title: Depressive-like behavior induced by tumor necrosis factor-α is abolished by agmatine administration.
abstract: Agmatine, an endogenous cationic amine, has been shown to exert antidepressant-like effects. This study investigated the ability of agmatine administered orally to abolish the depressive-like behavior induced by the administration of the pro-inflammatory cytokine, tumor necrosis factor (TNF-α) in mice. In control animals, agmatine (0.001, 0.01, 0.1, and 1 mg/kg) reduced the immobility time in the tail suspension test (TST). Acute administration of TNF-α (0.001 fg/mouse, i.c.v.) increased immobility time in the TST, indicative of a depressive-like behavior, and agmatine (0.0001, 0.1, and 1 mg/kg) prevented this effect. Additionally, we examined the effects of the combined administration of sub-effective doses of agmatine with antidepressants, the NMDA receptor antagonist MK-801 and the neuronal nitric oxide synthase inhibitor 7-nitroindazole (7-NI) in mice exposed to either TNF-α or saline. In control mice, administration of a sub-effective dose of agmatine (0.0001 mg/kg) combined with sub-effective doses of either fluoxetine (5 mg/kg, p.o.), imipramine (0.1 mg/kg, p.o.), bupropion (1 mg/kg, p.o.), MK-801 (0.001 mg/kg, p.o.) or 7-NI (25 mg/kg, i.p.) produced a synergistic antidepressant-like effect in the TST. All these administrations prevented the increased immobility time induced by TNF-α. The effect of agmatine in the TNF-α model of depression appears to be associated, at least partially, with an activation of the monoaminergic systems and inhibition of NMDA receptors and nitric oxide synthesis, although converging signal transduction pathways that may underlie the effect of agmatine should be further investigated. This set of results indicates that agmatine may constitute a new therapeutic alternative for the treatment of depression associated with inflammation.
authors.affiliation: Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900, Florianópolis, SC, Brazil.
authors.forename: Vivian Binder
authors.initials: VB
authors.lastname: Neis
authors.affiliation: Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900, Florianópolis, SC, Brazil.
authors.forename: Luana Meller
authors.initials: LM
authors.lastname: Manosso
authors.affiliation: Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900, Florianópolis, SC, Brazil.
authors.forename: Morgana
authors.initials: M
authors.lastname: Moretti
authors.affiliation: Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900, Florianópolis, SC, Brazil.
authors.forename: Andiara E
authors.initials: AE
authors.lastname: Freitas
authors.affiliation: Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900, Florianópolis, SC, Brazil.
authors.forename: Juliana
authors.initials: J
authors.lastname: Daufenbach
authors.affiliation: Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, 88040-900, Florianópolis, SC, Brazil. Electronic address: alsrodri@gmail.com.
authors.forename: Ana Lúcia S
authors.initials: AL
authors.lastname: Rodrigues
mesh_terms: D000376:Agmatine / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D003863:Depression / Q000139:chemically induced* / Q000188:drug therapy*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D019417:Hindlimb Suspension; D046353:Immobility Response, Tonic / Q000187:drug effects; D007191:Indazoles / Q000627:therapeutic use; D051379:Mice; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
chemical_list: D000928:Antidepressive Agents; D007191:Indazoles; D014409:Tumor Necrosis Factor-alpha; D016291:Dizocilpine Maleate; D000376:Agmatine; C080122:7-nitroindazole
keywords: 7-NI; 7-nitroindazole; ANOVA; Agmatine; Antidepressant; Depression; FST; N-methyl-D-aspartate; NMDA; NO; NOS; TNF-α; TST; Tail suspension test; analysis of variance; forced swimming test; nitric oxide; nitric oxide synthase; tail suspension test; tumor necrosis factor-α