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This study investigates the effect of chronic administration of the serotonin\u2010norepinephrine reuptake inhibitor, venlafaxine, on the expression and methylation status of <jats:italic>SOD1<\/jats:italic>, <jats:italic>SOD2<\/jats:italic>, <jats:italic>GPx1<\/jats:italic>, <jats:italic>GPx4<\/jats:italic>, <jats:italic>CAT<\/jats:italic>, <jats:italic>NOS1<\/jats:italic> and <jats:italic>NOS2<\/jats:italic> in the brain and blood of rats exposed to a chronic mild stress (CMS) model of depression. Separate groups of animals were exposed to CMS for 2 or 7\u00a0weeks; the second group received saline or venlafaxine (10\u00a0mg\/kg\/d, IP) for 5\u00a0weeks. After completion of both stress conditions and drug administration, the mRNA and protein expression of selected genes and the methylation status of their promoters were measured in peripheral mononuclear blood cells (PBMCs) and in brain structures (hippocampus, amygdala, hypothalamus, midbrain, cortex, basal ganglia) with the use of TaqMan Gene Expression Assay, Western blot and methylation\u2010sensitive high\u2010resolution melting techniques. CMS caused a decrease in sucrose consumption, and this effect was normalized by fluoxetine. In PBMCs, <jats:italic>SOD1<\/jats:italic>, <jats:italic>SOD2<\/jats:italic> and <jats:italic>NOS2<\/jats:italic> mRNA expression changed only after venlafaxine administration. In brain, <jats:italic>CAT, Gpx1, Gpx4<\/jats:italic> and <jats:italic>NOS1<\/jats:italic> gene expression changed following CMS or venlafaxine exposure, most prominently in the hippocampus, midbrain and basal ganglia. CMS increased the methylation of the Gpx1 promoter in PBMCs, the second <jats:italic>Gpx4<\/jats:italic> promoter in midbrain and basal ganglia, and <jats:italic>SOD1<\/jats:italic> and <jats:italic>SOD2<\/jats:italic> in hippocampus. The CMS animals treated with venlafaxine displayed a significantly higher CAT level in midbrain and cerebral cortex. CMS caused an elevation of Gpx4 in the hippocampus, which was lowered in cerebral cortex by venlafaxine. The results indicate that CMS and venlafaxine administration affect the methylation of promoters of genes involved in oxidative and nitrosative stress. They also indicate that peripheral and central tissue differ in their response to stress or antidepressant treatments. It is possible that that apart from DNA methylation, a crucial role of expression level of genes may be played by other forms of epigenetic regulation, such as histone modification or microRNA interference.<\/jats:p><jats:p>These findings provide strong evidence for thesis that analysis of the level of mRNA and protein expression as well as the status of promoter methylation can help in understanding the pathomechanisms of mental diseases, including depression, and the mechanisms of action of drugs effective in their therapy.<\/jats:p>","DOI":"10.1111\/jcmm.15231","type":"journal-article","created":{"date-parts":[[2020,4,13]],"date-time":"2020-04-13T09:10:13Z","timestamp":1586769013000},"page":"5675-5694","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Effects of venlafaxine on the expression level and methylation status of genes involved in oxidative stress in rats exposed to a chronic mild stress"],"prefix":"10.1111","volume":"24","author":[{"given":"Paulina","family":"Wigner","sequence":"first","affiliation":[{"name":"Laboratory of Medical Genetics Faculty of Biology and Environmental Protection University of Lodz Lodz Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewelina","family":"Synowiec","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics Faculty of Biology and Environmental Protection University of Lodz Lodz Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Czarny","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry Medical University of Lodz Lodz Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7838-4097","authenticated-orcid":false,"given":"Michal","family":"Bijak","sequence":"additional","affiliation":[{"name":"Department of General Biochemistry Faculty of Biology and Environmental Protection University of Lodz Lodz Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pawe\u0142","family":"J\u00f3\u017awiak","sequence":"additional","affiliation":[{"name":"Department of Cytobiochemistry Faculty of Biology and Environmental Protection University of Lodz Lodz Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janusz","family":"Szemraj","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry Medical University of Lodz Lodz Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Gruca","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology Polish Academy of Sciences Krakow Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariusz","family":"Papp","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology Polish Academy of Sciences Krakow Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8385-7744","authenticated-orcid":false,"given":"Tomasz","family":"\u015aliwi\u0144ski","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics Faculty of Biology and Environmental Protection University of Lodz Lodz Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,4,13]]},"reference":[{"issue":"21","key":"e_1_2_9_2_1","first-page":"2581","article-title":"World mental health surveys","volume":"291","author":"The WHO World Mental Health Survey Consortium Prevalence, Severity, and Unmet Need for Treatment of Mental Disorders in the World Health Organization","year":"2004","journal-title":"JAMA"},{"issue":"16","key":"e_1_2_9_3_1","first-page":"26","article-title":"The burden of disease for treatment\u2010resistant depression","volume":"62","author":"Greden JF","year":"2001","journal-title":"J Clin Psychiatry"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehl338"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1001\/archgenpsychiatry.2010.2"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc08-0985"},{"key":"e_1_2_9_7_1","first-page":"466","article-title":"Do stress related psychosocial factors contribute to cancer incidence and survival? 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