Sub-chronic agmatine treatment modulates hippocampal neuroplasticity and cell survival signaling pathways in mice

• Published in: Journal of psychiatric research 2014-11, Vol.58, p.137-146
• Main Authors: Freitas, Andiara E, Bettio, Luis E.B, Neis, Vivian B, Moretti, Morgana, Ribeiro, Camille M, Lopes, Mark W, Leal, Rodrigo B, Rodrigues, Ana Lúcia S
• Format: Article
• Language: English
• Subjects: Agmatine; Agmatine - pharmacology; Akt; Analysis of Variance; Animals; Antidepressive Agents - pharmacology; BDNF; Biological and medical sciences; Cell Survival - drug effects; CREB; Cyclic AMP-Dependent Protein Kinases - metabolism; Dose-Response Relationship, Drug; ERK1/2; Exploratory Behavior - drug effects; Female; Gene Expression Regulation - drug effects; GSK-3β; Hindlimb Suspension; Hippocampus - drug effects; Immobility Response, Tonic - drug effects; JNK1/2; Medical sciences; Mice; Neuronal Plasticity - drug effects; PKA; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Signal Transduction - drug effects
• ISSN: 0022-3956; 1879-1379
• DOI: 10.1016/j.jpsychires.2014.07.024

Abstract Agmatine is an endogenous neuromodulator which, based on animal and human studies, is a putative novel antidepressant drug. In this study, we investigated the ability of sub-chronic (21 days) p.o. agmatine administration to produce an antidepressant-like effect in the tail suspension test and examined the hippocampal cell signaling pathways implicated in such an effect. Agmatine at doses of 0.01 and 0.1 mg/kg (p.o.) produced a significant antidepressant-like effect in the tail suspension test and no effect in the open-field test. Additionally, agmatine (0.001–0.1 mg/kg, p.o.) increased the phosphorylation of protein kinase A substrates (237–258% of control), protein kinase B/Akt (Ser473 ) (116–127% of control), glycogen synthase kinase-3β (Ser9 ) (110–113% of control), extracellular signal-regulated kinases 1/2 (119–137% and 121–138% of control, respectively) and cAMP response elements (Ser133 ) (127–152% of control), and brain-derived-neurotrophic factor (137–175% of control) immunocontent in a dose-dependent manner in the hippocampus. Agmatine (0.001–0.1 mg/kg, p.o.) also reduced the c-jun N-terminal kinase 1/2 phosphorylation (77-71% and 65-51% of control, respectively). Neither protein kinase C nor p38MAPK phosphorylation was altered under any experimental conditions. Taken together, the present study extends the available data on the mechanisms that underlie the antidepressant action of agmatine by showing an antidepressant-like effect following sub-chronic administration. In addition, our results are the first to demonstrate the ability of agmatine to elicit the activation of cellular signaling pathways associated with neuroplasticity/cell survival and the inhibition of signaling pathways associated with cell death in the hippocampus.