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Number of manic episodes is associated with elevated DNA oxidation in bipolar I disorder

  • Márcio Gerhardt Soeiro-de-Souza (a1), Ana C. Andreazza (a2) (a3) (a4), Andre F. Carvalho (a5), Rodrigo Machado-Vieira (a6) (a7), L. Trevor Young (a2) (a3) (a4) and Ricardo Alberto Moreno (a1)...

Bipolar disorder (BD) is a major public health problem characterized by progressive functional impairment. A number of clinical variables have been associated with progression of the disease, most notably number of affective episodes and presence of psychotic symptoms, both of which correlate with greater cognitive impairment, lower response rates for lithium, and possibly lower levels of neurotrophic factors. Oxidative damage to cytosine and guanosine (8-OHdG) has been described as a modulator of DNA methylation, but the extent of DNA oxidative damage involvement in BD remains unclear. The aim of this study was to evaluate the extent of DNA oxidative damage to 8-OHdG and 5-methylcytosine (5-HMec), as well as global methylation (5-Mec), in BD patients and healthy controls. Potential association with clinical variables was also investigated. DNA levels of 8-OHdG, 5-HMec and 5-Mec were measured in 50 BD type I patients and 50 healthy controls. DNA 8-OHdG levels were higher in BD patients compared to healthy controls and found to be positively influenced by number of previous manic episodes. BD subjects had lower levels of 5-HMec compared to controls, whereas this measure was not influenced by the clinical features of BD. Number of manic episodes was correlated with higher levels of 8-OHdG, but not of 5-Mec or 5-HMec. Lower demethylation activity (5-HMec) but no difference in global 5-Mec levels was observed in BD. This finding suggests that oxidative damage to 8-OHdG might be a potential marker of disease progression, although further prospective cross-sectional studies to confirm neuroprogression in BD are warranted.

Corresponding author
Address for correspondence: Dr M. G. Soeiro-de-Souza, Ovidio Pires de Campos, 785, Instituto de Psiquiatria, 3° andar norte, CEAPESQ sala 12. CEP 05403-010, São Paulo, Brazil. Tel.: 55 11 26616648Fax:55 11
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HM Abdolmaleky , K-H Cheng , SV Faraone , M Wilcox , SJ Glatt , F Gao , CL Smith , R Shafa , B Aeali , J Carnevale , H Pan , P Papageorgis , JF Ponte , V Sivaraman , MT Tsuang , S Thiagalingam (2006) Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder. Hum Mol Genet 15:31323145.

F Altieri , C Grillo , M Maceroni , S Chichiarelli (2008) DNA damage and repair: from molecular mechanisms to health implications. Antioxid Redox Signal 10:891937.

AC Andreazza , BN Frey , B Erdtmann , M Salvador , F Rombaldi , A Santin , CA Gonçalves , F Kapczinski (2007) DNA damage in bipolar disorder. Psychiatry Res 153:2732.

AC Andreazza , M Kauer-Sant'Anna , BN Frey , DJ Bond , F Kapczinski , LT Young , LN Yatham (2008) Oxidative stress markers in bipolar disorder: a meta-analysis. J Affect Disord 111:135144.

M Berk (2009) Neuroprogression: pathways to progressive brain changes in bipolar disorder. Int J Neuropsychopharmacol 12:441445.

M Berk , F Kapczinski , AC Andreazza , OM Dean , F Giorlando , M Maes , M Yücel , CS Gama , S Dodd , B Dean , PVS Magalhães , P Amminger , P McGorry , GS Malhi (2011) Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev 35:804817.

E Bora , M Yücel , C Pantelis (2010) Neurocognitive markers of psychosis in bipolar disorder: a meta-analytic study. J Affect Disord 127:19.

A Bromberg , Y Bersudsky , J Levine , G Agam (2009) Global leukocyte DNA methylation is not altered in euthymic bipolar patients. J Affect Disord 118:234239.

N Buttner , S Bhattacharyya , J Walsh , FM Benes (2007) DNA fragmentation is increased in non-GABAergic neurons in bipolar disorder but not in schizophrenia. Schizophr Res 93:3341.

RN Campos , LF Costa , DS Bio , MGS de Souza , CRL Garcia , FN Demétrio , DH Moreno , RA Moreno (2010) LICAVAL: combination therapy in acute and maintenance treatment of bipolar disorder. Trials 11:72.

JTO Cavanagh , M Van Beck , W Muir , DHR Blackwood (2002) Case–control study of neurocognitive function in euthymic patients with bipolar disorder: an association with mania. Br J Psychiatry 180:320326.

Q Chen , A Fischer , JD Reagan , LJ Yan , BN Ames (1995) Oxidative DNA damage and senescence of human diploid fibroblast cells. Proc Natl Acad Sci USA 92:43374341.

