Ukr.Biochem.J. 2019; Volume 91, Issue 1, Jan-Feb, pp. 21-29
doi: https://doi.org/10.15407/ubj91.01.021
Altered sirtuins 1 and 2 expression in the brain of rats induced by experimental diabetes and the ways of its correction
M. M. Guzyk1, T. M. Tykhonenko1, K. O. Dyakun1,
L. V. Yanitska2, I. B. Pryvrotska3, T. M. Kuchmerovska1
1Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv;
2Bogomolets National Medical University, Kyiv, Ukraine;
3I. Horbachevsky Ternopil State Medical University, Ukraine;
e-mail: tkuchmerovska@gmail.com
Received: 03 August 2018; Accepted: 13 December 2018
The molecular pathogenesis of diabetic encephalopathy (DE), one of the serious complications of diabetes mellitus, is complex. In this study, we examined whether expression levels of SIRT1 and SIRT2 were the key for the development of brain dysfunctions and whether PARP-1 inhibitors could affect the expression of these proteins for prevention the development of DE in rats with type 1 diabetes. After 10 weeks of the streptozotocin-induced diabetes mellitus (70 mg/kg), Wistar male rats were treated by i.p. injection with PARP-1 inhibitors, 1.5-isoquinolinediol (ISO) or nicotinamide (NAm) (3 or 100 mg/kg/daily i.p., respectively) for 2 weeks. The rats with blood glucose levels over 19.7 ± 2.1 mmol/l were taken into experiments. Western blots were performed to evaluate effects of PAPR-1 inhibitors on the levels of sirtuins, SIRT1 and SIRT2 expression. Diabetes induced significant reduction of SIRT1 expression and SIRT2 overexpression in brain nuclear extracts of diabetic rats compared to non-diabetic control. In brain, NAm attenuated SIRT2 overexpression in nuclear extracts of diabetic rats and slightly elevated SIRT1 expression, while ISO didn’t affect expression of both sirtuins in diabetic rats. Furthermore, it was observed that in brain of diabetic rats, the ratio of free NAD/NADH couples decreased 3.1-fold compared to non-diabetic control. The administration of ISO increased only slightly the ratio of free NAD/NADH couples in the brain of diabetic rats while NAm increased this parameter 1.7-fold compared to diabetic rats. Therefore, we concluded that alterations in the expression of SIRT1 and SIRT2 in brain cell nuclei of diabetic rats can lead to the development of brain dysfunctions. One of the neuroprotective mechanisms of NAm action can also be realized through inhibition of SIRT2 expression in brain cell nuclei that down-regulate progression of diabetes-induced alterations and can be a therapeutic option for treatment of brain dysfunctions.
Keywords: 1.5-isoquinolinediol (ISO), diabetes mellitus, expression of sirtuins, nicotinamide (NAm), PARP-1 inhibitors, SIRT1, SIRT2
References:
- Grünblatt E, Bartl J, Riederer P. The link between iron, metabolic syndrome, and Alzheimer’s disease. J Neural Transm (Vienna). 2011 Mar;118(3):371-9.
