Antidepressant-like effect of agmatine and its possible mechanism.
ABSTRACT In mammalian brain, agmatine is an endogenous neurotransmitter and/or neuromodulator, which is considered as an endogenous ligand for imidazoline receptors. In this study, the antidepressant-like action of agmatine administered p.o. or s.c. was evaluated in three behavioral models in mice or rats. Agmatine at doses 40 and 80 mg/kg (p.o.) reduced immobility time in the tail suspension test and forced swim test in mice or at dose 20 mg/kg (s.c.) in the forced swim test. Agmatine also reduced immobility time at 10 mg/kg (p.o.) or at 1.25, 2.5 and 5 mg/kg (s.c.) in the forced swim test in rats. These results firstly indicated that agmatine possessed an antidepressant-like action. With 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and lactic dehydrogenase (LDH) assay, 1, 10 and 100 microM agmatine or a classical antidepressant, 2.5 and 10 microM desipramine, protected PC12 cells from the lesion induced by 300 microM N-methyl-D-aspartate (NMDA) treatment for 24 h. Using high-performance liquid chromatography with electrochemical detection (HPLC-ECD), it was found that the levels of monoamines including norepinephrine, epinephrine, dopamine or 5-hydroxytryptamine (5-HT) in PC12 cells decreased after the treatment with 200 microM NMDA for 24 h, while in the presence of 1 and 10 microM agmatine or 1 and 5 microM desipramine, the levels of norepinephrine, epinephrine or dopamine were elevated significantly while 5-HT did not change. Moreover, norepinephrine, 5-HT or dopamine had the same cytoprotective effect as agmatine at doses 0.1, 1 and 10 microM. In the fura-2/AM (acetoxymethyl ester) labeling assay, 1 and 10 microM agmatine, 1 and 5 microM desipramine or monoamines norepinephrine, 5-HT at doses 0.1 and 1 microM attenuated the intracellular Ca(2+) overloading induced by 200 microM NMDA treatment for 24 h in PC12 cells. In summary, we firstly demonstrated that agmatine has an antidepressant-like effect in mice and rats. A classical antidepressant, desipramine, as well as agmatine or monoamines protect the PC12 cells from the lesion induced by NMDA treatment. Agmatine reverses the NMDA-induced intracellular Ca(2+) overloading and the decrease of monoamines (including norepinephrine, epinephrine or dopamine) contents in PC12 cells, indicating that agmatine's antidepressant-like action may be related to its modulation of NMDA receptor activity and/or reversal of the decrease of monoamine contents and Ca(2+) overloading induced by NMDA.
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ABSTRACT: Agmatine is an endogenous polyamine, identified in mammalian brain, which meets the main criteria to be considered a neurotransmitter. Agmatine-like immunoreactivity has been described in numerous brain regions which have long been implicated in the regulation of anxiety. However, animal preclini- cal studies investigating effects of agmatine on anxiety are unclear. In this study, an attempt was ma- de to clarify the actions of agmatine (7.5-60 mg/kg, ip) on anxiety tested in the elevated plus maze mi- ce. Moreover, the possible development of tolerance to the effects of agmatine on anxiety after its subchronic administration for 7 consecutive days was also examined. A number of classical parame- ters were collected (open arm duration and frequency, closed arm duration and frequency and central platform duration and frequency). Different ethological measures were also obtained (rearings, head- dipping and stretched attend posture). Results showed that agmatine did not produce any significant behavioural change in any of the parameters examined, suggesting that it might not be involved in the regulation of anxiety in mice.Psicothema 01/2005; 17:492-496. · 0.96 Impact Factor
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ABSTRACT: Agmatine is a cationic amine formed by decarboxylation of L-arginine by the mitochondrial enzyme arginine decarboxylase and widely distributed in mammalian brain. Although the precise function of endogenous agmatine has been largely remained unclear, its exogenous administration demonstrated beneficial effects in several neurological and psychiatric disorders. This study was planned to examine the role of imidazoline binding sites in the anticompulsive-like effect of agmatine on marble-burying behavior. Agmatine (20 and 40 mg/kg, ip), mixed imidazoline I1/α2 agonists clonidine (60 µg/kg, ip) and moxonidine (0.25 mg/kg, ip), and imidazoline I2 agonist 2- BFI (10 mg/kg, ip) showed significant inhibition of marble burying behavior in mice. In combination studies, the anticompulsive-like effect of agmatine (10 mg/kg, ip) was significantly potentiated by prior administration of moxonidine (0.25 mg/kg, ip) or clonidine (30 µg/kg,) or 2-BFI (5 mg/kg, ip). Conversely, efaroxan (1 mg/kg, ip), an I1 antagonist and idazoxan (0.25 mg/kg, ip), an I2 antagonist completely blocked the anticompulsive-like effect of agmatine (10 mg/kg, ip). These drugs at doses used here did not influence the basal locomotor activity in experimental animals. These results clearly indicated the involvement of imidazoline binding sites in anti-compulsive-like effect of agmatine. Thus, imidazoline binding sites can be explored further as novel therapeutic target for treatment of anxiety and obsessive compulsive disorders.European journal of pharmacology 06/2014; · 2.59 Impact Factor
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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 1mg/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 1mg/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 (0.0001mg/kg) combined with sub-effective doses of either fluoxetine (5mg/kg, p.o.), imipramine (0.1mg/kg, p.o.), bupropion (1mg/kg, p.o.), MK-801 (0.001mg/kg, p.o.) or 7-NI (25mg/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.Behavioural brain research 01/2014; · 3.22 Impact Factor