Oxidative damage to RNA but not DNA in the hippocampus of patients with major mental illness

Abstract

Background: Oxidative damage in the central nervous system is increasingly recognized as an important pathological process in many diseases. Previously, our laboratory found that oxidative damage to lipids and proteins was increased in postmortem brain tissue from patients with bipolar disorder and schizophrenia. In the current study, we analyzed oxidative damage to nucleic acids in the CA1, CA3 and dentate gyrus regions of postmortem hippocampus tissue from patients with bipolar disorder, schizophrenia and major depression.

Methods: We examined oxidative damage to nucleic acids by performing immunohistochemistry with a monoclonal antibody that recognizes both 8-hydroxy-guanosine in RNA and 8-hydroxy-2'-deoxyguanosine in DNA.

Results: We found that the amount of oxidative damage to nucleic acids was elevated in the CA1, CA3 and dentate gyrus regions of the hippocampus among patients with bipolar disorder, schizophrenia and major depressive disorder. This damage was predominantly in the cytoplasm, suggesting that the damage was primarily to RNA. Compared with oxidative damage in control samples, the magnitude of damage was high in patients with schizophrenia, modest in patients with bipolar disorder and lower in patients with major depression.

Limitations: The interpretation of our results is limited by a number of factors, including the retrospective review of patient history, the relatively small sample size and the inclusion of patients who had substance abuse and were undergoing various drug treatments at the time of death.

Conclusion: Our results suggest that oxidative damage to RNA, rather than to DNA, occurs in vulnerable neurons of the brain in patients with major mental illness and may contribute to the pathology of these disorders. The magnitude of RNA oxidative damage may be associated with the severity of mental illness.

Fig. 1

Immunohistochemical staining of 8-oxo-7,8-dihydroguanosine (8-OHG) and 8-oxo-7,8-dihydro-2-deoxyguanosine (8-OHdG) in the dentate gyrus, CA3 and CA1 regions of postmortem tissue from patients with bipolar disorder. The sections were stained with a monoclonal antibody that recognizes both 8-OHG in RNA and 8-OHdG in DNA.

Fig. 2

RNA oxidative damage in the dentate gyrus region of postmortem hippocampus tissue from controls and patients with major depressive disorder (MDD), bipolar disorder or schizophrenia. We assessed the damage to the nucleic acids via immunohistochemical staining with an antibody that recognizes 8-oxo-7,8-dihydroguanosine (8-OHG) in RNA and 8-oxo-7,8-dihydro-2-deoxyguanosine (8-OHdG) in DNA (n = 15 patients per group; original magnification × 40). *p < 0.0167, **p < 0.0033 compared with control. SEM = standard error of the mean.

Fig. 3

RNA oxidative damage in the CA3 region of postmortem hippocampus tissue from controls and patients with major depressive disorder (MDD), bipolar disorder or schizophrenia. Damage to nucleic acids was assessed by immunohistochemistry with an antibody for both 8-oxo-7,8-dihydroguanosine (8-OHG) in RNA and 8-oxo-7,8-dihydro-2-deoxyguanosine (8-OHdG) in DNA (n = 15 patients per group; original magnification × 40). An average of 50, 60, 60 and 65 positive cells were counted in the control, MDD, bipolar disorder and schizophrenia groups, respectively. *p < 0.0167, **p < 0.0033 compared with control. SEM = standard error of the mean.

Fig. 4

RNA oxidative damage in the CA1 region of postmortem hippocampus from controls and patients with major depressive disorder (MDD), bipolar disorder and schizophrenia. Damage to nucleic acids was assessed using immunohistochemistry with an antibody for both 8-oxo-7,8-dihydroguanosine (8-OHG) in RNA and 8-oxo-7,8-dihydro-2-deoxyguanosine (8-OHdG) in DNA (n = 15 patients per group; original magnification × 40). An average of 56, 64, 68 and 71 positive cells were counted in controls, MDD, bipolar disorder and schizophrenia groups, respectively. *p < 0.0167, **p < 0.0033 compared with control. SEM = standard error of the mean.

Fig. 5

Difference in the amount of oxidative damage to RNA between men and women and the correlation between RNA oxidative damage and age, postmortem interval and pH in the postmortem hippocampus of control patients, patients with major depressive disorder, bipolar disorder or schizophrenia (n = 60; 36 men and 24 women). We used 2-tailed independent t tests to assess the effects of sex. The contributions of age, postmortem interval and pH were examined by Pearson correlation analysis.