PubMed, CrossRef - Monette MC, Baird A, Jackson DL. A meta-analysis of cognitive functioning in nondemented adults with type 2 diabetes mellitus. Can J Diabetes. 2014 Dec;38(6):401-8. PubMed, CrossRef
- Wong RH, Scholey A, Howe PR. Assessing premorbid cognitive ability in adults with type 2 diabetes mellitus — a review with implications for future intervention studies. Curr Diab Rep. 2014;14(11):547. PubMed, CrossRef
- Sima AA. Encephalopathies: the emerging diabetic complications. Acta Diabetol. 2010 Dec;47(4):279-93. PubMed, CrossRef
- Wayhs CA, Mescka CP, Guerreiro G, Moraes TB, Jacques CE, Rosa AP, Ferri MK, Nin MS, Dutra-Filho CS, Barros HM, Vargas CR. Diabetic encephalopathy-related depression: experimental evidence that insulin and clonazepam restore antioxidant status in rat brain. Cell Biochem Funct. 2014 Dec;32(8):711-9. PubMed, CrossRef
- Ray Chaudhuri A, Nussenzweig A. The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat Rev Mol Cell Biol. 2017 Oct;18(10):610-621. PubMed, CrossRef
- Chaitanya GV, Steven AJ, Babu PP. PARP-1 cleavage fragments: signatures of cell-death proteases in neurodegeneration. Cell Commun Signal. 2010 Dec 22;8:31. PubMed, PubMedCentral, CrossRef
- Drel VR, Pacher P, Stavniichuk R, Xu W, Zhang J, Kuchmerovska TM, Slusher B, Obrosova IG. Poly(ADP-ribose)polymerase inhibition counteracts renal hypertrophy and multiple manifestations of peripheral neuropathy in diabetic Akita mice. Int J Mol Med. 2011 Oct;28(4):629-35. PubMed, PubMedCentral, CrossRef
- Virág L, Szabó C. The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol Rev. 2002 Sep;54(3):375-429. PubMed, CrossRef
- Guzyk MM, Dyakun KO, Yanytska LV, Pryvrotska IB, Krynytska IYa, Pishel’ IM, Kuchmerovska TM. Inhibitors of poly(ADP-ribose)polymerase-1 as agents providing correction of brain dysfunctions induced by experimental diabetes. Neurophysiology. 2017;49(3):183-193. CrossRef
- Sugaya-Fukasawa M, Watanabe T, Tamura M, Egashira S, Hisatomi H. Glial fibrillary acidic protein is one of the key factors underlying neuron-like elongation in PC12 cells. Exp Ther Med. 2011 Jan;2(1):85-87. PubMed, PubMedCentral, CrossRef
- Kuchmerovska T, Shymanskyy I, Donchenko G, Kuchmerovskyy M, Pakirbaieva L, Klimenko A. Poly(ADP-ribosyl)ation enhancement in brain cell nuclei is associated with diabetic neuropathy. J Diabetes Complications. 2004 Jul-Aug;18(4):198-204. PubMed, CrossRef
- Kuchmerovska T, Shymanskyy I, Chlopicki S, Klimenko A. 1-methylnicotinamide (MNA) in prevention of diabetes-associated brain disorders. Neurochem Int. 2010 Jan;56(2):221-8. PubMed, CrossRef
- erdin E, Hirschey MD, Finley LW, Haigis MC. Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends Biochem Sci. 2010 Dec;35(12):669-75. PubMed, PubMedCentral, CrossRef
- Flick F, Lüscher B. Regulation of sirtuin function by posttranslational modifications. Front Pharmacol. 2012 Feb 28;3:29. PubMed, PubMedCentral, CrossRef
- Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol. 2010;5:253-95. PubMed, PubMedCentral, CrossRef
- Chalkiadaki A, Guarente L. Sirtuins mediate mammalian metabolic responses to nutrient availability. Nat Rev Endocrinol. 2012 Jan 17;8(5):287-96. PubMed, CrossRef
- Austad SN. Ageing: Mixed results for dieting monkeys. Nature. 2012 Sep 13;489(7415):210-11. PubMed, CrossRef
- Bishop NA, Guarente L. Genetic links between diet and lifespan: shared mechanisms from yeast to humans. Nat Rev Genet. 2007 Nov;8(11):835-44. PubMed, CrossRef
