The evaluation of oxidative DNA damage in children with brain damage using 8-hydroxydeoxyguanosine levels

doi:10.1016/j.braindev.2007.07.005

Brain and Development

Volume 30, Issue 2, February 2008, Pages 131-136

https://doi.org/10.1016/j.braindev.2007.07.005 Get rights and content

Abstract

Urinary and cerebrospinal fluid (CSF) levels of 8-hydroxydeoxyguanosine (8-OHdG) were examined to estimate the relevance of oxidative stress in children with brain damage. Urinary 8-OHdG levels were measured in 51 children with various forms of central nervous system (CNS) disorders (status epilepticus [SE], hypoxic–ischemic encephalopathy [HIE], CNS infections and chronic epilepsy) and these levels were compared with those in 51 healthy children. CSF 8-OHdG levels were measured in 25 children with brain damage and in 19 control subjects. In addition, urinary and CSF levels of 8-OHdG were compared between the children with brain damage and healthy children. Finally, the relationship between urinary and CSF levels of 8-OHdG was determined in 12 children that provided both urinary and CSF samples. Our results showed that urinary 8-OHdG levels in children with HIE and CNS infections were higher than those of controls (Steel test; p < 0.05 and p < 0.05, respectively) and that CSF 8-OHdG levels were higher in children with SE, HIE, and CNS infections than in control subjects (Steel test; p < 0.01, 0.05 and 0.05, respectively). In addition, a positive correlation between the levels of urinary and CSF 8-OHdG was noted in the 12 children that provided both CSF and urinary samples (Spearman’s rank correlation; ρ = 0.82, p < 0.01). Further, we observed changes in the urinary 8-OHdG in a patient with HHV-6 encephalopathy, and found that the changes correlated well with the patient’s clinical condition. These results suggest that oxidative stress is strongly related to acute brain damage in children, and that 8-OHdG is a useful marker of brain damage. Therefore, repeated measurements of urinary 8-OHdG may be helpful in estimating the extent of brain damage.

Introduction

Reactive oxygen intermediates can damage various biomolecules in humans, such as DNA, lipids, and proteins [1], [2]. Biomarkers for DNA damage by oxidative stress include 8-hydroxydeoxyguanosine (8-OHdG), an enzyme that repairs damaged DNA and is excreted to urine [2], [3]. Currently, 8-OHdG is used as a sensitive marker for oxidative DNA damage [4], [5], [6]. It has been reported that oxidative stress accelerates brain tissue damage at the early phase of certain pathological processes such as cerebrovascular injury, brain edema, and meningeal inflammation [7], [8], [9]. Previously, we reported the time course of urinary 8-OHdG levels in adults with chronic arsenic poisoning, and suggested the clinical utility of urinary 8-OHdG to assess the recovery from DNA damage [10]. Few studies have analyzed urinary or CSF 8-OHdG levels in children with organic brain damage [7], [11], [12]. In the present study, we compared urinary and CSF 8-OHdG levels in children with probable brain damage with those of healthy children in order to determine whether urinary 8-OHdG level can be used as a reliable marker of oxidative stress in brain-damaged children.

Section snippets

Patients and methods

All of this research received prior approval from the university institutional review body (Nos. 697, 738), and informed consent was obtained from the parents of each patient. We measured urinary and CSF 8-OHdG levels using the samples remaining after the routine diagnostic examinations.

The concentration of 8-OHdG in urine samples from children with brain damage

The mean ± SD concentration of 8-OHdG in the healthy control children (n = 51, aged 0–15 years) was 18.9 ± 8.50 ng/mg cr. The urinary 8-OHdG concentrations in children with brain damage are shown in Table 1. The levels in children with SE averaged 2 times higher than that in healthy children, but this difference was not statistically significant (Fig. 1). The mean concentration of 8-OHdG in urine samples of HIE patients and CNS infections was significantly higher than that in control subjects (Fig. 2,

8-OHdG in childhood disease

Currently, the influence of oxidative stress that occurs in various disorders is estimated using a reactive oxygen species (ROS) modulator, active oxygen erasing system enzymatic antioxidants, or genetic transcription factors. In this study, we measured 8-OHdG to estimate oxidative stress in vivo. 8-OHdG is widely used as a biomarker of oxidative DNA damage [2], [5], [6], [10]. A few groups have identified high levels of 8-OHdG in the CSF of patients with Alzheimer’s disease and Parkinson’s

Conclusion

This study examined 8-OHdG levels in childhood CNS disorders using CSF and urine samples. Our results suggest that oxidative stress plays an important role in brain damage in children and correlates with the disease state. CSF 8-OHdG reflects active oxidative stress-induced brain injury in children more closely than urinary 8-OHdG. On the other hand, urinary 8-OHdG is thought to be useful as a clinical marker due to its simple and non-invasive collection compared with CSF 8-OHdG. Urinary 8-OHdG

Acknowledgements

The authors greatly appreciate the expert advices and helpful suggestions of Eishi Asano, MD, PhD, MS, Anannit Visudtibhan, MD, Andrew L. Lux, MD, Tilman Ruff, MD, PhD and Shinobu Tatsunami, PhD. We also thank MC medical, Inc. for technical support for the measurement of CSF 8-OHdG levels and Mitsubishi Pharma Corporation for the great support.

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^☆: This work was supported in part by funding from the Grant-in-Aid 15406030 (to H. Yamauchi) for scientific research from the Ministry of Education, Culture, Sport, and Technology.

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Original articleThe evaluation of oxidative DNA damage in children with brain damage using 8-hydroxydeoxyguanosine levels☆

Abstract

Introduction

Section snippets

Patients and methods

The concentration of 8-OHdG in urine samples from children with brain damage

8-OHdG in childhood disease

Conclusion

Acknowledgements

FEBS Lett

Free Radic Biol Med

J Neurol Sci

Toxicol Appl Pharmacol

Free Radic Biol Med

Neurobiol Dis

Neuroscience

Prog Brain Res

Pharmacol Biochem Behav

DNA damage induced by asbestos in the presence of hydrogen peroxide

Gann

Life style and urinary 8-hydroxydeoxyguanosine, a marker of oxidative DNA damage: effects of exercise, working conditions, meat intake, body mass index, and smoking

Jpn J Cancer Res

Quantitative determination of urinary 8-hydroxydeoxyguanosine (8-OH-dg) by using ELIZA

Res Commun Mol Pathol Pharmacol

Original article
The evaluation of oxidative DNA damage in children with brain damage using 8-hydroxydeoxyguanosine levels☆