Background: Recent studies have revealed that recurrent depressive disorders (rDD) are linked with dysregulation of the immune system. Previous studies have found that manganese superoxide dismutase (MnSOD, SOD2) may be a key inflammatory enzyme involved in this disorder. The purpose of this study was to determine the mRNA and protein levels of MnSOD in patients with rDD and to define the relationship between serum MnSOD levels and cognitive performance. Methods: The study comprised 236 subjects, which included patients with rDD (n = 131) and healthy subjects (n = 105, healthy control group, HC). Assessment of cognitive function was based on performance on the Trail Making test (TMT), the Stroop test, the Verbal Fluency test (VFT) and the Auditory Verbal Learning test (AVLT). Results: MnSOD gene expression at mRNA and protein level was significantly lower in rDD patients than in the HC group (p < 0.01). In the rDD and HC groups separately, there were no statistically significant associations between mRNA and protein expression levels of the MnSOD and psychological tests. In the total study group (n = 236), there was a statistically significant correlation between both MnSOD gene levels and the following tests (p < 0.01): the TMT parts A and B (negative correlation), the Stroop test parts RCNb (reading color names in black) and NCWd (naming color of word - different; negative correlation), the VFT (positive correlation) and the AVLT (positive correlation). Conclusions: Our study provides evidence that the MnSOD enzyme-coding gene and MnSOD expression are important for the regulation of cognitive functioning.

Keywords:
Depression, Cognition, Inflammation, Manganese superoxide dismutase
1.
Leonard B, Maes M: Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci Biobehav Rev 2012;36:764-785.
2.
Dowlati Y, Hermann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctot KL: A meta-analysis of cytokines in major depression. Biol Psychiatry 2010;67:446-457.
3.
Maes M, Gałecki P, Chang YS, Berk M: A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness. Prog Neuropsychopharmacol Biol Psychiatry 2011;35:676-692.
4.
Raison CL, Capuron L, Miller AH: Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol 2006;27:24-31.
5.
Maes M, Berk M, Goehler L, Song C, Anderson G, Gałecki P, Leonard B: Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways. BMC Med 2012;10:66.
6.
Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW: From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008;9:46-56.
7.
Johnson F, Giulivi C: Superoxide dismutases and their impact upon human health. Mol Aspect Med 2005;26:340-352.
8.
Halliwell B: Oxidative stress and neurodegeneration: where are we now? J Neurochem 2006;97:1634-1658.
9.
Khanzode SD, Dakhale GN, Khanzode SS, Saoji A, Palasodkar R: Oxidative damage and major depression: the potential antioxidant action of selective serotonin re-uptake inhibitors. Redox Rep 2003;8:365-370.
10.
Sarandol A, Sarandol E, Eker SS, Erdinc S, Vatansever E, Kirli S: Major depressive disorder is accompanied with oxidative stress: short-term antidepressant treatment does not alter oxidative-antioxidative systems. Hum Psychopharmacol 2007;22:67-73.
11.
ICD-10 Classification of Mental and Behavioural Disorders. Geneva, World Health Organization, 1993.
12.
Patten SB: Performance of the Composite International Diagnostic Interview Short Form for major depression in community and clinical samples. Chronic Dis Can 1997;18:109-112.
13.
Talarowska M, Gałecki P, Maes M, Bobińska K, Kowalczyk E: Total antioxidant status correlates with cognitive impairment in patients with recurrent depressive disorder. Neurochem Res 2012;37:1761-1767.
14.
Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56-62.
15.
Demyttenaere K, De Fruyt J: Getting what you ask for: on the selectivity of depression rating scales. Psychother Psychosom 2003;72:61-70.
16.
Chomczyński P, Sacchi N: Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987;162:156-159.
17.
Winer J, Jung CK, Shackel I, Williams PM: Development and validation of real-time quantitative reverse transcriptase-polymerase chain reaction for monitoring gene expression in cardiac myocytes in vitro. Anal Biochem 1999;270:41-49.
18.
Kirkwood B, Sterne J: Essential Medical Statistics, ed 2. Wiley-Bleckwell, 2003.
19.
Szuster-Ciesielska A, Słotwińska M, Stachura A, Marmurowska-Michałowska H, Dubas-Slemp H, Bojarska-Junak A, Kandefer-Szerszeń M: Accelerated apoptosis of blood leukocytes and oxidative stress in blood of patients with major depression. Prog Neuropsychopharmacol Biol Psychiatry 2008;32:686-694.
20.
Herken H, Gurel A, Selek S, Armutcu F, Ozen ME, Bulut M, Kap O, Yumru M, Savas HA, Akyol O: Adenosine deaminase, nitric oxide, superoxide dismutase, and xanthine oxidase in patients with major depression: impact of antidepressant treatment. Arch Med Res 2007;38:247-252.
21.
Selek S, Savas HA, Gergerlioglu HS, Bulbul F, Uz E, Yumru M: The course of nitric oxide and superoxide dismutase during treatment of bipolar depressive episode. J Affect Disord 2008;107:89-94.
