Skip to main content
Download PDF

Sirtuin-2 inhibition affects hippocampal functions and sodium butyrate ameliorates the reduction in novel object memory, cell proliferation, and neuroblast differentiation

Laboratory Animal Research volume 32, pages 224–230 (2016)Cite this article

Abstract

We investigated the effects of the sirtuin-2 (SIRT2) inhibitor AK-7 on novel object memory, cell proliferation, and neuroblast differentiation in the dentate gyrus. In addition, we also observed the relationships with sodium butyrate, a histone deacetylase inhibitor, on the hippocampal functions. To investigate the effects of AK-7 on hippocampal functions, 10-week-old C57BL/6 mice were daily injected intraperitoneally with 20 mg/kg AK-7 alone or in combination with subcutaneous administration of 300 mg/kg sodium butyrate, a histone deacetylase inhibitor, for 21 days. A novel object recognition test was conducted on days 20 (training) and 21 (testing) of treatment. Thereafter, the animals were sacrificed for immunohistochemistry for Ki67 (cell proliferation) and doublecortin (DCX, neuroblast differentiation). AK-7 administration significantly reduced the time spent exploring new objects, while treatment in combination with sodium butyrate significantly alleviated this reduction. Additionally, AK-7 administration significantly reduced the number of Ki67-positive cells and DCX-immunoreactive neuroblasts in the dentate gyrus, while the treatment in combination with sodium butyrate ameliorated these changes. This result suggests that the reduction of SIRT2 may be closely related to age-related phenotypes including novel object memory, as well as cell proliferation and neuroblast differentiation in the dentate gyrus. In addition, sodium butyrate reverses SIRT2-related age phenotypes.

References

  1. Crepaldi L, Riccio A. Chromatin learns to behave. Epigenetics 2009; 4(1): 23–26.

    CAS  PubMed  Google Scholar 

  2. Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, Gao J, Nieland TJ, Zhou Y, Wang X, Mazitschek R, Bradner JE, DePinho RA, Jaenisch R, Tsai LH. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 2009; 459(7243): 55–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Morrison BE, Majdzadeh N, D’Mello SR. Histone deacetylases: focus on the nervous system. Cell Mol Life Sci 2007; 64(17): 2258–2269.

    CAS  PubMed  Google Scholar 

  4. Dillin A, Kelly JW. Medicine. The yin-yang of sirtuins. Science 2007; 317(5837): 461–462.

    CAS  PubMed  Google Scholar 

  5. Finkel T, Deng CX, Mostoslavsky R. Recent progress in the biology and physiology of sirtuins. Nature 2009; 460(7255): 587–591.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Gan L, Mucke L. Paths of convergence: sirtuins in aging and neurodegeneration. Neuron 2008; 58(1): 10–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. de Oliveira RM, Pais TF, Outeiro TF. Sirtuins: common targets in aging and in neurodegeneration. Curr Drug Targets 2010; 11(10): 1270–1280.

    PubMed  Google Scholar 

  8. Longo VD, Kennedy BK. Sirtuins in aging and age-related disease. Cell 2006; 126(2): 257–268.

    CAS  PubMed  Google Scholar 

  9. Liu L, Arun A, Ellis L, Peritore C, Donmez G. SIRT2 enhances 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigrostriatal damage via apoptotic pathway. Front Aging Neurosci 2014; 6: 184.

    PubMed  PubMed Central  Google Scholar 

  10. Luthi-Carter R, Taylor DM, Pallos J, Lambert E, Amore A, Parker A, Moffitt H, Smith DL, Runne H, Gokce O, Kuhn A, Xiang Z, Maxwell MM, Reeves SA, Bates GP, Neri C, Thompson LM, Marsh JL, Kazantsev A G. SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis. Proc Natl Acad Sci USA 2010; 107(17): 7927–7932.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Outeiro TF, Kontopoulos E, Altmann SM, Kufareva I, Strathearn KE, Amore AM, Volk CB, Maxwell MM, Rochet JC, McLean PJ, Young AB, Abagyan R, Feany MB, Hyman BT, Kazantsev AG. Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson’s disease. Science 2007; 317(5837): 516–519.

