Huzayyin Aya A, Andreazza Ana C, Turecki Gustavo, Cruceanu Cristiana, Rouleau Guy A, Alda Martin, Young L Trevor
Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
McGill Group for Suicide Studies, Depressive Disorders Program, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada.
Int J Neuropsychopharmacol. 2014 Apr;17(4):561-9. doi: 10.1017/S1461145713001569. Epub 2013 Dec 17.
Mitochondrial dysfunction, oxidative stress, and alterations in DNA methylation, are all associated with the pathophysiology of bipolar disorder (BD). We therefore studied the relationship between oxidative stress and DNA methylation in patients with BD with an excellent response to lithium treatment, their affected and unaffected relatives and healthy controls. Transformed lymphoblasts were cultured in the presence or absence of lithium chloride (0.75 mM). DNA and proteins were extracted from the cells to determine levels of 8-hydroxy-2-deoxyguanosine (8-OHdG), 5-methylcytosine (5-mc), mitochondrial complex I and glutathione peroxidase (GPx) activities. Methylation was decreased in BD subjects and their relatives compared to controls and remained so after lithium treatment in BD subjects but not in their relatives. 8-OHdG levels and complex I activity did not differ between groups before and after lithium treatment. Finally, relatives of patients showed increased GPx activity before and after lithium treatment, which negatively correlated with 5-mc levels. Changes in global methylation may be specific for BD and lithium may be involved in glutathione regulation. The present study supports the importance of DNA methylation to the pathophysiology of BD and the therapeutic potential of antioxidants in this illness.
线粒体功能障碍、氧化应激以及DNA甲基化改变均与双相情感障碍（BD）的病理生理学相关。因此，我们研究了对锂治疗反应良好的BD患者、其患病和未患病亲属以及健康对照者中氧化应激与DNA甲基化之间的关系。将转化的淋巴细胞在存在或不存在氯化锂（0.75 mM）的情况下进行培养。从细胞中提取DNA和蛋白质，以测定8-羟基-2'-脱氧鸟苷（8-OHdG）、5-甲基胞嘧啶（5-mc）、线粒体复合物I和谷胱甘肽过氧化物酶（GPx）的活性水平。与对照组相比，BD患者及其亲属的甲基化水平降低，BD患者经锂治疗后仍保持降低状态，但其亲属则不然。锂治疗前后，各组之间的8-OHdG水平和复合物I活性无差异。最后，患者亲属在锂治疗前后的GPx活性增加，且与5-mc水平呈负相关。整体甲基化的变化可能是BD所特有的，锂可能参与谷胱甘肽调节。本研究支持DNA甲基化对BD病理生理学的重要性以及抗氧化剂在该疾病中的治疗潜力。
