Antidepressant-like Effect Of Agmatine Research Articles

Involvement of agmatine in antidepressant-like effect of HMG-CoA reductase inhibitors in mice

3-Hydroxy-3-methyl-glutaryl-co-enzyme–A (HMG-CoA) reductase inhibitors (statins) are popularly used for the treatment of obesity and hypercholesterolemia with established safety profile. Statins exhibits a wide range of neurobehavioral effects in addition to their peripheral actions, and may be beneficial in treatment of psychiatric conditions. Present study investigated the role of agmatine and imidazoline receptors in antidepressant-like effect of statins in mouse forced swimming test (FST). The antidepressant-like effect of atorvastatin (5 mg/kg, p.o.) and simvastatin (10 mg/kg, p.o.) was potentiated by pretreatment with agmatine (5 mg/kg, i.p.) as well as the drugs known to increase endogenous agmatine levels in brain viz., L-arginine (40 μg/mouse, i.c.v.), an agmatine biosynthetic precursor; arcaine (50 μg/mouse, i.c.v), agmatinase inhibitor; and aminoguanidine (6.5 μg/mouse, i.c.v.), a diamine oxidase inhibitor. Further, both the statins increased agmatine levels within hippocampus and prefrontal cortex. Conversely, prior administration of I1 receptor antagonist, efaroxan (1 mg/kg, i.p.) and I2 receptor antagonist, idazoxan (0.25 mg/kg, i.p.) blocked the antidepressant-like effect of statins and their synergistic combination with agmatine. These results demonstrate the involvement of agmatine and imidazoline receptors in antidepressant-like effect of statins and suggest as a potential therapeutic target for the treatment of depressive disorders.

The involvement of GABAergic system in the antidepressant-like effect of agmatine.

Considering the involvement of GABAergic system in the action of the fast-acting antidepressant ketamine, and that agmatine may exert an antidepressant-like effect through mechanisms similar to ketamine, the purpose of the present study was to evaluate the involvement of GABAA and GABAB receptors in the antidepressant-like effect of agmatine. The administration of muscimol (0.1 mg/kg, i.p., GABAA receptor agonist) or diazepam (0.05 mg/kg, p.o., GABAA receptor positive allosteric modulator) at doses that caused no effect in the tail suspension test (TST) combined with a subeffective dose of agmatine (0.0001 mg/kg, p.o.) produced a synergistic antidepressant-like effect in the TST. In another set of experiments, the administration of baclofen (1 mg/kg, i.p., GABAB receptor agonist) abolished the reduction of immobility time in the TST elicited by agmatine (0.1 mg/kg, p.o., active dose). In another cohort of animals, treatment with NMDA (0.1 pmol/site, i.c.v.) prevented the antidepressant-like effect of the combined administration of agmatine and muscimol as well as ketamine and muscimol in the TST. Results suggest that the effect of agmatine in the TST may involve an activation of GABAA receptors dependent on NMDA receptor inhibition, similar to ketamine, as well as modulation of GABAB receptors.

Agmatine ameliorates manifestation of depression-like behavior and hippocampal neuroinflammation in mouse model of Alzheimer’s disease

Extensive clinical and experimental studies established that depression and mood disorders are highly prevalent neuropsychiatric conditions in Alzheimer’s disease (AD). However, its neurochemical basis is not clearly understood. Thus, understanding the neural mechanisms involved in mediating the co-morbidity of depression and AD may be crucial in exploring new pharmacological treatments for this condition. The present study investigated the role of the agmatinergic system in β-amyloid (Aββ1−42) peptide-induced depression using forced swim test (FST) in mice. Following the 28th days of its administration, Aβ1−42 peptide produced depression-like behavior in mice as evidenced by increased immobility time in FST and increased expression of pro-inflammatory cytokines like IL-6 and TNF-α compared to the control animals. The Aβ1−42 peptide-induced depression and neuroinflammatory markers were significantly inhibited by agmatine −, moxonidine, 2-BFI and l-arginine by once-daily administration during day 8–27 of the protocol. The antidepressant-like effect of agmatine in Aβ1−42 peptide in mice was potentiated by imidazoline receptor I1 agonist, moxonidine and imidazoline receptor I2 agonist 2-BFI at their sub-effective doses. On the other hand, it was completely blocked by imidazoline receptor I1 antagonist, efaroxan and imidazoline receptor I2 antagonist, idazoxan Also, agmatine levels were significantly reduced in brain samples of β-amyloid injected mice as compared to the control animals. In conclusion, the present study suggests the importance of endogenous agmatinergic system and imidazoline receptors system in β-amyloid induced a depressive-like behavior in mice. The data projects agmatine as a potential therapeutic target for the AD-associated depression and comorbidities.

