Antidepressant-like effect of agmatine and its possible mechanism

被引:92
作者
Li, YF [1 ]
Gong, ZH [1 ]
Cao, JB [1 ]
Wang, HL [1 ]
Luo, ZP [1 ]
Li, J [1 ]
机构
[1] Beijing Inst Pharmacol & Toxicol, Div Psychopharmacol, Beijing 100850, Peoples R China
关键词
agmatine; antidepressant; PC12; cell; monoamine; Ca2+;
D O I
10.1016/S0014-2999(03)01735-7
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 muM agmatine or a classical antidepressant, 2.5 and 10 muM desipramine, protected PC12 cells from the lesion induced by 300 muM 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 PC 12 cells decreased after the treatment with 200 muM NMDA for 24 h, while in the presence of 1 and 10 muM agmatine or 1 and 5 muM 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 muM. In the fura-2/AM (acetoxymethyl ester) labeling assay, 1 and 10 muM agmatine, 1 and 5 muM desipramine or monoamines norepinephrine, 5-HT at doses 0.1 and 1 muM attenuated the intracellular Ca2+ overloading induced by 200 muM 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 Ca2+ 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 Ca2+ overloading induced by NMDA. (C) 2003 Elsevier Science B.V All rights reserved.
引用
收藏
页码:81 / 88
页数:8
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