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 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 01/2014; · 2.59 Impact Factor
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ABSTRACT: ETHNOPHARMACOLOGICAL RELEVANCE: Acanthopanax senticosus, classified into the family of Araliaceae, has been known for thousands of years as a remedy and is used to treat various diseases in traditional Chinese medicine system including hypertension, ischemic heart disease and hepatitis. AIM OF THE STUDY: This study aimed to examine the protective effects of aqueous extract from Acanthopanax senticosus (ASE) on corticosterone-induced neurotoxicity and its possible mechanisms, using PC12 cells as a suitable in vitro model of depression. MATERIALS AND METHODS: In this paper, PC12 cells were treated with 200μM of corticosterone in the absence or presence of ASE in varying concentrations for 24h. Then, cell viability was measured by MTT assay. The release amount of lactate dehydrogenase (LDH) was quantified using LDH assay kit. Apoptosis of PC12 cells was measured by Annexin V-FITC and PI labeling. The intracellular Ca(2+) content was tested by fluorescent labeling. The mRNA level of brain-derived neurotrophic factor (BDNF) was examined by real-time RT-PCR, and the expression of cAMP response element binding protein (CREB) was determined by western blotting. RESULTS: The results showed that treatment with 200μM of corticosterone could induce cytotoxicity in PC12 cells. However, different concentrations of ASE (50, 100, 200, and 400μg/mL) significantly increased the cell viability, decreased the LDH release, suppressed the apoptosis of PC12 cells, attenuated the intracellular Ca(2+) overloading, up-regulated the BDNF mRNA level and CREB protein expression compared with the corresponding corticosterone-treated group. CONCLUSION: The present results suggest that ASE exerts a neuroprotective effect on corticosterone-induced neurotoxicity in PC12 cells, which may be one of the acting mechanisms that accounts for the in vivo antidepressant activity of ASE.Journal of ethnopharmacology 05/2013; · 2.32 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