- Jiang H, Medintz I, Zhang B, Michels CA. Metabolic signals trigger glucose-induced inactivation of maltose permease in Saccharomyces. J Bacteriol. 2000 Feb;182(3):647-54. PubMed, PubMedCentral, CrossRef
- Mair W, Goymer P, Pletcher SD, Partridge L. Demography of dietary restriction and death in Drosophila. Science. 2003 Sep 19;301(5640):1731-3. PubMed, CrossRef
- Cohen MJ, Carstenn S, Lane CR. Floristic quality indices for biotic assessment of depressional marsh condition in Florida. Ecol Appl. 2004;14(3):784-794. CrossRef
- Utani K, Fu H, Jang SM, Marks AB, Smith OK, Zhang Y, Redon CE, Shimizu N, Aladjem MI. Phosphorylated SIRT1 associates with replication origins to prevent excess replication initiation and preserve genomic stability. Nucleic Acids Res. 2017 Jul 27;45(13):7807-7824. PubMed, PubMedCentral, CrossRef
- Frye RA. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys Res Commun. 2000 Jul 5;273(2):793-8. PubMed, CrossRef
- Guarente L. Sirtuins, aging, and metabolism. Cold Spring Harb Symp Quant Biol. 2011;76:81-90. PubMed, CrossRef
- Guarente L. Calorie restriction and sirtuins revisited. Genes Dev. 2013 Oct 1;27(19):2072-85. PubMed, PubMedCentral, http://dx.doi.org/10.1101/gad.227439.113″]
- Tanno M, Sakamoto J, Miura T, Shimamoto K, Horio Y. Nucleocytoplasmic shuttling of the NAD+-dependent histone deacetylase SIRT1. J Biol Chem. 2007 Mar 2;282(9):6823-32. PubMed, CrossRef
- Serrano L, Martínez-Redondo P, Marazuela-Duque A, Vazquez BN, Dooley SJ, Voigt P, Beck DB, Kane-Goldsmith N, Tong Q, Rabanal RM, Fondevila D, Muñoz P, Krüger M, Tischfield JA, Vaquero A. The tumor suppressor SirT2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of H4K20 methylation. Genes Dev. 2013 Mar 15;27(6):639-53. PubMed, PubMedCentral, CrossRef
- Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000 Feb 17;403(6771):795-800. PubMed, CrossRef
- Hallows WC, Yu W, Denu JM. Regulation of glycolytic enzyme phosphoglycerate mutase-1 by Sirt1 protein-mediated deacetylation. J Biol Chem. 2012 Feb 3;287(6):3850-8. PubMed, PubMedCentral, CrossRef
- Mattagajasingh I, Kim CS, Naqvi A, Yamamori T, Hoffman TA, Jung SB, DeRicco J, Kasuno K, Irani K. SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proc Natl Acad Sci USA. 2007 Sep 11;104(37):14855-60. PubMed, PubMedCentral, CrossRef
- Planavila A, Iglesias R, Giralt M, Villarroya F. Sirt1 acts in association with PPARα to protect the heart from hypertrophy, metabolic dysregulation, and inflammation. Cardiovasc Res. 2011 May 1;90(2):276-84. PubMed, CrossRef
- 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-κB p65 acetylation and activation. J Neurochem. 2016 Feb;136(3):581-93. PubMed
- Yu TT, McIntyre JC, Bose SC, Hardin D, Owen MC, McClintock TS. Differentially expressed transcripts from phenotypically identified olfactory sensory neurons. J Comp Neurol. 2005 Mar 14;483(3):251-62. PubMed, PubMedCentral, CrossRef
- Dryden SC, Nahhas FA, Nowak JE, Goustin AS, Tainsky MA. Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle. Mol Cell Biol. 2003 May;23(9):3173-85. PubMed, PubMedCentral, CrossRef
- Bai P, Cantó C, Oudart H, Brunyánszki A, Cen Y, Thomas C, Yamamoto H, Huber A, Kiss B, Houtkooper RH, Schoonjans K, Schreiber V, Sauve AA, Menissier-de Murcia J, Auwerx J. PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metab. 2011 Apr 6;13(4):461-468. PubMed, PubMedCentral, CrossRef
- Shaiken TE, Opekun AR. Dissecting the cell to nucleus, perinucleus and cytosol. Sci Rep. 2014 May 12;4:4923. PubMed, PubMedCentral, CrossRef
- Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680-5. PubMed, CrossRef
- Bergmeyer HU. Methods of Enzymatic Analysis. 1963; 1064 p.
