Agata Orzechowska

The expression of genes encoding for COX-2, MPO, iNOS, and sPLA2-IIA in patients with recurrent depressive disorder

BACKGROUND There is evidence that inflammation, oxidative and nitrosative stress (IO&NS) play a role in the pathophysiology of depression. There are also data indicating altered inflammatory gene expression in depressive disorder and that genetic variants of IO&NS genes are associated with increased risk of the disease in question. The aim of this study was to explore mRNA expression of four IO&NS genes PTGS2, MPO, NOS2A, and PLA2G2A coding respectively: cyclooxygenase-2 (COX-2), myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS) and secretory phospholipase A2 type IIA (sPLA2-IIA). METHOD Expression of the mRNA was determined using quantitative real-time PCR, in peripheral blood cells of patients with recurrent depressive disorder (rDD) and normal controls. RESULTS The mRNA expressions of the genes encoding for COX-2, MPO, iNOS and sPLA2-IIA were significantly increased in the peripheral blood cells of depressed patients versus controls. LIMITATIONS Patients were treated with antidepressants. CONCLUSION Our results indicate and may confirm the role of peripheral IO&NS pathways in the pathophysiology of depression. The results represent a promising way to investigate biological markers of depression.

Nitric oxide plasma concentration associated with cognitive impairment in patients with recurrent depressive disorder

BACKGROUND/AIM Depressive disorders are multifactorial diseases, in which cognitive impairment is one of the characteristic feature. One of the molecules that regulate of various cognitive, emotional and behavioural processes is nitric oxide (NO), synthesized from l-arginine by a family of isoformic enzymes known as nitric oxide synthases (NOS). NO is a gaseous compounds that acts as a biological second messenger in a number of organ system. In addition, NO is a ubiquitous free radical (NO) that affects many normal physiologic functions but is also implicated in the etiology and progression of many diseases. The aim of the study was to determine the concentration of NO in patients with recurrent depressive disorder (rDD) and to define relationship between plasma NO levels and the cognitive performance. METHODS The study comprised 78 subjects: patients with rDD (n=45), healthy controls (CG, n=33). Cognitive function assessment was based on: TMT, The Stroop Test, VFT, AVLT. RESULTS Statistically significant differences were found among patients with rDD in the intensity of depression symptoms, measured by the HDRS on therapy onset vs. the examination results after 8 weeks of treatment (p<0.001). The level of NO was substantially higher in patients with rDD compared to CG. For all examined subjects (p<0.001), elevated levels of NO in blood plasma adversely affect the efficiency of visual-spatial and auditory-verbal working memory as well as short-term declarative memory. For rDD patients, elevated NO levels were associated with worse cognitive test performance. The higher was the concentration of plasma NO, the greater was the severity of depressive symptoms measured by HDRS (p=0.03). CONCLUSIONS (1) Higher concentration of plasma NO in rDD patients is associated with the severity of depressive symptoms. (2) Elevated levels of plasma NO are related to impairment of visual-spatial and auditory-verbal working memory as well as to impairment of short-term declarative memory.

Elevated Level of DNA Damage and Impaired Repair of Oxidative DNA Damage in Patients with Recurrent Depressive Disorder

Background Depressive disorder (DD), including recurrent DD (rDD), is a severe psychological disease, which affects a large percentage of the world population. Although pathogenesis of the disease is not known, a growing body of evidence shows that inflammation together with oxidative stress may contribute to development of DD. Since reactive oxygen species produced during stress may damage DNA, we wanted to evaluate the extent of DNA damage and efficiency of DNA repair in patients with depression. Material/Methods We measured and compared the extent of endogenous DNA damage – single- and double-strand breaks, alkali-labile sites, and oxidative damage of the pyrimidines and purines – in peripheral blood mononuclear cells isolated from rDD patients (n=40) and healthy controls (n=46) using comet assay. We also measured DNA damage evoked by hydrogen peroxide and monitored changes in DNA damage during repair incubation. Results We found an increased number DNA breaks, alkali-labile sites, and oxidative modification of DNA bases in the patients compared to the controls. Exposure to hydrogen peroxide evoked the same increased damage in both groups. Examination of the repair kinetics of both groups revealed that the lesions were more efficiently repaired in the controls than in the patients. Conclusions For the first time we showed that patients with depression, compared with non-depresses individuals, had more DNA breaks, alkali-labile sites, and oxidative DNA damage, and that those lesions may be accumulated by impairments of the DNA repair systems. More studies must be conducted to elucidate the role of DNA damage and repair in depression.