22.
Gałecki P, Szemraj J, Bieńkiewicz M, Florkowski A, Gałecka E: Lipid peroxidation and antioxidant protection in patients during acute depressive episodes and in remission after fluoxetine treatment. Pharmacol Rep 2009;61:436-447.
23.
Cumurcu BE, Ozyurt H, Ates O, Gul IG, Demir S, Karlıdag R: Analysis of manganese superoxide dismutase (MnSOD: Ala-9Val) and glutathione peroxidase (GSH-Px: Pro 197 Leu) gene polymorphisms in mood disorders. Bosn J Basic Med Sci 2013;13:109-113.
24.
Maes M: Depression is an inflammatory disease, but cell-mediated immune activation is the key component of depression. Prog Neuropsychopharmacol Biol Psychiatry 2011;35:664-675.
25.
Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J: Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 2007;39:44-84.
26.
Müller GJ, Lassmann H, Johansen FF: Anti-apoptotic signaling and failure of apoptosis in the ischemic rat hippocampus. Neurobiol Dis 2007;25:582-593.
27.
Radenović L, Selaković V, Kartelija G: Mitochondrial superoxide production and MnSOD activity after exposure to agonist and antagonists of ionotropic glutamate receptors in hippocampus. Ann NY Acad Sci 2005;1048:363-365.
28.
Li Y, Huang TT, Carlson EJ, Melov S, Ursell PC, Olson JL, Noble LJ, Yoshimura MP, Berger C, Chan PH, Wallace DC, Epstein CJ: Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nat Genet 1995;11:376-381.
29.
Herring A, Blome M, Ambrée O, Sachser N, Paulus W, Keyvani K: Reduction of cerebral oxidative stress following environmental enrichment in mice with Alzheimer-like pathology. Brain Pathol 2010;20:166-175.
30.
Michel TM, Frangou S, Thiemeyer D, Camara S, Jecel J, Nara K, Brunklaus A, Zoechling R, Riederer P: Evidence for oxidative stress in the frontal cortex in patients with recurrent depressive disorder - a postmortem study. Psychiatry Res 2007;151:145-150.
31.
Fabrizio P, Liou LL, Moy VN, Diaspro A, Valentine JS, Gralla EB, Longo VD: SOD2 functions downstream of Sch9 to extend longevity in yeast. Genetics 2003;163:35-46.
32.
Hinerfeld D, Traini MD, Weinberger RP, Cochran B, Doctrow SR, Harry J, Melov S: Endogenous mitochondrial oxidative stress: neurodegeneration, proteomic analysis, specific respiratory chain defects, and efficacious antioxidant therapy in superoxide dismutase 2 null mice. J Neurochem 2004;88:657-667.
33.
Hu D, Cao P, Thiels E, Chu CT, Wu GY, Oury TD, Klann E: Hippocampal long-term potentiation, memory, and longevity in mice that overexpress mitochondrial superoxide dismutase. Neurobiol Learn Mem 2007;87:372-384.
34.
Soerensen M, Christensen K, Stevnsner T, Christiansen L: The Mn-superoxide dismutase single nucleotide polymorphism rs4880 and the glutathione peroxidase 1 single nucleotide polymorphism rs1050450 are associated with aging and longevity in the oldest old. Mech Ageing Dev 2009;130:308-314.
35.
Dumont M, Wille E, Stack C, Calingasan NY, Beal MF, Lin MT: Reduction of oxidative stress, amyloid deposition, and memory deficit by manganese superoxide dismutase overexpression in a transgenic mouse model of Alzheimer's disease. FASEB J 2009;23:2459-2466.
36.
Li F, Calingasan NY, Yu F, Mauck WM, Toidze M, Almeida CG, Takahashi RH, Carlson GA, Flint Beal M, Lin MT, Gouras GK: Increased plaque burden in brains of APP mutant MnSOD heterozygous knockout mice. J Neurochem 2004;89:1308-1312.
37.
Melov S, Adlard PA, Morten K, Johnson F, Golden TR, Hinerfeld D, Schilling B, Mavros C, Masters CL, Volitakis I, Li QX, Laughton K, Hubbard A, Cherny RA, Gibson B, Bush AI: Mitochondrial oxidative stress causes hyperphosphorylation of tau. PLoS One 2007;2:e536.
38.
Esposito L, Raber J, Kekonius L, Yan F, Yu GQ, Bien-Ly N, Puolivali J, Scearce-Levie K, Masliah E, Mucke L: Reduction in mitochondrial superoxide dismutase modulates Alzheimer's disease-like pathology and accelerates the onset of behavioral changes in human amyloid precursor protein transgenic mice. J Neurosci 2006;26:5167-5179.
39.
Mehta D, Menke A, Binder EB: Gene expression studies in major depression. Cur Psychiatry Rep 12010;2:135-144.
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2014
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