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1.
Brain Res ; 1725: 146438, 2019 12 15.
Article in English | MEDLINE | ID: mdl-31518574

ABSTRACT

Innate immunity activation in the central nervous system (CNS) is known to contribute to the development of depression through NOD-like receptors containing pyrin domain 3 (NLRP3) inflammasome assembly. Furthermore, administration of agmatine (AGM), a nitric oxide synthase (NOS) inhibitor, reverses stress-induced NLRP3 inflammasome activation in rats. We examined the effects of chronically-administered nitric oxide (NO) pathway modulating drugs on NLRP1/3-mediated neuroinflammatory responses and depressive-like behaviors in chronic unpredictable mild stress (CUMS) depression model of rats. CUMS model was applied to the adult male Sprague-Dawley rats for 6 weeks and the treatments were daily administered via intraperitoneal route in the last 3 weeks of CUMS procedure. Depressive-like behaviors were assessed by sucrose preference and forced swimming tests. The levels of NLRP inflammasome components (NLRP1, NLRP3, ASC, caspase-1 and IL-1ß) were investigated in the prefrontal cortex by real time PCR and western blot methods. CUMS-induced depressive-like behaviors were coupled with the overactivation of NLRP1 and NLRP3 inflammasome sensors and increased levels of IL-1ß. Depressive-like behaviors were ameliorated by chronic AGM and NOS inhibitor treatments. AGM and other NOS inhibitor treatments were found to be more effective in suppressing NLRP3 and NLRP1, respectively. All inhibitor reagents downregulated inflammasome components and IL-1ß. These results suggest that both neuronal NLRP1 and microglial NLRP3 inflammasomes are involved in chronic stress-induced depressive-like behaviors. The antidepressant effects of AGM, iNOS and nNOS inhibitors are associated with the downregulation of CNS inflammasome expression levels. NO-pathway modulating drugs might provide novel therapeutic strategies for depression.


Subject(s)
Agmatine/antagonists & inhibitors , Antidepressive Agents/administration & dosage , Depression/drug therapy , Inflammasomes/drug effects , NLR Proteins/metabolism , Nitric Oxide Synthase/antagonists & inhibitors , Stress, Psychological/complications , Animals , Depression/etiology , Depression/metabolism , Disease Models, Animal , Inflammasomes/metabolism , Male , RNA, Messenger/metabolism , Rats, Sprague-Dawley
2.
Alcohol Clin Exp Res ; 43(4): 747-757, 2019 04.
Article in English | MEDLINE | ID: mdl-30735249

ABSTRACT

BACKGROUND: Locomotor sensitization to repeated ethanol (EtOH) administration is proposed to play a role in early and recurring steps of addiction. The present study was designed to examine the effect of agmatine on EtOH-induced locomotor sensitization in mice. METHODS: Mice received daily single intraperitoneal injection of EtOH (2.5 g/kg, 20 v/v) for 7 consecutive days. Following a 3-day EtOH-free phase, the mice were challenged with EtOH on day 11 with a single injection of EtOH. Agmatine (10 to 40 µg/mouse), endogenous agmatine enhancers (l-arginine [80 µg/mouse], arcaine [50 µg/mouse], aminoguanidine [25 µg/mouse]), and imidazoline receptor agonist/antagonists were injected (intracerebroventricular [i.c.v.]) either daily before the injection of EtOH during the 7-day development phase or on days 8, 9, and 10 (EtOH-free phase). The horizontal locomotor activity was determined on days 1, 3, 5, 7, and 11. RESULTS: Agmatine (20 to 40 µg/mouse) administration for 7 days (development phase) significantly attenuated the locomotor sensitization response of EtOH challenge on day 11. Further, the agmatine administered only during EtOH-free period (days 8, 9, and 10) also inhibited the enhanced locomotor activity on the 11th day to EtOH challenge as compared to control mice indicating blockade of expression of sensitization. Daily treatment (i.c.v.) with endogenous agmatine enhancers like l-arginine (80 µg/mouse) or arcaine (50 µg/mouse) and aminoguanidine (25 µg/mouse) restrained the development as well as expression of sensitization to EtOH. Imidazoline I1 receptor agonist, moxonidine, and I2 agonist, 2-BFI, not only decreased the development and expression of locomotor sensitization but also potentiated the effect of agmatine when employed in combination. Importantly, I1 receptor antagonist, efaroxan, and I2 antagonist, idazoxan, blocked the effect of agmatine, revealing the involvement of imidazoline receptors in agmatine-mediated inhibition of EtOH sensitization. CONCLUSIONS: Inhibition of EtOH sensitization by agmatine is mediated through imidazoline receptors and project agmatine and imidazoline agents in the pharmacotherapy of alcohol addiction.


Subject(s)
Agmatine/pharmacology , Central Nervous System Sensitization/drug effects , Ethanol/antagonists & inhibitors , Agmatine/antagonists & inhibitors , Animals , Arginine/administration & dosage , Arginine/pharmacology , Benzofurans/pharmacology , Biguanides/administration & dosage , Biguanides/pharmacology , Dose-Response Relationship, Drug , Drug Interactions , Ethanol/pharmacology , Guanidines/administration & dosage , Guanidines/pharmacology , Idazoxan/pharmacology , Imidazoles/pharmacology , Imidazoline Receptors/agonists , Imidazoline Receptors/antagonists & inhibitors , Infusions, Intraventricular , Male , Mice , Microinjections , Motor Activity/drug effects
3.
Pharmacol Biochem Behav ; 167: 42-49, 2018 04.
Article in English | MEDLINE | ID: mdl-29530492