Agmatine Reverses Sub-chronic Stress induced Nod-like Receptor Protein 3 (NLRP3) Activation and Cytokine Response in Rats.

The activation of Nod-like receptor protein 3 (NLRP3) has lately been implicated in stress and depression as an initiator mechanism required for the production of interleukin (IL)-1β and IL-18. Agmatine, an endogenous polyamine widely distributed in mammalian brain, is a novel neurotransmitter/neuromodulator, with antistress, anxiolytic and antidepressant-like effects. In this study, we examined the effect of exogenously administered agmatine on NLRP3 inflammasome pathway/cytokine responses in rats exposed to restraint stress for 7 days. The rats were divided into three groups: stress, stress+agmatine (40 mg/kg; i.p.) and control groups. Agmatine significantly down-regulated the gene expressions of all stress-induced NLRP3 inflammasome components (NLRP3, NF-κB, PYCARD, caspase-1, IL-1β and IL-18) in the hippocampus and prefrontal cortex (PFC) and reduced pro-inflammatory cytokine levels not only in both brain regions, but also in serum. Stress-reduced levels of IL-4 and IL-10, two major anti-inflammatory cytokines, were restored back to normal by agmatine treatment in the PFC. The findings of the present study suggest that stress-activated NLRP3 inflammasome and cytokine responses are reversed by an acute administration of agmatine. Whether antidepressant-like effect of agmatine can somehow, at least partially, be mediated by the inhibition of NLRP3 inflammasome cascade and relevant inflammatory responses requires further studies in animal models of depression.

Agmatine produces antidepressant-like effects by activating AMPA receptors and mTOR signaling

The activation of AMPA receptors and mTOR signaling has been reported as mechanisms underlying the antidepressant effects of fast-acting agents, specially the NMDA receptor antagonist ketamine. In the present study, oral administration of agmatine (0.1mg/kg), a neuromodulator that has been reported to modulate NMDA receptors, caused a significant reduction in the immobility time of mice submitted to the tail suspension test (TST), an effect prevented by the administration of DNQX (AMPA receptor antagonist, 2.5μg/site, i.c.v.), BDNF antibody (1μg/site, i.c.v.), K-252a (TrkB receptor antagonist, 1μg/site, i.c.v.), LY294002 (PI3K inhibitor, 10nmol/site, i.c.v.) or rapamycin (selective mTOR inhibitor, 0.2nmol/site, i.c.v.). Moreover, the administration of lithium chloride (non-selective GSK-3β inhibitor, 10mg/kg, p.o.) or AR-A014418 (selective GSK-3β inhibitor, 0.01μg/site, i.c.v.) in combination with a sub-effective dose of agmatine (0.0001mg/kg, p.o.) reduced the immobility time in the TST when compared with either drug alone. Furthermore, increased immunocontents of BDNF, PSD-95 and GluA1 were found in the prefrontal cortex of mice just 1h after agmatine administration. These results indicate that the antidepressant-like effect of agmatine in the TST may be dependent on the activation of AMPA and TrkB receptors, PI3K and mTOR signaling as well as inhibition of GSK-3β, and increase in synaptic proteins. The results contribute to elucidate the complex signaling pathways involved in the antidepressant effect of agmatine and reinforce the pivotal role of these molecular targets for antidepressant responses.

Agmatine attenuates chronic unpredictable mild stress induced behavioral alteration in mice

Chronic stress exposure and resulting dysregulation of the hypothalamic pituitary adrenal axis develops susceptibility to variety of neurological and psychiatric disorders. Agmatine, a putative neurotransmitter has been reported to be released in response to various stressful stimuli to maintain the homeostasis. Present study investigated the role of agmatine on chronic unpredictable mild stress (CUMS) induced behavioral and biochemical alteration in mice. Exposure of mice to CUMS protocol for 28 days resulted in diminished performance in sucrose preference test, splash test, forced swim test and marked elevation in plasma corticosterone levels. Chronic agmatine (5 and10mg/kg, ip, once daily) treatment started on day-15 and continued till the end of the CUMS protocol significantly increased sucrose preference, improved self-care and motivational behavior in the splash test and decreased duration of immobility in the forced swim test. Agmatine treatment also normalized the elevated corticosterone levels and prevented the body weight changes in chronically stressed animals. The pharmacological effect of agmatine was comparable to selective serotonin reuptake inhibitor, fluoxetine (10mg/kg, ip). Results of present study clearly demonstrated the anti-depressant like effect of agmatine in chronic unpredictable mild stress induced depression in mice. Thus the development of drugs based on brain agmatinergic modulation may represent a new potential approach for the treatment of stress related mood disorders like depression.