JY Choi , HS Kim , HK Kang , DW Lee , EM Choi , MH Chung (1999) Thermolabile 8-hydroxyguanine DNA glycosylase with low activity in senescence-accelerated mice due to a single-base mutation. Free Radic Biol Med 27:848854.

L Clark , SD Iversen , GM Goodwin (2002) Sustained attention deficit in bipolar disorder. Br J Psychiatry 180:313319.

W Coryell , AC Leon , C Turvey , HS Akiskal , T Mueller , J Endicott (2001) The significance of psychotic features in manic episodes: a report from the NIMH collaborative study. J Affect Disord 67:7988.

EL Dempster , R Pidsley , LC Schalkwyk , S Owens , A Georgiades , F Kane , S Kalidindi , M Picchioni , E Kravariti , T Toulopoulou , RM Murray , J Mill (2011) Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder. Hum Mol Genet 20:47864796.

SM El-Badri , CH Ashton , PB Moore , VR Marsh , IN Ferrier (2001) Electrophysiological and cognitive function in young euthymic patients with bipolar affective disorder. Bipolar Disord 3:7987.

DL Evans (2005) Mood disorders in the medically ill: scientific review and recommendations. Biol Psychiatry 58:175189.

SA Everson-Rose , JS House , RP Mero (2004) Depressive symptoms and mortality risk in a national sample: confounding effects of health status. Psychosom Med 66:823830.

IN Ferrier , JM Thompson (2002) Cognitive impairment in bipolar affective disorder: implications for the bipolar diathesis. Br J Psychiatry 180:293295.

MJ Forlenza , GE Miller (2006) Increased serum levels of 8-hydroxy-2′-deoxyguanosine in clinical depression. Psychosom Med 68:17.

BB Gump , KA Matthews , LE Eberly , Y-F Chang , MRFIT Research Group (2005) Depressive symptoms and mortality in men: results from the Multiple Risk Factor Intervention Trial. Stroke 36:98102.

JM Gutteridge , B Halliwell (2010) Antioxidants: molecules, medicines, and myths. Biochem Biophys Res Commun 393:561564.

JU Guo , Y Su , C Zhong , G-L Ming , H Song (2011) Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell 145:423434.

JM Gutteridge , B Halliwell (2000) Free radicals and antioxidants in the year 2000. A historical look to the future. Ann N Y Acad Sci 899:136147.

R-P Juster , BS McEwen , SJ Lupien (2010) Allostatic load biomarkers of chronic stress and impact on health and cognition. Neurosci Biobehav Rev 35:216.

F Kapczinski , E Vieta , AC Andreazza , BN Frey , FA Gomes , J Tramontina , M Kauer-Sant'Anna , R Grassi-Oliveira , RM Post (2008) Allostatic load in bipolar disorder: implications for pathophysiology and treatment. Neurosci Biobehav Rev 32:675692.

M Kauer-Sant'Anna , F Kapczinski , AC Andreazza , DJ Bond , RW Lam , LT Young , LN Yatham (2009) Brain-derived neurotrophic factor and inflammatory markers in patients with early- vs. late-stage bipolar disorder. Int J Neuropsychopharmacol 12:447458.

JE Klaunig , LM Kamendulis (2004) The role of oxidative stress in carcinogenesis. Annu Rev Pharmacol Toxicol 44:239267.

A Klungland , I Rosewell , S Hollenbach , E Larsen , G Daly , B Epe , E Seeberg , T Lindahl , DE Barnes (1999) Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage. Proc Natl Acad Sci USA 96:1330013305.

R Kohen , A Nyska (2002) Oxidation of biological systems: oxidative stress phenomena, antioxidants, redox reactions, and methods for their quantification. Toxicol Pathol 30:620650.

TB Kryston , AB Georgiev , P Pissis , AG Georgakilas (2011) Role of oxidative stress and DNA damage in human carcinogenesis. Mutat Res 711:193201.

DJ Kupfer (2005) The increasing medical burden in bipolar disorder. J Am Med Assoc 293:25282530.

N Kupper , Y Gidron , J Winter , J Denollet (2009) Association between type D personality, depression, and oxidative stress in patients with chronic heart failure. Psychosom Med 71:973980.

G Kuratomi , K Iwamoto , M Bundo , I Kusumi , N Kato , N Iwata , N Ozaki , T Kato (2008) Aberrant DNA methylation associated with bipolar disorder identified from discordant monozygotic twins. Mol Psychiatry 13:429441.

G Lenaz (2001) The mitochondrial production of reactive oxygen species: mechanisms and implications in human pathology. IUBMB Life 52:159164.

S-O Lim , J-M Gu , MS Kim , H-S Kim , YN Park , CK Park , JW Cho , YM Park , G Jung (2008) Epigenetic changes induced by reactive oxygen species in hepatocellular carcinoma: methylation of the E-cadherin promoter. Gastroenterology 135:21282140.

