title: Modulation of the antioxidant nuclear factor (erythroid 2-derived)-like 2 pathway by antidepressants in rats.
abstract: Patients with major depression who are otherwise medically healthy have activated inflammatory pathways in their organism. It has been described that depression is not only escorted by inflammation but also by induction of multiple oxidative/nitrosative stress pathways. Nevertheless, there are finely regulated mechanisms involved in preserving cells from damage, such as the antioxidant nuclear transcription factor Nrf2. We aim to explore in a depression-like model the Nrf2 pathway in the prefrontal cortex (PFC) and the hippocampus of rats and to analyze whether antidepressants affect the antioxidant activity of the Nrf2 pathway. Male Wistar rats were exposed to chronic mild stress (CMS) and some of them were treated with desipramine, escitalopram or duloxetine. We studied the expression of upstream and downstream elements of the Nrf2 pathway and the oxidative damage induced by the CMS. After CMS, there is an inhibition of upstream and downstream elements of the Nrf2 pathway in the PFC (e.g. PI3K/Akt, GPx…). Moreover, antidepressant treatments, particularly desipramine and duloxetine, are able to recover some of these elements and to reduce the oxidative damage induced by the CMS. However, in the hippocampus, Nrf2 pathways are not that affected and antidepressants do not have many actions. In conclusion, Nrf2 pathway is differentially regulated by antidepressants in the PFC and hippocampus. The Nrf2 pathway is involved in the oxidative/nitrosative damage detected in the PFC and antidepressants have a therapeutic action through this pathway. However, it seems that Nrf2 is not involved in the effects caused by CMS in the hippocampus.
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre (Imas12), Instituto de Investigación Neuroquímica (UCM), Avda. Complutense s/n, 28040, Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Martín-Hernández
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre (Imas12), Instituto de Investigación Neuroquímica (UCM), Avda. Complutense s/n, 28040, Madrid, Spain.
authors.forename: Álvaro G
authors.initials: ÁG
authors.lastname: Bris
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre (Imas12), Instituto de Investigación Neuroquímica (UCM), Avda. Complutense s/n, 28040, Madrid, Spain.
authors.forename: Karina S
authors.initials: KS
authors.lastname: MacDowell
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre (Imas12), Instituto de Investigación Neuroquímica (UCM), Avda. Complutense s/n, 28040, Madrid, Spain.
authors.forename: Borja
authors.initials: B
authors.lastname: García-Bueno
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre (Imas12), Instituto de Investigación Neuroquímica (UCM), Avda. Complutense s/n, 28040, Madrid, Spain.
authors.forename: José L M
authors.initials: JL
authors.lastname: Madrigal
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre (Imas12), Instituto de Investigación Neuroquímica (UCM), Avda. Complutense s/n, 28040, Madrid, Spain. Electronic address: jcleza@med.ucm.es.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Leza
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre (Imas12), Instituto de Investigación Neuroquímica (UCM), Avda. Complutense s/n, 28040, Madrid, Spain; Department of Psychiatry, School of Medicine, Universidad Complutense de Madrid, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Investigación Sanitaria Hospital 12 de Octubre (Imas12), Instituto de Investigación Neuroquímica (UCM), Avda. Complutense s/n, 28040, Madrid, Spain. Electronic address: jrcaso@med.ucm.es.
authors.forename: Javier R
authors.initials: JR
authors.lastname: Caso
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage*; D000975:Antioxidants / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D003866:Depressive Disorder / Q000378:metabolism*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009573:Nitrites / Q000097:blood; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D013315:Stress, Psychological / Q000378:metabolism*
chemical_list: D000928:Antidepressive Agents; D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D009573:Nitrites; D047495:PPAR gamma; D003345:Corticosterone
keywords: Antidepressants; Chronic mild stress; Keap-1; Oxidative damage; PI3K/Akt complex; Transcription factor Nrf2