Possible involvement of neuropeptide Y Y1 receptors in antidepressant like effect of agmatine in rats

Agmatine and neuropeptide Y (NPY) are widely distributed in central nervous system and critically involved in modulation of depressive behavior in experimental animals. However their mutual interaction, if any, in regulation of depression remain largely unexplored. In the present study we explored the possible interaction between agmatine and neuropeptide Y in regulation of depression like behavior in forced swim test. We found that acute intracerebroventricular (i.c.v.) administration of agmatine (20–40μg/rat), NPY (5 and 10μg/rat) and NPY Y1 receptor agonist, [Leu31, Pro34]-NPY (0.4 and 0.8ng/rat) dose dependently decreased immobility time in forced swim test indicating their antidepressant like effects. In combination studies, the antidepressant like effect of agmatine (10μg/rat) was significantly potentiated by NPY (1 and 5μg/rat, icv) or [Leu31, Pro34]-NPY (0.2 and 0.4ng/rat, icv) pretreatment. Conversely, pretreatment of animals with NPY Y1 receptor antagonist, BIBP3226 (0.1ng/rat, i.c.v.) completely blocked the antidepressant like effect of agmatine (20–40μg/rat) and its synergistic effect with NPY (1μg/rat, icv) or [Leu31, Pro34]-NPY (0.2ng/rat, icv). The results of the present study showed that, agmatine exerts antidepressant like effects via NPYergic system possibly mediated by the NPY Y1 receptor subtypes and suggest that interaction between agmatine and neuropeptide Y may be relevant to generate the therapeutic strategies for the treatment of depression.

Antidepressant-like effect of agmatine is not mediated by serotonin

The aim of this study was to characterize the behavioral effects of systemically administered agmatine in animal models predictive of antidepressant- and anxiolytic-like activity and clarify whether the effects of agmatine depend on the intact serotonergic system. Only the highest dose of agmatine tested (50 mg/kg) decreased immobility of mice in the forced swimming test. The magnitude of the effect was slightly smaller than that of the tricyclic antidepressant imipramine (15 mg/kg). Agmatine did not change the locomotion of mice in the open field. Pretreatment with the tryptophane hydroxylase inhibitor PCPA for 3 days resulted in more than 70% drop in the tissue levels of 5-HT and 5-HIIA but did not counteract the antidepressant-like effect of agmatine. The administration of agmatine did not modify behavior of animals in the light–dark compartment test of anxiety. We conclude that the antidepressant-like effect of agmatine seems not to be mediated by the serotonergic system. We failed to confirm the reported anxiolytic-like activity of agmatine.

P.1.c.028 Role of different types of potassium channels in the antidepressant-like effect of agmatine in the forced swimming test

P.1.c.028 Role of different types of potassium channels in the antidepressant-like effect of agmatine in the forced swimming test

Role of different types of potassium channels in the antidepressant-like effect of agmatine in the mouse forced swimming test

The administration of agmatine elicits an antidepressant-like effect in the mouse forced swimming test by a mechanism dependent on the inhibition of the NMDA receptors and the l-arginine-nitric oxide (NO) pathway. Since it has been reported that the NO can activate different types of potassium (K +) channels in several tissues, the present study investigates the possibility of synergistic interactions between different types of K + channel inhibitors and agmatine in the forced swimming test. Treatment of mice by i.c.v. route with subeffective doses of tetraethylammonium (a non specific inhibitor of K + channels, 25 pg/site), glibenclamide (an ATP-sensitive K + channels inhibitor, 0.5 pg/site), charybdotoxin (a large- and intermediate-conductance calcium-activated K + channel inhibitor, 25 pg/site) or apamin (a small-conductance calcium-activated K + channel inhibitor, 10 pg/site), augmented the effect of agmatine (0.001 mg/kg, i.p.) in the forced swimming test. Furthermore, the administration of agmatine and the K + channel inhibitors, alone or in combination, did not affect locomotion in the open-field test. Moreover, the reduction in the immobility time elicited by an active dose of agmatine (10 mg/kg, i.p.) in the forced swimming test was prevented by the pre-treatment of mice with the K + channel openers cromakalim (10 μg/site, i.c.v.) and minoxidil (10 μg/site, i.c.v.), without affecting locomotion. Together these data raise the possibility that the antidepressant-like effect of agmatine in the forced swimming test is related to its modulatory effects on neuronal excitability, via inhibition of K + channels.