IK Lyoo , YH Sung , SR Dager , SD Friedman , J-Y Lee , SJ Kim , N Kim , DL Dunner , PF Renshaw (2006) Regional cerebral cortical thinning in bipolar disorder. Bipolar Disord 8:6574.

BS McEwen (2003) Interacting mediators of allostasis and allostatic load: towards an understanding of resilience in aging. Metab Clin Exp 52:1016.

SA Montgomery , M Asberg (1979) A new depression scale designed to be sensitive to change. Br J Psychiatry 134:382389.

S Nohesara , M Ghadirivasfi , S Mostafavi , M-R Eskandari , H Ahmadkhaniha , S Thiagalingam , HM Abdolmaleky (2011) DNA hypomethylation of MB-COMT promoter in the DNA derived from saliva in schizophrenia and bipolar disorder. J Psychiatr Res 45:14321438.

BW Penninx , JM Guralnik , M Pahor , L Ferrucci , JR Cerhan , RB Wallace , RJ Havlik (1998) Chronically depressed mood and cancer risk in older persons. J Natl Cancer Inst 90:18881893.

JM Plume , SRH Beach , GH Brody , RA Philibert (2012) A cross-platform genome-wide comparison of the relationship of promoter DNA methylation to gene expression. Front Genet 3:12.

Z Radak , I Boldogh (2010) 8-Oxo-7,8-dihydroguanine: links to gene expression, aging, and defense against oxidative stress. Free Radic Biol Med 49:587596.

LJ Robinson , IN Ferrier (2006) Evolution of cognitive impairment in bipolar disorder: a systematic review of cross-sectional evidence. Bipolar Disord 8:103116.

A Rosa , MM Picchioni , S Kalidindi , CS Loat , J Knight , T Toulopoulou , R Vonk , AC van der Schot , W Nolen , RS Kahn , P McGuffin , RM Murray , IW Craig (2008) Differential methylation of the X-chromosome is a possible source of discordance for bipolar disorder female monozygotic twins. Am J Med Genet B Neuropsychiatr Genet 147B:459462.

J Shen , P Deininger , JD Hunt , H Zhao (2007) 8-Hydroxy-2′-deoxyguanosine (8-OH-dG) as a potential survival biomarker in patients with nonsmall-cell lung cancer. Cancer 109:574580.

A Spassky , D Angelov (1997) Influence of the local helical conformation on the guanine modifications generated from one-electron DNA oxidation. Biochemistry 36:65716576.

SM Strakowski , MP DelBello , ME Zimmerman , GE Getz , NP Mills , J Ret , P Shear , CM Adler (2002) Ventricular and periventricular structural volumes in first- vs. multiple-episode bipolar disorder. Am J Psychiatry 159:18411847.

AC Swann , CL Bowden , JR Calabrese , SC Dilsaver , DD Morris (2000) Mania: differential effects of previous depressive and manic episodes on response to treatment. Acta Psychiatr Scand 101:444451.

AC Swann , CL Bowden , D Morris , JR Calabrese , F Petty , J Small , SC Dilsaver , JM Davis (1997) Depression during mania. Treatment response to lithium or divalproex. Arch Gen Psychiatry 54:3742.

M Tahiliani , KP Koh , Y Shen , WA Pastor , H Bandukwala , Y Brudno , S Agarwal , LM Iyer , DR Liu , L Aravind , A Rao (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324:930935.

M Tohen , CM Waternaux , MT Tsuang (1990) Outcome in mania. A 4-year prospective follow-up of 75 patients utilizing survival analysis. Arch Gen Psychiatry 47:11061111.

M Valko , M Izakovic , M Mazur , CJ Rhodes , J Telser (2004) Role of oxygen radicals in DNA damage and cancer incidence. Mol Cell Biochem 266:3756.

M Valko , CJ Rhodes , J Moncol , M Izakovic , M Mazur (2006) Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 160:140.

JT Wachsman (1997) DNA methylation and the association between genetic and epigenetic changes: relation to carcinogenesis. Mutat Res 375:18.

Y-C Wei , F-L Zhou , D-L He , J-R Bai , H Ding , X-Y Wang , K-J Nan (2009) Oxidative stress in depressive patients with gastric adenocarcinoma. Int J Neuropsychopharmacol 12:10891096.

ML Wood , M Dizdaroglu , E Gajewski , JM Essigmann (1990) Mechanistic studies of ionizing radiation and oxidative mutagenesis: genetic effects of a single 8-hydroxyguanine (7-hydro-8-oxoguanine) residue inserted at a unique site in a viral genome. Biochemistry 29:70247032.

RC Young , JT Biggs , VE Ziegler , DA Meyer (1978) A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 133:429435.

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