    CAS  PubMed  Google Scholar 

  12. Pandithage R, Lilischkis R, Harting K, Wolf A, Jedamzik B, Luscher-Firzlaff J, Vervoorts J, Lasonder E, Kremmer E, Knoll B, Luscher B. The regulation of SIRT2 function by cyclin-dependent kinases affects cell motility. J Cell Biol 2008; 180(5): 915–929.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Yuan F, Xu ZM, Lu LY, Nie H, Ding J, Ying WH, Tian HL. SIRT2 inhibition exacerbates neuroinflammation and blood-brain barrier disruption in experimental traumatic brain injury by enhancing NF-êB p65 acetylation and activation. J Neurochem 2016; 136(3): 581–593.

    CAS  PubMed  Google Scholar 

  14. Chen X, Wales P, Quinti L, Zuo F, Moniot S, Herisson F, Rauf NA, Wang H, Silverman RB, Ayata C, Maxwell MM, Steegborn C, Schwarzschild MA, Outeiro TF, Kazantsev AG. 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): e0116919.

    Google Scholar 

  15. Ramakrishnan G, Davaakhuu G, Kaplun L, Chung WC, Rana A, Atfi A, Miele L, Tzivion G. Sirt2 deacetylase is a novel AKT binding partner critical for AKT activation by insulin. J Biol Chem 2014; 289(9): 6054–6066.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Derakhshan F, Toth C. Insulin and the brain. Curr Diabetes Rev 2013; 9(2): 102–116.

    PubMed  Google Scholar 

  17. Ziegler AN, Levison SW, Wood TL. Insulin and IGF receptor signalling in neural-stem-cell homeostasis. Nat Rev Endocrinol 2015; 11(3): 161–170.

    CAS  PubMed  Google Scholar 

  18. Davie JR. Inhibition of histone deacetylase activity by butyrate. J Nutr 2003; 133(7 Suppl): 2485S–2493S.

    CAS  PubMed  Google Scholar 

  19. Valvassori SS, Varela RB, Arent CO, Dal-Pont GC, Bobsin TS, Budni J, Reus GZ, Quevedo J. Sodium butyrate functions as an antidepressant and improves cognition with enhanced neurotrophic expression in models of maternal deprivation and chronic mild stress. Curr Neurovasc Res 2014; 11(4): 359–366.

    CAS  PubMed  Google Scholar 

  20. Pandey K, Sharma KP, Sharma SK. Histone deacetylase inhibition facilitates massed pattern-induced synaptic plasticity and memory. Learn Mem 2015; 22(10): 514–518.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Yoo DY, Kim DW, Kim MJ, Choi JH, Jung HY, Nam SM, Kim JW, Yoon YS, Choi S Y, Hwang IK. Sodium butyrate, a histone deacetylase Inhibitor, ameliorates SIRT2-induced memory impairment, reduction of cell proliferation, and neuroblast differentiation in the dentate gyrus. Neurol Res 2015; 37(1): 69–76.

    CAS  PubMed  Google Scholar 

  22. Yoo DY, Kim W, Kim IH, Nam SM, Chung JY, Choi JH, Yoon YS, Won MH, Hwang IK. Combination effects of sodium butyrate and pyridoxine treatment on cell proliferation and neuroblast differentiation in the dentate gyrus of D-galactose-induced aging model mice. Neurochem Res 2012; 37(1): 223–231.

    CAS  PubMed  Google Scholar 

  23. Yoo DY, Kim W, Nam SM, Kim DW, Chung JY, Choi SY, Yoon YS, Won MH, Hwang IK. Synergistic effects of sodium butyrate, a histone deacetylase inhibitor, on increase of neurogenesis induced by pyridoxine and increase of neural proliferation in the mouse dentate gyrus. Neurochem Res 2011; 36(10): 1850–1857.

    CAS  PubMed  Google Scholar 

  24. Kim HJ, Leeds P, Chuang DM. The HDAC inhibitor, sodium butyrate, stimulates neurogenesis in the ischemic brain. J Neurochem 2009; 110(4): 1226–1240.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Yao X, Zhang JR, Huang HR, Dai LC, Liu QJ, Zhang M. Histone deacetylase inhibitor promotes differentiation of embryonic stem cells into neural cells in adherent monoculture. Chin Med J (Engl) 2010; 123(6): 734–738.

