title: Agmatine, by Improving Neuroplasticity Markers and Inducing Nrf2, Prevents Corticosterone-Induced Depressive-Like Behavior in Mice.
abstract: Agmatine, an endogenous neuromodulator, is a potential candidate to constitute an adjuvant/monotherapy for the management of depression. A recent study by our group demonstrated that agmatine induces Nrf2 and protects against corticosterone effects in a hippocampal neuronal cell line. The present study is an extension of this previous study by assessing the antidepressant-like effect of agmatine in an animal model of depression induced by corticosterone in mice. Swiss mice were treated simultaneously with agmatine or imipramine at a dose of 0.1 mg/kg/day (p.o.) and corticosterone for 21 days and the daily administrations of experimental drugs were given immediately prior to corticosterone (20 mg/kg/day, p.o.) administrations. Wild-type C57BL/6 mice (Nrf2 (+/+)) and Nrf2 KO (Nrf2 (-/-)) were treated during 21 days with agmatine (0.1 mg/kg/day, p.o.) or vehicle. Twenty-four hours after the last treatments, the behavioral tests and biochemical assays were performed. Agmatine treatment for 21 days was able to abolish the corticosterone-induced depressive-like behavior and the alterations in the immunocontent of mature BDNF and synaptotagmin I, and in the serotonin and glutamate levels. Agmatine also abolished the corticosterone-induced changes in the morphology of astrocytes and microglia in CA1 region of hippocampus. In addition, agmatine treatment in control mice increased noradrenaline, serotonin, and dopamine levels, CREB phosphorylation, mature BDNF and synaptotagmin I immunocontents, and reduced pro-BDNF immunocontent in the hippocampus. Agmatine's ability to produce an antidepressant-like effect was abolished in Nrf2 (-/-) mice. The present results reinforce the participation of Nrf2 in the antidepressant-like effect produced by agmatine and expand literature data concerning its mechanisms of action.
authors.affiliation: Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, University of California, San Francisco, San Francisco, CA, 94158, USA. andiaraef@gmail.com.|Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade 88040-900, Florianópolis, Santa Catarina, Brazil. andiaraef@gmail.com.|Departamento de Farmacología y Terapéutica and Instituto Teófilo Hernando. Facultad de Medicina, Universidad Autónoma de Madrid, 28029, Madrid, Spain. andiaraef@gmail.com.
authors.forename: Andiara E
authors.initials: AE
authors.lastname: Freitas
authors.affiliation: Departamento de Farmacología y Terapéutica and Instituto Teófilo Hernando. Facultad de Medicina, Universidad Autónoma de Madrid, 28029, Madrid, Spain.|Instituto de Investigación Sanitaria Hospital de la Princesa and Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Egea
authors.affiliation: Departamento de Farmacología y Terapéutica and Instituto Teófilo Hernando. Facultad de Medicina, Universidad Autónoma de Madrid, 28029, Madrid, Spain.|Instituto de Investigación Sanitaria Hospital de la Princesa and Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, Madrid, Spain.
authors.forename: Izaskun
authors.initials: I
authors.lastname: Buendia
authors.affiliation: Departamento de Farmacología y Terapéutica and Instituto Teófilo Hernando. Facultad de Medicina, Universidad Autónoma de Madrid, 28029, Madrid, Spain.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Gómez-Rangel
authors.affiliation: Departamento de Farmacología y Terapéutica and Instituto Teófilo Hernando. Facultad de Medicina, Universidad Autónoma de Madrid, 28029, Madrid, Spain.|Instituto de Investigación Sanitaria Hospital de la Princesa and Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, Madrid, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Parada
authors.affiliation: Departamento de Farmacología y Terapéutica and Instituto Teófilo Hernando. Facultad de Medicina, Universidad Autónoma de Madrid, 28029, Madrid, Spain.|Instituto de Investigación Sanitaria Hospital de la Princesa and Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, Madrid, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Navarro
authors.affiliation: Departamento de Farmacología y Terapéutica and Instituto Teófilo Hernando. Facultad de Medicina, Universidad Autónoma de Madrid, 28029, Madrid, Spain.|Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Casas
authors.affiliation: Instituto de Investigación Sanitaria Hospital de la Princesa and Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, Madrid, Spain.
authors.forename: Aneta
authors.initials: A
authors.lastname: Wojnicz
authors.affiliation: Instituto de Investigación Sanitaria Hospital de la Princesa and Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, Madrid, Spain.
authors.forename: José Avendaño
authors.initials: JA
authors.lastname: Ortiz
authors.affiliation: Departamento de Bioquímica e Instituto de Investigaciones Biomédicas Alberto Sols UAM-CSIC, Centro de Investigación en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cuadrado
authors.affiliation: Instituto de Investigación Sanitaria Hospital de la Princesa and Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Ruiz-Nuño
authors.affiliation: Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade 88040-900, Florianópolis, Santa Catarina, Brazil.
authors.forename: Ana Lúcia S
authors.initials: ALS
authors.lastname: Rodrigues
authors.affiliation: Departamento de Farmacología y Terapéutica and Instituto Teófilo Hernando. Facultad de Medicina, Universidad Autónoma de Madrid, 28029, Madrid, Spain.|Instituto de Investigación Sanitaria Hospital de la Princesa and Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, Madrid, Spain.
authors.forename: Manuela G
authors.initials: MG
authors.lastname: Lopez
mesh_terms: D000376:Agmatine / Q000494:pharmacology*; D059445:Anhedonia / Q000187:drug effects; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001522:Behavior, Animal; D015415:Biomarkers / Q000378:metabolism; D003345:Corticosterone; D003863:Depression / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D007099:Imipramine / Q000494:pharmacology / Q000627:therapeutic use; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects*; D018377:Neurotransmitter Agents / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000928:Antidepressive Agents; D015415:Biomarkers; D051267:NF-E2-Related Factor 2; D018377:Neurotransmitter Agents; D000376:Agmatine; D007099:Imipramine; D003345:Corticosterone
keywords: Agmatine; BDNF; Corticosterone; Depression; Nrf2