Evidence for imidazoline receptors involvement in the agmatine antidepressant-like effect in the forced swimming test

This study investigated the involvement of the imidazoline receptors in the antidepressant-like effect of agmatine in the forced swimming test. The antidepressant-like effects of agmatine (10 mg/kg, i.p.) in the forced swimming test was blocked by pretreatment of mice with efaroxan (1 mg/kg, i.p., an imidazoline I 1/α 2-adrenoceptor antagonist), idazoxan (0.06 mg/kg, i.p., an imidazoline I 2/α 2-adrenoceptor antagonist) and antazoline (5 mg/kg, i.p., a ligand with high affinity for the I 2 receptor). A subeffective dose of agmatine (0.001 mg/kg, i.p.) produced a synergistic antidepressant-like effect with clonidine (0.06 mg/kg, i.p, an imidazoline I 1/α 2-adrenoceptor agonist), moxonidine (0.5 mg/kg, i.p., an imidazoline I 1/α 2-adrenoceptor agonist), antazoline (1 mg/kg, i.p.) and MK-801 (0.001 mg/kg, i.p., a non-competitive NMDA receptor antagonist), but not with efaroxan (1 mg/kg, i.p.) and idazoxan (0.06 mg/kg, i.p.). Pretreatment of mice with yohimbine (1 mg/kg, i.p., an α 2-adrenoceptor antagonist) blocked the synergistic antidepressant-like effect of agmatine (0.001 mg/kg, i.p.) with clonidine (0.06 mg/kg, i.p). A subeffective dose of MK-801 (0.001 mg/kg, i.p.) produced a synergistic antidepressant-like effect with antazoline (5 mg/kg, i.p.), but not with efaroxan (1 mg/kg, i.p.) or idazoxan (0.06 mg/kg, i.p.). In conclusion, this study suggests that the anti-immobility effect of agmatine in the forced swimming test is dependent on its interaction with imidazoline I 1 and I 2 receptors.

Evidence for the involvement of the opioid system in the agmatine antidepressant-like effect in the forced swimming test

This study investigated the involvement of the opioid system in the antidepressant-like effect of agmatine in the mouse forced swimming test (FST). The antidepressant-like effects of agmatine (10 mg/kg, i.p.), as well as those of fluoxetine (32 mg/kg, i.p, a selective serotonin reuptake inhibitor, SSRI) or morphine (5 mg/kg, s.c., a nonselective opioid receptor agonist) in the FST was completely blocked by pretreatment of mice with naloxone (1 mg/kg, i.p., a nonselective opioid receptor antagonist). Pretreatment of mice with naltrindole (3 mg/kg, i.p., a selective δ-opioid receptor antagonist), clocinnamox (1 mg/kg, i.p., an irreversible μ-opioid receptor antagonist), but not with 2-(3,4-dichlorophenyl)- N-methyl- N-[(1 S)-1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl]acetamide (DIPPA; 1 mg/kg, i.p., a selective κ-opioid receptor antagonist) completely blocked the anti-immobility effect of agmatine (10 mg/kg, i.p.) in the FST. These results firstly demonstrate that the antidepressant-like effects of agmatine in the FST seem to be mediated, at least in part, by an interaction with the opioid system, that involves an activation of δ- and μ-opioid receptors.

Antidepressant-like effect of agmatine and its possible mechanism

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 μM agmatine or a classical antidepressant, 2.5 and 10 μM desipramine, protected PC12 cells from the lesion induced by 300 μM 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 μM NMDA for 24 h, while in the presence of 1 and 10 μM agmatine or 1 and 5 μM 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 μM. In the fura-2/AM (acetoxymethyl ester) labeling assay, 1 and 10 μM agmatine, 1 and 5 μM desipramine or monoamines norepinephrine, 5-HT at doses 0.1 and 1 μM attenuated the intracellular Ca 2+ overloading induced by 200 μM 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.