    CAS  Google Scholar 

  26. Fessler EB, Chibane FL, Wang Z, Chuang DM. Potential roles of HDAC inhibitors in mitigating ischemia-induced brain damage and facilitating endogenous regeneration and recovery. Curr Pharm Des 2013; 19(28): 5105–5120.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Clelland CD, Choi M, Romberg C, Clemenson GD Jr, Fragniere A, Tyers P, Jessberger S, Saksida LM, Barker RA, Gage FH, Bussey TJ. A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 2009; 325(5937): 210–213.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Nakashiba T, Cushman JD, Pelkey KA, Renaudineau S, Buhl DL, McHugh TJ, Rodriguez Barrera V, Chittajallu R, Iwamoto KS, McBain CJ, Fanselow MS, Tonegawa S. Young dentate granule cells mediate pattern separation, whereas old granule cells facilitate pattern completion. Cell 2012; 149(1): 188–201.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Sahay A, Scobie KN, Hill AS, O’Carroll CM, Kheirbek MA, Burghardt NS, Fenton AA, Dranovsky A, Hen R. Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 2011; 472(7344): 466–470.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Drapeau E, Nora Abrous D. Stem cell review series: role of neurogenesis in age-related memory disorders. Aging Cell 2008; 7(4): 569–589.

    CAS  PubMed  Google Scholar 

  31. Ngwenya LB, Heyworth NC, Shwe Y, Moore TL, Rosene DL. Age-related changes in dentate gyrus cell numbers, neurogenesis, and associations with cognitive impairments in the rhesus monkey. Front Syst Neurosci 2015; 9: 102.

    PubMed  PubMed Central  Google Scholar 

  32. Braidy N, Poljak A, Grant R, Jayasena T, Mansour H, Chan-Ling T, Smythe G, Sachdev P, Guillemin GJ. Differential expression of sirtuins in the aging rat brain. Front Cell Neurosci 2015; 9: 167.

    PubMed  PubMed Central  Google Scholar 

  33. Kireev RA, Vara E, Tresguerres JA. Growth hormone and melatonin prevent age-related alteration in apoptosis processes in the dentate gyrus of male rats. Biogerontology 2013; 14(4): 431–442.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Taylor DM, Balabadra U, Xiang Z, Woodman B, Meade S, Amore A, Maxwell MM, Reeves S, Bates GP, Luthi-Carter R, Lowden PA, Kazantsev AG. A brain-permeable small molecule reduces neuronal cholesterol by inhibiting activity of sirtuin 2 deacetylase. ACS Chem Biol 2011; 6(6): 540–546.

    CAS  PubMed  Google Scholar 

  35. Brown JP, Couillard-Despres S, Cooper-Kuhn CM, Winkler J, Aigner L, Kuhn H G. Transient expression of doublecortin during adult neurogenesis. J Comp Neurol 2003; 467(1): 1–10.

    CAS  PubMed  Google Scholar 

  36. Couillard-Despres S, Winner B, Schaubeck S, Aigner R, Vroemen M, Weidner N, Bogdahn U, Winkler J, Kuhn HG, Aigner L. Doublecortin expression levels in adult brain reflect neurogenesis. Eur J Neurosci 2005; 21(1): 1–14.

    PubMed  Google Scholar 

  37. Franklin KBJ, Paxinos G. The mouse brain in stereotaxic coordinates. Academic Press, San Diego, 1997.

    Google Scholar 

  38. Liu R, Dang W, Du Y, Zhou Q, Jiao K, Liu Z. SIRT2 is involved in the modulation of depressive behaviors. Sci Rep 2015; 5: 8415.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Erburu M, Munoz-Cobo I, Dominguez-Andres J, Beltran E, Suzuki T, Mai A, Valente S, Puerta E, Tordera RM. Chronic stress and antidepressant induced changes in Hdac5 and Sirt2 affect synaptic plasticity. Eur Neuropsychopharmacol 2015; 25(11): 2036–2048.

    CAS  PubMed  Google Scholar 

  40. Pfister JA, Ma C, Morrison BE, D’Mello SR. Opposing effects of sirtuins on neuronal survival: SIRT1-mediated neuroprotection is independent of its deacetylase activity. PLoS One 2008; 3(12): e4090.

    Google Scholar 

  41. Chopra V, Quinti L, Kim J, Vollor L, Narayanan KL, Edgerly C, Cipicchio PM, Lauver MA, Choi SH, Silverman RB, Ferrante RJ, Hersch S, Kazantsev AG. The sirtuin 2 inhibitor AK-7 is neuroprotective in Huntington’s disease mouse models. Cell Rep 2012; 2(6): 1492–1497.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Pais TF, Szegõ ÉM, Marques O, Miller-Fleming L, Antas P, Guerreiro P, de Oliveira RM, Kasapoglu B, Outeiro TF. The NAD-dependent deacetylase sirtuin 2 is a suppressor of microglial activation and brain inflammation. EMBO J 2013; 32(19): 2603–2616.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Levenson JM, O’Riordan KJ, Brown KD, Trinh MA, Molfese DL, Sweatt JD. Regulation of histone acetylation during memory formation in the hippocampus. J Biol Chem 2004; 279(39): 40545–40559.

