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Agmatine Induces Nrf2 and Protects Against Corticosterone Effects in Hippocampal Neuronal Cell Line

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Abstract

Hyperactivation of the hypothalamic-pituitary-adrenal axis is a common finding in major depression; this may lead to increased levels of cortisol, which are known to cause oxidative stress imbalance and apoptotic neuronal cell death, particularly in the hippocampus, a key region implicated in mood regulation. Agmatine, an endogenous metabolite of l-arginine, has been proposed for the treatment of major depression. Corticosterone induced apoptotic cell death and increased ROS production in cultured hippocampal neuronal cells, effects that were abolished in a concentration- and time-dependent manner by agmatine. Interestingly, the combination of sub-effective concentrations of agmatine with fluoxetine or imipramine afforded synergic protection. The neuroprotective effect of agmatine was abolished by yohimbine (α2-adrenoceptor antagonist), ketanserin (5-HT2A receptor antagonist), LY294002 (PI3K inhibitor), PD98059 (MEK1/2 inhibitor), SnPP (HO-1 inhibitor), and cycloheximide (protein synthesis inhibitor). Agmatine increased Akt and ERK phosphorylation and induced the transcription factor Nrf2 and the proteins HO-1 and GCLc; induction of these proteins was prevented by yohimbine, ketanserin, LY294002, and PD98059. In conclusion, agmatine affords neuroprotection against corticosterone effects by a mechanism that implicates Nrf2 induction via α2-adrenergic and 5-HT2A receptors, Akt and ERK pathways, and HO-1 and GCLc expression.

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Abbreviations

7-AAD:

7-aminoactinomycin D

ANOVA:

Analysis of variance

ARE:

Antioxidant response element

ERK:

Extracellular signal-regulated kinase

GCLc:

Glutamate cysteine ligase, catalytic subunit

GSTA2:

Glutathione S-transferase α2

HO-1:

Heme oxygenase-1

HPA:

Hypothalamic-pituitary-adrenal

JNK:

c-Jun NH 2-terminal kinase

Keap1:

Kelch-like-ECH-associated protein 1

NQO1:

NAD(P)H/quinone oxidoreductase

Nrf2:

Nuclear factor (erythroid 2 derived)-like 2

PI3K:

Phosphatidylinositol 3-kinase

PKC:

Protein kinase C

SSRI:

Selective serotonin reuptake inhibitor

TCA:

Tricyclic antidepressant

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Acknowledgments

This study was supported by the FINEP research grant “Rede Instituto Brasileiro de Neurociência (IBN-Net/CNPq),” CNPq, FAPESC, 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, and Spanish Ministry of Health (Instituto de Salud Carlos III) RETICS-RD06/0026 to MGL.

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  1. Instituto Teofilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, 4-28029, Madrid, Spain

    Andiara E. Freitas, Javier Egea, Izaskun Buendía, Elisa Navarro & Manuela G. López

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

    Andiara E. Freitas & Ana Lúcia S. Rodrigues

  3. Departamento de Bioquímica e Instituto de Investigaciones Biomédicas Alberto Sols UAM-CSIC, Centro de Investigación en Red Sobre Enfermedades Neurodegenerativas, Madrid, Spain

    Patricia Rada & Antonio Cuadrado

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Freitas, A.E., Egea, J., Buendía, I. et al. Agmatine Induces Nrf2 and Protects Against Corticosterone Effects in Hippocampal Neuronal Cell Line. Mol Neurobiol 51, 1504–1519 (2015). https://doi.org/10.1007/s12035-014-8827-1

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