Evidence for Oxidative DNA Damage in the Hippocampus of Elderly Patients With Chronic Schizophrenia

Nishioka, Naoya

doi:10.1176/appi.ajgp.12.2.167

Cited by 23 publications

(27 citation statements)

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“…A recent study found increased levels of phosphorylated histone variant H2AX, an index of DNA double strand breaks, in cultured lymphoblasts from schizophrenia patients compared to healthy controls, and an attenuated activation of the same marker after cell irradiation in patients (Catts et al, 2012). In a post-mortem study, an increased intra-neuronal 8-oxodG immunoreactivity in the hippocampus of elderly, poor-outcome schizophrenia patients was observed (Nishioka and Arnold, 2004). However, to our knowledge, this study provides the first evidence for increased systemic DNA and RNA oxidation in vivo in schizophrenia.…”

Section: Discussionmentioning

confidence: 94%

Increased systemic oxidatively generated DNA and RNA damage in schizophrenia

Jørgensen

Broedbaek

Fink-Jensen

et al. 2013

Psychiatry Research

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a b s t r a c tSchizophrenia 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 0 -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 ¼ 0.003 and o 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.

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Section: Discussionmentioning

confidence: 94%

Increased systemic oxidatively generated DNA and RNA damage in schizophrenia

Jørgensen

Broedbaek

Fink-Jensen

et al. 2013

Psychiatry Research

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“…A smaller collection of studies has been published in relation to markers of DNA damage in schizophrenia. A post-mortem study examining the hippocampi of patients with ' poor outcome ' schizophrenia and non-psychiatric controls, found a ten-fold higher presence of neuronal 8-hydroxy-2'-deoxyguanosine (8-OhdG) among the patients compared with controls, which correlated with elevated quantities of a cell-cycle activation marker (Ki-67) (Nishioka and Arnold, 2004). One study reported a trend increase in lymphocyte DNA damage in schizophrenia patients compared with control subjects , but another found no difference, although those with schizophrenia showed a non-significant increase in sensitivity to externally induced DNA damage and decrease in DNA repair efficiency (Psimadas et al, 2004).…”

Section: Assays Of Oxidative Productsmentioning

confidence: 99%

Oxidative stress in psychiatric disorders: evidence base and therapeutic implications

Berk

Dean

et al. 2008

Int. J. Neuropsychopharm.

864

569

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Oxidative stress has been implicated in the pathogenesis of diverse disease states, and may be a common pathogenic mechanism underlying many major psychiatric disorders, as the brain has comparatively greater vulnerability to oxidative damage. This review aims to examine the current evidence for the role of oxidative stress in psychiatric disorders, and its academic and clinical implications. A literature search was conducted using the Medline, Pubmed, PsycINFO, CINAHL PLUS, BIOSIS Previews, and Cochrane databases, with a time-frame extending to September 2007. The broadest data for oxidative stress mechanisms have been derived from studies conducted in schizophrenia, where evidence is available from different areas of oxidative research, including oxidative marker assays, psychopharmacology studies, and clinical trials of antioxidants. For bipolar disorder and depression, a solid foundation for oxidative stress hypotheses has been provided by biochemical, genetic, pharmacological, preclinical therapeutic studies and one clinical trial. Oxidative pathophysiology in anxiety disorders is strongly supported by animal models, and also by human biochemical data. Pilot studies have suggested efficacy of N-acetylcysteine in cocaine dependence, while early evidence is accumulating for oxidative mechanisms in autism and attention deficit hyperactivity disorder. In conclusion, multi-dimensional data support the role of oxidative stress in diverse psychiatric disorders. These data not only suggest that oxidative mechanisms may form unifying common pathogenic pathways in psychiatric disorders, but also introduce new targets for the development of therapeutic interventions.

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“…Immunohistochemistry for 8-OHdG formation 8-OHdG immunoreactivity in the mouse brain was examined as described previously 23,24) . Briefly, paraffin sections (6 µm thickness) were incubated with mouse monoclonal anti-8-OHdG antibody (4 µg/ml) (Japan Institute for the Control of Aging, Fukuroi, Japan) overnight at room temperature.…”

Section: Measurement Of 8-ohdg Formation In the Brainmentioning

confidence: 99%

“…The immunostained sections were examined under a microscope. A histopathological study was performed after hematoxylin and eosin staining of paraffin sections as described previously 23) .…”

Section: Measurement Of 8-ohdg Formation In the Brainmentioning

confidence: 99%

Oxidative DNA Damage in Relation to Neurotoxicity in the Brain of Mice Exposed to Arsenic at Environmentally Relevant Levels

Piao¹,

Ma²,

Hiraku³

et al. 2005

Journal of Occupational Health

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as an index of oxidative DNA damage in the brain was examined in mice fed with drinking water containing 1 or 2 ppm arsenic, using a n H P L C -e l e c t r o c h e m i c a l d e t e c t o r a n d immunohistochemical method. 8-OHdG levels were significantly increased in the brain of mice given arsenic and its immunoreactivity was distributed in the cerebral and cerebellar cortexes. Cerebral cortex neurons and Purkinje cells in the cerebellar cortex showed degenerative changes in accordance with the distribution of 8-OHdG immunoreactivity. The levels of arsenic in this study were lower than those reported in epidemiological studies. Thus, we conclude that environmentally relevant levels of arsenic induce pathological changes through oxidative DNA damage in the brain tissues in vivo and that cerebral and cerebellar cortex neurons seem to be the major targets of arsenic neurotoxicity. (J Occup Health 2005; 47: 445-449)

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Evidence for Oxidative DNA Damage in the Hippocampus of Elderly Patients With Chronic Schizophrenia

Abstract: Our data provide evidence for oxidative DNA damage and coordinated cell-cycle activation in elderly "poor-outcome" schizophrenia. These findings could have important implications for cellular metabolism, gene expression, and membrane functioning in schizophrenia.

Cited by 23 publications

References 0 publications

Increased systemic oxidatively generated DNA and RNA damage in schizophrenia

Increased systemic oxidatively generated DNA and RNA damage in schizophrenia

Oxidative stress in psychiatric disorders: evidence base and therapeutic implications

Oxidative DNA Damage in Relation to Neurotoxicity in the Brain of Mice Exposed to Arsenic at Environmentally Relevant Levels

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