title: Alterations in the Nrf2-Keap1 signaling pathway and its downstream target genes in rat brain under stress.
abstract: Knowledge of the antioxidant defense in the stress-responding structures of the CNS is of crucial importance, since oxidative damage is a phenomenon accompanying many stress-related disorders. Regulation of antioxidative and anti-inflammatory defense through Nrf2 (nuclear factor 2 eritroid related factor 2) pathway has emerged as a promising approach for neuroprotection. In this study, we used chronic social isolation of male Wistar rats to induce depressive-like behavior. We hypothesized that Nrf2-Keap1 pathway is compromised in the limbic brain after prolonged stress. Since subcellular trafficking of Nrf2 and its inhibitor Keap1 (Kelch ECH associating protein 1) is essential for the activation of Nrf2, we determined their protein level in cytosolic and nuclear compartments of hippocampus and prefrontal cortex (PFC). We also determined mRNA levels of Nrf2-regulated genes involved in the production and utilization of glutathione, glutamate cysteine ligase (Gclm), glutathione S-transferase (Gsta3) and glutathione reductase (Gsr). Our results showed that chronic isolation induced anxiety and depressive-like behavior, decreased Nrf2 and in parallel increased Keap1 and nuclear factor kappa B (NFκB) in the hippocampus, which were not accompanied by expression profiles of Nrf2-regulated genes. Chronically stressed rats challenged with acute stress failed to induce any response of examined genes in either of brain structures, even though Nrf2/Keap1 was altered, while in naïve animals Nrf2 activity corresponded with an expression of Nrf2-regulated genes. Our results reveal maladaptive character of chronic stress at Nrf2/Keap1 level followed by pro-inflammatory conditions, and suggest a possible role of these alterations in pathogenesis of depressive/anxiety disorders.
authors.affiliation: Department of Molecular Biology and Endocrinology, VINCA Institute of Nuclear Sciences, University of Belgrade, 11000 Belgrade, Serbia. Electronic address: jdjordje@vinca.rs.
authors.forename: Jelena
authors.initials: J
authors.lastname: Djordjevic
authors.affiliation: Department of Biochemistry, Institute for Biological Research "Siniša Stanković", University of Belgrade, 142 Despot Stefan Blvd., 11000 Belgrade, Serbia.
authors.forename: Ana
authors.initials: A
authors.lastname: Djordjevic
authors.affiliation: Department of Molecular Biology and Endocrinology, VINCA Institute of Nuclear Sciences, University of Belgrade, 11000 Belgrade, Serbia.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Adzic
authors.affiliation: Department of Molecular Biology and Endocrinology, VINCA Institute of Nuclear Sciences, University of Belgrade, 11000 Belgrade, Serbia.
authors.forename: Milos
authors.initials: M
authors.lastname: Mitic
authors.affiliation: Department of Molecular Biology and Endocrinology, VINCA Institute of Nuclear Sciences, University of Belgrade, 11000 Belgrade, Serbia.
authors.forename: Iva
authors.initials: I
authors.lastname: Lukic
authors.affiliation: Department of Molecular Biology and Endocrinology, VINCA Institute of Nuclear Sciences, University of Belgrade, 11000 Belgrade, Serbia.
authors.forename: Marija B
authors.initials: MB
authors.lastname: Radojcic
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002908:Chronic Disease; D003600:Cytosol / Q000378:metabolism; D003863:Depression / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D015398:Signal Transduction; D012934:Social Isolation / Q000523:psychology; D013315:Stress, Psychological / Q000378:metabolism* / Q000523:psychology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C486610:KEAP1 protein, rat; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495637:Nfe2l2 protein, rat; D012333:RNA, Messenger; D005980:Glutathione Reductase; D005982:Glutathione Transferase; C000593996:GCLM protein, rat; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione
keywords: Behavior; Hippocampus; Keap1; NFkB; Nrf2; Oxidative stress; Prefrontal cortex