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Agmatine, by Improving Neuroplasticity Markers and Inducing Nrf2, Prevents Corticosterone-Induced Depressive-Like Behavior in Mice

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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.

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Abbreviations

ANOVA:

Analysis of variance

AFAR:

Aflotoxin B1 aldehyde reductase

ARE:

Antioxidant response element

BDNF:

Brain-derived-neurotrophic factor

CRE:

cAMP response elements

CREB:

Cyclic-AMP responsive-element binding protein

DA:

Dopamine

EAAT:

Excitatory amino-acid transporter

EH:

Epoxide hydrolase

ERK:

Extracellular signal-regulated kinase

FST:

Forced swimming test

GCLc:

Glutamate cysteine ligase, catalytic subunit

Gln:

Glutamine

Glu:

Glutamate

GSTs:

Glutathione S-transferases

HO-1:

Heme oxygenase-1

HPA:

Hypothalamic pituitary adrenal

5-HT:

5-Hydroxytryptamine

Keap1:

Kelch-like-ECH-associated protein 1

NE:

Norepinephrine

NMDA:

N-methyl-d-aspartate

NQO1:

NAD(P)H:quinone oxidoreductase 1

Nrf2:

(Erythroid 2-derived)-like 2

Syt I:

Synaptotagmin I

TCAs:

Tricyclic antidepressants

TrkB:

Tropomyosin-related kinase B

TST:

Tail suspension test

UDPGTs:

UDP-glucuronosyltransferases

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Acknowledgments

This work was supported by CNPq, CAPES/PDSE, CAPES/PROCAD, Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC) Project/ PRONEX Program CNPq/FAPESC (Brazil) to ALSR. The 8th Convocatoria de proyectos de Cooperación Interuniversitaria UAM-Santander con America Latina, Spanish Ministry of Economy and Competence Ref. SAF2012-32223 to MGL and ALSR. This work was also supported by FIS CA12/00122 to ARN and FPU12/02220 to AW.

Conflict of Interest

All authors have no conflict of interest.

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  1. Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, University of California, San Francisco, San Francisco, CA, 94158, USA

    Andiara E. Freitas

  2. Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade 88040-900, Florianópolis, Santa Catarina, Brazil

    Andiara E. Freitas & Ana Lúcia S. Rodrigues

  3. Departamento de Farmacología y Terapéutica and Instituto Teófilo Hernando. Facultad de Medicina, Universidad Autónoma de Madrid, 28029, Madrid, Spain

    Andiara E. Freitas, Javier Egea, Izaskun Buendia, Vanessa Gómez-Rangel, Esther Parada, Elisa Navarro, Ana Isabel Casas & Manuela G. Lopez

  4. Instituto de Investigación Sanitaria Hospital de la Princesa and Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, Madrid, Spain

    Javier Egea, Izaskun Buendia, Esther Parada, Elisa Navarro, Aneta Wojnicz, José Avendaño Ortiz, Ana Ruiz-Nuño & Manuela G. Lopez

  5. Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands

    Ana Isabel Casas

  6. 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

    Antonio Cuadrado

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  1. Andiara E. Freitas
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  2. Javier Egea
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  3. Izaskun Buendia
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  4. Vanessa Gómez-Rangel
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  5. Esther Parada
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  6. Elisa Navarro
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  7. Ana Isabel Casas
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  8. Aneta Wojnicz
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  9. José Avendaño Ortiz
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  10. Antonio Cuadrado
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  11. Ana Ruiz-Nuño
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  12. Ana Lúcia S. Rodrigues
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  13. Manuela G. Lopez
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Correspondence to Andiara E. Freitas.

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Freitas, A.E., Egea, J., Buendia, I. et al. Agmatine, by Improving Neuroplasticity Markers and Inducing Nrf2, Prevents Corticosterone-Induced Depressive-Like Behavior in Mice. Mol Neurobiol 53, 3030–3045 (2016). https://doi.org/10.1007/s12035-015-9182-6

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  • DOI: https://doi.org/10.1007/s12035-015-9182-6

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