Antidepressant-like effect of agmatine and its possible mechanism

Division of Psychopharmacology, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing 100850, China.
European Journal of Pharmacology (Impact Factor: 2.53). 06/2003; 469(1-3):81-8. DOI: 10.1016/S0014-2999(03)01735-7
Source: PubMed


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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    • "A study performed by Li and co-workers [40] also reported that agmatine administered orally once a day for three days produces an antidepressant-like effect in the TST in male Kunming mice, but when used in higher doses (40 and 80 mg/kg, p.o.). The remarkable potency differences of agmatine in the TST between the current report and the data of Li et al. (2003) may be attributed Fig. 7. Effect of the administration of a sub-effective dose of agmatine (0.0001 mg/kg, p.o.) with a sub-effective dose of 7-nitroindazole (25 mg/kg, i.p.) in animals treated with vehicle or TNF-␣ (0.001 fg/mouse, i.c.v.) in the TST (panel A) and open-field test (panel B). Each column represents the mean + S.E.M of 8–11 animals. "
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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; 261. DOI:10.1016/j.bbr.2013.12.038 · 3.03 Impact Factor
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    • "Plants that fall under the genus Mesua have been used for various complementary medicine purposes such as antiallergic, rheumatism, antidiarrhoetic, and antibacterial as they are the fruitful sources of phytochemicals such as phloroglucinols, xanthones, neoflavonoids, and coumarins. These phytochemicals particularly coumarins, which are derivatives of cinnamic acid with the presence of a benzo-α-pyrene skeleton, have been shown to exert multifarious biological activities such as neuromodulator, antidepressant, anti-HIV-1, anti-inflammatory, antitumor, antimicrobial, antiviral, antifungal, and hepatoprotective effects [11–13]. The bark of M. kunstleri has been locally used to cure dyspepsis, a chronic, recurrent pain centered in the upper abdomen and renal diseases [14]. "
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    Evidence-based Complementary and Alternative Medicine 07/2012; 2012(20):156521. DOI:10.1155/2012/156521 · 1.88 Impact Factor
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    • "In this study, the pretreatment of animals with a subeffective dose of putrescine produced a synergistic antidepressant-like effect with agmatine. Agmatine, an amine formed by the enzymatic decarboxylation of L-arginine by arginine decarboxylase, produces antidepressant-like effect in the FST and in the TST in mice and rats (Zomkowski et al., 2002; Li et al., 2003). The antidepressant-like effect of agmatine in the FST is dependent of the inhibition of NMDA receptor and NOS as well as an interaction with α 2 -adrenoreceptors (Zomkowski et al., 2002), as well as with an interaction with the serotonergic system (Zomkowski et al., 2004) and opioid system (Zomkowski et al., 2005). "
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    ABSTRACT: Putrescine, a polyamine present at high concentrations in the mammalian brain, was suggested to play a role in the modulation of depression. Thus, this study investigated the effect of putrescine in the mouse forced swimming test (FST) and in the tail suspension test (TST), two models predictive of antidepressant activity. Putrescine significantly reduced the immobility time both in the FST and in the TST (dose range of 1-10 mg/kg, i.p.), without changing locomotion in an open-field. I.c.v. injection of putrescine (0.1-10 nmol/site) also reduced the immobility time in the FST and in the TST. The pretreatment of mice with arcaine (1 mg/kg, i.p., an antagonist of the polyamine-site of NMDA receptor) completely blocked the anti-immobility effect of putrescine (10 mg/kg, i.p.). A subeffective dose of putrescine (0.1 mg/kg, i.p.) produced a synergistic antidepressant-like effect with agmatine (0.001 mg/kg, i.p.) in the FST. Moreover, a subeffective dose of putrescine (0.01 nmol/site, i.c.v.) produced a synergistic antidepressant-like effect with arcaine (50 microg/site, i.c.v.). The results indicate that putrescine produces antidepressant-like effects in the FST that seems to be mediated through its interaction with the polyamine-site of NMDA receptors.
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