    CAS  PubMed  Google Scholar 

  44. Vecsey C. G., Hawk JD, Lattal KM, Stein JM, Fabian SA, Attner MA, Cabrera SM, McDonough CB, Brindle PK, Abel T, Wood MA. Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB:CBP-dependent transcriptional activation. J Neurosci 2007; 27(23): 6128–6140.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Gundersen BB, Blendy JA. Effects of the histone deacetylase inhibitor sodium butyrate in models of depression and anxiety. Neuropharmacology 2009; 57(1): 67–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Takuma K, Hara Y, Kataoka S, Kawanai T, Maeda Y, Watanabe R, Takano E, Hayata-Takano A, Hashimoto H, Ago Y, Matsuda T. Chronic treatment with valproic acid or sodium butyrate attenuates novel object recognition deficits and hippocampal dendritic spine loss in a mouse model of autism. Pharmacol Biochem Behav 2014; 126: 43–49.

    CAS  PubMed  Google Scholar 

  47. Valvassori SS, Calixto KV, Budni J, Resende WR, Varela RB, de Freitas KV, Goncalves CL, Streck EL, Quevedo J. Sodium butyrate reverses the inhibition of Krebs cycle enzymes induced by amphetamine in the rat brain. J Neural Transm (Vienna) 2013; 120(12): 1737–1742.

    CAS  Google Scholar 

  48. Rana P, Gupta M, Khan AR, Hemanth Kumar BS, Roy R, Khushu S. NMR based metabolomics reveals acute hippocampal metabolic fluctuations during cranial irradiation in murine model. Neurochem Int 2014; 74: 1–7.

    CAS  PubMed  Google Scholar 

  49. Achanta P, Fuss M, Martinez JL Jr. Ionizing radiation impairs the formation of trace fear memories and reduces hippocampal neurogenesis. Behav Neurosci 2009; 123(5): 1036–1045.

    PubMed  Google Scholar 

  50. Monje ML, Mizumatsu S, Fike JR, Palmer TD. Irradiation induces neural precursor-cell dysfunction. Nat Med 2002; 8(9): 955–962.

    CAS  PubMed  Google Scholar 

  51. Roughton K, Kalm M, Blomgren K. Sex-dependent differences in behavior and hippocampal neurogenesis after irradiation to the young mouse brain. Eur J Neurosci 2012; 36(6): 2763–2772.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Anatomy and Cell Biology, College of Veterinary Medicine, and Research Institute for Veterinary Science, Seoul National University, Seoul, Korea

    Hyo Young Jung, Dae Young Yoo, Jong Whi Kim, Yeo Sung Yoon & In Koo Hwang

  2. Department of Biochemistry and Molecular Biology, Research Institute of Oral Sciences, College of Dentistry, Gangneung-Wonju National University, Gangneung, Korea

    Dae Won Kim

  3. Department of Anatomy, College of Veterinary Medicine, Kangwon National University, Chuncheon, Korea

    Jung Hoon Choi

  4. Department of Veterinary Internal Medicine and Geriatrics, College of Veterinary Medicine, Kangwon National University, Chuncheon, Korea

    Jin Young Chung

  5. Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Korea

    Moo-Ho Won

  6. Department of Anatomy and Cell Biology, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Korea

    In Koo Hwang

Authors
  1. Hyo Young Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dae Young Yoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jong Whi Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dae Won Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jung Hoon Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jin Young Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Moo-Ho Won
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yeo Sung Yoon
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. In Koo Hwang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to In Koo Hwang.

Rights and permissions

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://doi.org/creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jung, H.Y., Yoo, D.Y., Kim, J.W. et al. Sirtuin-2 inhibition affects hippocampal functions and sodium butyrate ameliorates the reduction in novel object memory, cell proliferation, and neuroblast differentiation. Lab Anim Res 32, 224–230 (2016). https://doi.org/10.5625/lar.2016.32.4.224

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.5625/lar.2016.32.4.224

Keywords

  • AK-7
  • neurogenesis
  • novel object recognition test
  • sirtuin 2
  • sodium butyrate

Laboratory Animal Research

ISSN: 2233-7660