8-hydroxyguanosine and Schizophrenia

Elevated systemic oxidative stress levels of 8-oxoGuo and 8-oxodG have been reported in individuals with severe mental illness (SMI). As no previous studies have addressed the link between local levels of 8-oxoGuo and 8-oxodG in the central nervous system (CNS), measured in cerebrospinal fluid (CSF), and urinary systemic levels, we employed autopsy-based material to elucidate this aspect. Additionally, we investigated the impact of 8-oxoGuo and 8-oxodG levels on the prevalence of somatic co-morbidities. Based on post mortem samples from deceased individuals with SMI (N = 107), we found significantly elevated urinary levels of both 8-oxoGuo and 8-oxodG compared to mentally healthy living controls. While we found an association between urinary and CSF 8-oxodG levels (r = 0.50, P < 0.001), a similar correlation was not evident for 8-oxoGuo (r = 0.15, P = 0.16). Additionally, the two r-values were significantly different (P < 0.001). Neither marker in urine or CSF was associated with obesity-related variables, metabolic syndrome or type 2 diabetes. The post mortem interval did not affect the results, but the agonal phase seemingly introduced bias. This study provided novel insights into the cellular oxidative stress levels in individuals with SMI. We demonstrated that increased oxidative stress locally and systemically is correlated and is a clear phenomenon in SMI. Although post mortem measurements contain some weaknesses, our study indicates DNA as the main site of oxidative stress modifications in the CNS in SMI. This may provide novel opportunities for treatment modalities. Additionally, our study demonstrated the applicability of post mortem material investigating systemic and local 8-oxoGuo and 8-oxodG levels.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Autopsy; Bipolar Disorder; Central Nervous System; Deoxyguanosine; Depression; Female; Guanosine; Humans; Male; Mental Disorders; Middle Aged; Oxidative Stress; Schizophrenia

It has been suggested that patients with schizophrenia develop higher levels of oxidative stress, which may contribute to deteriorating mental illness. In order to examine oxidative stress in the early stages of severe mental illness, we examined the levels of systemic Deoxyribonucleic Acid (DNA) and Ribonucleic Acid (RNA) oxidation, 8-oxo-7,8-dihydro-2'-deoxyguanosine and 8-oxo-7,8-dihydroguanosine, perceived stress and recent life events in patients at ultra high-risk (UHR) of developing psychosis, in antipsychotic naïve patients with first-episode schizophrenia (FES), and in healthy controls. We included 41 UHR patients, 35 FES patients, and 29 healthy controls. There was no difference in the level of DNA/RNA oxidative damage between UHR patients and FES patients compared with healthy controls. We found no association between levels of DNA/RNA oxidative damage and perceived stress/life events. Based on the results, we suggest that DNA and RNA oxidative markers are not increased during the early stages of illness, but further longitudinal studies in first-episode psychosis should be carried out to examine whether DNA and RNA oxidative damage are potential markers of severe illness.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Adult; Biomarkers; Case-Control Studies; Deoxyguanosine; DNA; DNA Damage; Female; Guanosine; Humans; Male; Oxidative Stress; Risk Factors; RNA; Schizophrenia; Schizophrenic Psychology; Stress, Psychological; Young Adult

Schizophrenia is associated with a substantially increased somatic morbidity and mortality, which may partly be caused by accelerated cellular aging. Oxidative stress is an established mediator of aging and a suggested aetiological mechanism in both schizophrenia and age-related medical disorders such as cardiovascular disease, type 2 diabetes and dementia. We determined the urinary excretion of markers of systemic Deoxyribonucleic Acid (DNA) and Ribonucleic Acid (RNA) oxidation, 8-oxo-7,8-dihydro-2'-deoxyguanosine and 8-oxo-7,8-dihydroguanosine, respectively, in 40 schizophrenia patients and 40 age- and sex-matched controls, using ultra-performance liquid chromatography with tandem mass spectrometry. Measures of psychopathology, perceived stress and cortisol secretion were collected. Patients were re-examined after four months. We found a 20% increase in the median excretion of both markers in schizophrenia patients vs. healthy controls (P=0.003 and <0.001, respectively). This difference persisted after the adjustment for multiple demographical, lifestyle and metabolic factors. In patients, the marker excretion was not influenced by medication load, and was not driven by symptom severity, perceived stress or cortisol secretion, neither at baseline nor in relation to changes at follow-up. We conclude that schizophrenia is associated with increased systemic nucleic acid damage from oxidation, which could constitute a molecular link between schizophrenia and its associated signs of accelerated aging.

Topics: Adult; Case-Control Studies; Deoxyguanosine; DNA Damage; Female; Guanosine; Humans; Hydrocortisone; Male; Malondialdehyde; Oxidation-Reduction; Oxidative Stress; Retrospective Studies; RNA; Saliva; Schizophrenia; Young Adult

Both non-pathological psychological stress states and mental disorders are associated with molecular, cellular and epidemiological signs of accelerated aging. Oxidative stress on nucleic acids is a critical component of cellular and organismal aging, and a suggested pathogenic mechanism in several age-related somatic disorders. The overall aim of the PhD project was to investigate the relation between psychopathology, psychological stress, stress hormone secretion and oxidatively generated DNA and RNA damage, as measured by the urinary excretion of markers of whole-body DNA/RNA oxidation (8-oxodG and 8-oxoGuo, respectively). The main hypothesis was that psychological stress states are associated with increased DNA/RNA damage from oxidation. In a study of 40 schizophrenia patients and 40 healthy controls matched for age and gender, we found that 8-oxodG/8-oxoGuo excretion was increased in schizophrenia patients, providing a possible molecular link between schizophrenia and its associated signs of accelerated aging. We found no association between psychopathology, perceived stress or cortisol secretion and 8-oxodG/8-oxoGuo excretion in the patients. In the controls, there were positive correlations between 8-oxodG/8-ocoGuo excretion and 9AM plasma cortisol, but no associations to perceived stress. In an animal study of experimentally induced chronic stress performed in metabolism cages, we found no increase in urinary 8-oxodG/8-oxoGuo or cerebral (hippocampal and frontal cortex) levels of oxidatively generated nucleic acid damage. However, there was a trend towards an increased expression of genes involved in DNA repair, possibly reflecting a compensatory mechanism. In a study of 220 elderly, mostly healthy individuals from the Italian InChianti cohort, we found a significant association between the 24 h urinary cortisol excretion and the excretion of 8-oxodG/8-oxoGuo, determined in the same samples. Collectively, the studies could not confirm an association between psychological stress and oxidative stress on nucleic acids. Systemic oxidatively generated DNA/RNA damage was increased in schizophrenia, and linked to cortisol levels in healthy humans. Finally, the cerebral repair of DNA may be an aspect of the adaptation that, to our knowledge, has not previously been addressed.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Aged, 80 and over; Aging; Animals; Biomarkers; Case-Control Studies; Corticosterone; Cross-Sectional Studies; Deoxyguanosine; DNA Damage; DNA Repair; Female; Frontal Lobe; Guanosine; Hippocampus; Humans; Hydrocortisone; Male; Oxidative Stress; Psychological Tests; Rats; Rats, Sprague-Dawley; Restraint, Physical; RNA; Schizophrenia; Stress, Psychological