- Guzyk MM, Tykhomyrov AA, Nedzvetsky VS, Prischepa IV, Grinenko TV, Yanitska LV, Kuchmerovska TM. Poly(ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors Reduce Reactive Gliosis and Improve Angiostatin Levels in Retina of Diabetic Rats. Neurochem Res. 2016 Oct;41(10):2526-2537. PubMed, CrossRef
- Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248-54. PubMed, CrossRef
- Chen J, Zhou Y, Mueller-Steiner S, Chen LF, Kwon H, Yi S, Mucke L, Gan L. SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling. J Biol Chem. 2005 Dec 2;280(48):40364-74. PubMed, CrossRef
- Satoh A, Brace CS, Ben-Josef G, West T, Wozniak DF, Holtzman DM, Herzog ED, Imai S. SIRT1 promotes the central adaptive response to diet restriction through activation of the dorsomedial and lateral nuclei of the hypothalamus. J Neurosci. 2010 Jul 28;30(30):10220-32. PubMed, PubMedCentral, CrossRef
- Rajesh M, Mukhopadhyay P, Godlewski G, Bátkai S, Haskó G, Liaudet L, Pacher P. Poly(ADP-ribose)polymerase inhibition decreases angiogenesis. Biochem Biophys Res Commun. 2006 Dec 1;350(4):1056-62. PubMed, PubMedCentral, CrossRef
- Jeon SM. Regulation and function of AMPK in physiology and diseases. Exp Mol Med. 2016 Jul 15;48(7):e245. PubMed, PubMedCentral, CrossRef
- Katsyuba E, Auwerx J. Modulating NAD(+) metabolism, from bench to bedside. EMBO J. 2017 Sep 15;36(18):2670-2683. PubMed, PubMedCentral, CrossRef
- Cantó C, Menzies KJ, Auwerx J. NAD(+) Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus. Cell Metab. 2015 Jul 7;22(1):31-53. PubMed, PubMedCentral, CrossRef
- Erecińska M, Wilson DF. Regulation of cellular energy metabolism. J Membr Biol. 1982;70(1):1-14. PubMed
- Momsen G. Effect of increasing the intracellular ratio of NADH to NAD+ on human erythrocyte metabolism: new estimation of the turnover through the phosphoglycerate shunt. Arch Biochem Biophys. 1981 Aug;210(1):160-6. PubMed, CrossRef
- Milne JC, Lambert PD, Schenk S, Carney DP, Smith JJ, Gagne DJ, Jin L, Boss O, Perni RB, Vu CB, Bemis JE, Xie R, Disch JS, Ng PY, Nunes JJ, Lynch AV, Yang H, Galonek H, Israelian K, Choy W, Iffland A, Lavu S, Medvedik O, Sinclair DA, Olefsky JM, Jirousek MR, Elliott PJ, Westphal CH. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 2007 Nov 29;450(7170):712-6. PubMed, PubMedCentral
- de Kreutzenberg SV, Ceolotto G, Papparella I, Bortoluzzi A, Semplicini A, Dalla Man C, Cobelli C, Fadini GP, Avogaro A. Downregulation of the longevity-associated protein sirtuin 1 in insulin resistance and metabolic syndrome: potential biochemical mechanisms. Diabetes. 2010 Apr;59(4):1006-15. PubMed, PubMedCentral, CrossRef
- Harrison IF, Smith AD, Dexter DT. Pathological histone acetylation in Parkinson’s disease: Neuroprotection and inhibition of microglial activation through SIRT 2 inhibition. Neurosci Lett. 2018 Feb 14;666:48-57. PubMed, PubMedCentral, CrossRef
- Inoue T, Hiratsuka M, Osaki M, Oshimura M. The molecular biology of mammalian SIRT proteins: SIRT2 in cell cycle regulation. Cell Cycle. 2007 May 2;6(9):1011-8. PubMed, CrossRef
- Jangra A, Datusalia AK, Sharma SS. Reversal of neurobehavioral and neurochemical alterations in STZ-induced diabetic rats by FeTMPyP, a peroxynitrite decomposition catalyst and 1,5-Isoquinolinediol a poly(ADP-ribose) polymerase inhibitor. Neurol Res. 2014 Jul;36(7):619-26. PubMed, CrossRef
- Hirst J, Roessler MM. Energy conversion, redox catalysis and generation of reactive oxygen species by respiratory complex I. Biochim Biophys Acta. 2016 Jul;1857(7):872-83. PubMed, PubMedCentral, CrossRef