Normalization of the Verbal Fluency Test on the basis of results for healthy subjects, patients with schizophrenia, patients with organic lesions of the chronic nervous system and patients with type 1 and 2 diabetes

Introduction Verbal fluency is the ability to form and express words compatible with required criteria. Verbal fluency is necessary for optimal communication and for normal social and occupational functioning. The Verbal Fluency Test is a good indicator of frontal lobe dysfunction, particularly of the left frontal cortex. Material and methods The aim of the study was to compare verbal fluency in healthy subjects (n = 50), patients with paranoid schizophrenia (n = 36), patients with organic lesions of the central nervous system (CNS) (n = 33), and patients with diabetes (n = 62) – type 1 diabetes (n = 31) and type 2 diabetes (n = 31). Results Healthy subjects and patients with diabetes achieved the highest results in all categories of the Verbal Fluency Test. Patients with paranoid schizophrenia achieved significantly lower results. Sten norms of the Verbal Fluency Test were developed for the general population. Using these norms it was found that subjects with schizophrenia or with organic lesions of the CNS had very poor results more often and very high results less frequently compared to healthy subjects and also to patients with diabetes. Conclusions This observation is consistent with the neurodevelopmental hypothesis of schizophrenia, in which cognitive functions of the frontal lobe (e.g. verbal fluency) play a major role in the psychopathological picture. We have also demonstrated that in patients with type 1 and 2 diabetes verbal fluency is comparable with healthy subjects.

Depression and ways of coping with stress: A preliminary study

Background Coping with stress is defined as all activities undertaken by a human in a stressful situation. The effect of stress on depression, its role in triggering the subsequent phases of the disease, and the factors that mediate the stress-depression relationship become more and more often subjects of research in psychiatry and psychology. Factors important for the formation of depressive symptoms and disease progression are significantly associated with coping strategies used in the face of stress. The main aim of the study was to evaluate the most popular strategies of coping with stress in people with depression in comparison to healthy subjects. Material/Methods Initial research was carried on 80 patients aged from 20 to 66 years with a diagnosis of depression. The control group consisted of 30 healthy subjects aged 22 to 57 years. Analysis of the most popular strategies of coping with stress was performed with the Multiphasic Inventory for Measuring Coping (COPE) by Carver, Scheier, and Weintraub. Results In contrast with healthy people, patients with depression in stressful situations more often use strategies based on avoidance and denial and have more difficulties in finding positive aspects of stressful events. Conclusions Depression may be an important factor in the negative assessment of one’s own ability to cope with difficult situations and can aggravate a tendency to perceive stressful events as overwhelming.

Vascular endothelial growth factor gene (VEGFA) polymorphisms may serve as prognostic factors for recurrent depressive disorder development.

Recurrent depressive disorder (rDD) is a multifactorial disease. Vascular endothelial growth factor (VEGF) is one of the factors that have been suggested to play a role in the etiology and/or development of this disease. Limited information related to the role of VEGFA gene polymorphism in depressive disorder is available. The aim of the study was to analyze the association between VEGFA gene polymorphisms (+405G/C; rs2010963, +936C/T; rs 3025039), VEGFA gene expression, and its serum protein levels in rDD in the Caucasian population. In the current study, 268 patients and 200 healthy controls of the Caucasian origin were involved. Genotyping and gene expression were performed using polymerase chain reaction (PCR)-based methods. Enzyme-linked immunosorbent assay (ELISA) was used for detection of circulating serum VEGF levels. The distribution of VEGFA polymorphism +405G/C differed significantly between rDD patients and healthy subjects. The results of this study indicated that the C allele and CC genotype of VEGFA are risk factors for rDD. Haplotypes CC and TG are the important factors for depression development. Further, VEGFA mRNA expression and VEGF levels were higher in rDD patients than in controls. The VEGFA gene polymorphism may serve as a prognostic factor for rDD development. Our study showed higher levels of both VEGFA mRNA in the peripheral blood cells and serum VEGF in patients diagnosed with rDD than in healthy controls. The obtained results suggest VEGF and the gene encoding the molecule play a role in the etiology of the disease and should be further investigated.

