Number of manic episodes is associated with elevated DNA oxidation in bipolar I disorder

Abstract

Bipolar disorder (BD) is a major public health problem characterized by progressive functional impairment. A number of clinical variables have been associated with progression of the disease, most notably number of affective episodes and presence of psychotic symptoms, both of which correlate with greater cognitive impairment, lower response rates for lithium, and possibly lower levels of neurotrophic factors. Oxidative damage to cytosine and guanosine (8-OHdG) has been described as a modulator of DNA methylation, but the extent of DNA oxidative damage involvement in BD remains unclear. The aim of this study was to evaluate the extent of DNA oxidative damage to 8-OHdG and 5-methylcytosine (5-HMec), as well as global methylation (5-Mec), in BD patients and healthy controls. Potential association with clinical variables was also investigated. DNA levels of 8-OHdG, 5-HMec and 5-Mec were measured in 50 BD type I patients and 50 healthy controls. DNA 8-OHdG levels were higher in BD patients compared to healthy controls and found to be positively influenced by number of previous manic episodes. BD subjects had lower levels of 5-HMec compared to controls, whereas this measure was not influenced by the clinical features of BD. Number of manic episodes was correlated with higher levels of 8-OHdG, but not of 5-Mec or 5-HMec. Lower demethylation activity (5-HMec) but no difference in global 5-Mec levels was observed in BD. This finding suggests that oxidative damage to 8-OHdG might be a potential marker of disease progression, although further prospective cross-sectional studies to confirm neuroprogression in BD are warranted.

Pathophysiology of Depression: Molecular Regulation of Melatonin Homeostasis – Current Status

“…It is important to determine the contents of these 2 modified nucleotides and their ratios in order to examine their complete role in psychiatric disorders. Two studies have observed a decreased level of 5-hmC in patients with major DD [87] and bipolar disorder [88]. The results of most of these studies indicate reduced levels of 5-mC and 5-hmC.…”

Thiobarbituric acid reactive substances (TBARS) is a state biomarker of oxidative stress in bipolar patients in a manic phase

“…Several recent studies have reported inconsistent data involving SOD, CAT, GPx, DNA damage and protein carbonylation in bipolar patients (Andreazza et al, 2007b(Andreazza et al, , 2008a(Andreazza et al, , 2009Kapczinski et al, 2011;Soeiro-de-Souza et al, 2013). SOD, GPx and CAT are primary antioxidant enzymes that act against oxidative stress and prevent the oxidation of DNA, protein and lipid (Sabens Liedhegner et al, 2012;Roszkowski, 2014).…”

“…In addition, free radicals react with guanosine DNA residues and produce 8-hydroxy 2 0 -deoxyguanosine (8-OHdG); free radicals also lead to cytosine damage (Lenaz, 2001;Kohen and Nyska, 2002). Oxidative stress-induced DNA damage in bipolar patients has been reported (Frey et al, 2007;Andreazza, 2012;Soeiro-de-Souza et al, 2013). Furthermore, ROS leads to protein damage measured by protein carbonyl content (PCC).…”

Current State of Biomarkers in Bipolar Disorder

“…Also, Scola and collaborators reported that mitochondrial dysfunction may lead to alteration on methylation and hydroxymethylation levels in cortical primary neurons [31]. Oxidative damage to guanosine, measured by 8-hydroxy-2-deoxyguanosine levels (8-OHdG), was found to be higher in patients with BD when compared to healthy controls, and, importantly, it was found to be positively correlated to the number of manic episodes [32]. The same study also found that patients with BD presented decreased global 5-methylcytosine (5mc) levels similarly to the findings reported by Huzayyin and collaborators (2014).…”