun X, Schreiber SS, Thompson LM, et al. Nicotinamide restores cognition in Alzheimer’s disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau. J Neurosci. 2008;28(45):11500–10. doi:10.1523/JNEUROSCI.3203-08.2008.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  172. Zhou X-M, Zhang X, Zhang X-S, Zhuang Z, Li W, Sun Q, et al. SIRT1 inhibition by sirtinol aggravates brain edema after experimental subarachnoid hemorrhage. J Neurosci Res. 2014;92(6):714–22. doi:10.1002/jnr.23359.

    CAS  PubMed  Article  Google Scholar 

  173. Spires-Jones TL, Fox LM, Rozkalne A, Pitstick R, Carlson GA, Kazantsev AG. Inhibition of Sirtuin 2 with Sulfobenzoic acid derivative AK1 is non-toxic and potentially Neuroprotective in a mouse model of Frontotemporal dementia. Front Pharmacol. 2012;3:42. doi:10.3389/fphar.2012.00042.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  174. Luthi-Carter R, Taylor DM, Pallos J, Lambert E, Amore A, Parker A, et al. SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis. Proc Natl Acad Sci U S A. 2010;107(17):7927–32. doi:10.1073/pnas.1002924107.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  175. Chopra V, Quinti L, Kim J, Vollor L, Narayanan KL, Edgerly C, et al. The sirtuin 2 inhibitor AK-7 is neuroprotective in Huntington’s disease mouse models. Cell Rep. 2012;2(6):1492–7. doi:10.1016/j.celrep.2012.11.001.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  176. Outeiro TF, Kontopoulos E, Altmann SM, Kufareva I, Strathearn KE, Amore AM, et al. Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson’s disease. Science. 2007;317(5837):516–9. doi:10.1126/science.1143780.

    CAS  PubMed  Article  Google Scholar 

  177. Kim DH, Jeon SJ, Son KH, Jung JW, Lee S, Yoon BH, et al. Effect of the flavonoid, oroxylin a, on transient cerebral hypoperfusion-induced memory impairment in mice. Pharmacol Biochem Behav. 2006;85(3):658–68. doi:10.1016/j.pbb.2006.10.025.

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Medical Research Council Research Grant (NMRC/CBRG/0102/2016), National University Health System Seed Fund for Basic Science Research (R-185-000-255-112), and Singapore Ministry of Education Academic Research Fund Tier 1 Grant (R-185-000-285-112) to TVA and Swee Liew Wadsworth Concept Grant (Research) to DTS. DTS is a recipient of National University of Singapore Research Scholarship.

Author information

Affiliations

  1. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore

    David T. She & Thiruma V. Arumugam

  2. Neurobiology/Ageing Programme, Life Sciences Institute, National University of Singapore, Singapore, 117456, Singapore

    David T. She & Thiruma V. Arumugam

  3. School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea

    Dong-Gyu Jo & Thiruma V. Arumugam

Authors
  1. David T. She
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dong-Gyu Jo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thiruma V. Arumugam
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thiruma V. Arumugam.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

She, D.T., Jo, DG. & Arumugam, T.V. Emerging Roles of Sirtuins in Ischemic Stroke. Transl. Stroke Res. 8, 405–423 (2017). https://doi.org/10.1007/s12975-017-0544-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12975-017-0544-4

Keywords

  • Sirtuins
  • Ischemic stroke
  • Cell death
  • Neuroprotection
  • Inflammation