Association between single nucleotide polymorphisms of MUTYH, hOGG1 and NEIL1 genes, and depression

BACKGROUND An elevated levels oxidative modified DNA bases and a decreased efficiency of oxidative DNA damage repair were found in patients with depression disorders, including recurrent type (rDD). The glycosylases are involved in base excision repair (BER), which eliminates oxidative DNA damage. Therefore, we genotyped the single nucleotide polymorphisms (SNPs) of genes encoding three glycosylases: hOGG1, MUTYH and NEIL1. METHODS We selected three polymorphisms: c.977C > G - hOGG1 (rs1052133), c.972G > C - MUTYH (rs3219489) and c.*589G > C - NEIL1 (rs4462560). A total of 555 DNA samples (257 cases and 298 controls) were genotyped using TaqMan probes. RESULTS The C/C genotype and allele C of the c.*589G > C decreased the risk of rDD occurrence, while the G/G genotype and allele G of the same SNP increased the risk. This polymorphism had a stronger association with early-onset depression (patients with first episode <35 years of age) than with late-onset depression (first episode ≥ 35 years of age). We did not find any significant differences in distribution of alleles and genotypes of other SNPs; however, the G/G genotype of the c.972G > C increased the risk of late-onset rDD. We also found that combined genotype C/C-C/C of c.977C > G and c.*589G > C significantly reduced the risk of rDD. LIMITATIONS Limited sample size and ethnic homogeneity of the studied population. CONCLUSION This is the first study to show that SNPs of genes involved in DNA repair, particularly in BER pathway, may modulate the risk of rDD. These results further support the hypothesis on the involvement of DNA repair mechanisms in pathogenesis of depression.

Variants of Base Excision Repair Genes MUTYH , PARP1 and XRCC1 in Alzheimer's Disease Risk

Background: Many clinical studies have shown that oxidative stress pathways and the efficiency of the oxidative DNA damage base excision repair (BER) system are associated with the pathogenesis of Alzheimers disease (AD). Reduced BER efficiency may result from polymorphisms of BER-related genes. In the present study, we examine whether single nucleotide polymorphisms (SNPs) of BER genes are associated with increased risk of AD. Methods: SNP genotyping was carried out on DNA isolated from peripheral blood mononuclear cells obtained from 120 patients with AD and 110 healthy volunteers. Samples were genotyped for the presence of BER-related SNPs, i.e. XRCC1-rs1799782, rs25487; MUTYH-rs3219489, and PARP1-rs1136410. Results: We found a positive association between AD risk and the presence of G/A genotype variant of the XRCC1 rs25487 polymorphism [odds ratio (OR) = 3.762, 95% CI: 1.793-7.891]. The presence of the A/A genotype of this polymorphism reduced the risk of AD (OR = 0.485, 95% CI: 0.271-0.870). In cases of the PARP1 gene rs1136410 polymorphism, we observed that the T/C variant increases (OR = 4.159, 95% CI: 1.978-8.745) while the T/T variant reduces risk (OR = 0.240, 95% CI: 0.114-0.556) of AD. Conclusions: We conclude that BER gene polymorphisms may play an important role in the etiology of AD. Diagnosing the presence or absence of particular genetic variants may be an important marker of AD. Further research on a larger population is needed. There is also a need to examine polymorphisms of other BER in the context of AD risk.

Vascular endothelial growth factor receptor 2 gene (KDR) polymorphisms and expression levels in depressive disorder.

Recent research findings suggest that vascular endothelial growth factor (VEGF) participates in the development of depressive disorder. VEGF is involved in neurogenesis and neuroprotection processes, mediated by vascular endothelial growth factor receptor 2 (VEGFR2). VEGFR2 also plays a role in angiogenesis, a process related to neurogenesis and other biological processes. We examined VEGFR2 (KDR) gene polymorphism, mRNA expression levels, as well as VEGFR2 protein levels in 268 patients diagnosed with a recurrent depressive disorder (rDD) using the ICD-10 criteria, and in 200 healthy controls. Genotyping and gene expression level analysis was performed using polymerase chain reaction (PCR)-based methods. An Enzyme-Linked Immunosorbent Assay (ELISA) was used for measurement of KDR protein levels. Our study found that distribution of KDR polymorphism +1416T/A differs significantly in patients with rDD when compared to healthy subjects, while A allele and AA genotype are risk factors for rDD. KDR mRNA and protein expression are higher in patients with rDD. We also observed a significant association between the -271A/G variant and gene and protein levels. Our study is the first to demonstrate that the KDR gene may serve as a novel genetic marker that could participate in the etiology of rDD. This new pathway may play a role in the inflammatory pathophysiology of depression.

Manganese Superoxide Dismutase Gene Expression and Cognitive Functions in Recurrent Depressive Disorder

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.