ABSTRACT

Nicotine abstinence following chronic exposure is associated with impairments in memory and variety of cognitive functions. Daily nicotine (2 mg/kg, sc, four times daily) administration for 14 days and its abrupt withdrawal significantly impaired avoidance learning in inhibitory avoidance task as indicated by a significant decrease in the step through latency. Animals injected with agmatine (10-40 µg/rat, icv) from day 7 to 14 before the first daily dose of nicotine (2 mg/kg, sc) showed increased step through latencies during retrieval test. Similarly Intracerebroventricular injection of l-arginine (25-100 µg/rat), a biosynthetic precursor of agmatine and arcaine (50 µg -100 µg/rat), an agmatinase inhibitor, also increased the step through latency during retrieval test in nicotine withdrawn animals. In separate experiments, α2-adrenoceptor agonist, clonidine (0.5-1 µg/rat, icv) not only demonstrated significant increase in the step through latency as in nicotine withdrawn rats but also potentiated the pharmacological effect of agmatine. In contrast, pre-treatment of α2-adrenoceptor antagonist, yohimbine (0.5 µg/rat, icv) antagonized the memory enhancing effect of agmatine (20 µg/rat, icv) in nicotine withdrawn rats. In addition, brain agmatine analysis carried out at 72 h time point of nicotine withdrawal showed marked decrease in basal brain agmatine content as compared to control. Overall, the data indicate that agmatine attenuates nicotine withdrawal induced memory impairment through modulation of α2adrenergic receptors. Thus, agmatine might have therapeutic implications in the treatment of cognitive deficits following nicotine withdrawal.


Subject(s)
Agmatine/pharmacology , Avoidance Learning/drug effects , Cognitive Dysfunction/prevention & control , Inhibition, Psychological , Nicotine/adverse effects , Receptors, Adrenergic, alpha-2/metabolism , Substance Withdrawal Syndrome/prevention & control , Agmatine/administration & dosage , Agmatine/antagonists & inhibitors , Agmatine/metabolism , Animals , Arginine/pharmacology , Biguanides/pharmacology , Brain/metabolism , Clonidine/pharmacology , Cognitive Dysfunction/psychology , Dose-Response Relationship, Drug , Drug Synergism , Infusions, Intraventricular , Male , Memory/drug effects , Nicotine/pharmacology , Rats , Yohimbine/pharmacology
4.
Biochem Pharmacol ; 118: 109-120, 2016 Oct 15.
Article in English | MEDLINE | ID: mdl-27565891

ABSTRACT

Mercury compounds are well-known toxic environmental pollutants and potently induce severe neurotoxicological effects in human and experimental animals. Previous studies showed that one of the mechanisms of mercury compounds neurotoxicity arose from the over-activation of the N-methyl d-aspartate (NMDA)-type glutamate receptor induced by increased glutamate release. In this work, we aimed to investigate the molecular mechanisms of Hg compounds neurotoxicities by identifying their biological targets in cells. Firstly, the inhibitory effects of four Hg compounds, including three organic (methyl-, ethyl- and phenyl-mercury) and one inorganic (Hg2+) Hg compounds, on the activity of arginine decarboxylase (ADC), a key enzyme in the central agmatinergic system, were evaluated. They were found to inhibit the ADC activity significantly with methylmercury (MeHg) being the strongest (IC50=7.96nM). Furthermore, they showed remarkable inhibitory effects on ADC activity in PC12 cells (MeHg>EtHg>PhHg>HgCl2), and led to a marked loss in the level of agmatine, an endogenous neuromodulatory and neuroprotective agent that selectively blocks the activation of NMDA receptors. MeHg was detected in the immunoprecipitated ADC from the cells, providing unequivocal evidence for the direct binding of MeHg with ADC in the cell. Molecular dynamics simulation revealed that Hg compounds could form the coordination bond not only with cofactor PLP of ADC, but also with substrate arginine. Our finding indicated that MeHg could attenuate the neuroprotective effects of agmatine by the inhibition of ADC, a new cellular target of MeHg, which might be implicated in molecular mechanism of MeHg neurotoxicity.


Subject(s)
Carboxy-Lyases/antagonists & inhibitors , Environmental Pollutants/toxicity , Enzyme Inhibitors/toxicity , Methylmercury Compounds/toxicity , Models, Molecular , Nerve Tissue Proteins/antagonists & inhibitors , Neurons/drug effects , Absorption, Physiological , Agmatine/antagonists & inhibitors , Agmatine/metabolism , Animals , Arginine/metabolism , Binding Sites , Biocatalysis/drug effects , Carboxy-Lyases/chemistry , Carboxy-Lyases/genetics , Carboxy-Lyases/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Coordination Complexes/antagonists & inhibitors , Coordination Complexes/chemistry , Coordination Complexes/metabolism , Decarboxylation/drug effects , Environmental Pollutants/antagonists & inhibitors , Environmental Pollutants/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Ethylmercuric Chloride/antagonists & inhibitors , Ethylmercuric Chloride/metabolism , Ethylmercuric Chloride/toxicity , Gene Expression Regulation, Enzymologic/drug effects , Mercuric Chloride/antagonists & inhibitors , Mercuric Chloride/metabolism , Mercuric Chloride/toxicity , Methylmercury Compounds/antagonists & inhibitors , Methylmercury Compounds/metabolism , Molecular Dynamics Simulation , Nerve Tissue Proteins/chemistry , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neurons/enzymology , Neurons/metabolism , Phenylmercury Compounds/antagonists & inhibitors , Phenylmercury Compounds/metabolism , Phenylmercury Compounds/toxicity , Rats
5.
Amino Acids ; 47(5): 1025-34, 2015 May.
Article in English | MEDLINE | ID: mdl-25655388

ABSTRACT

Agmatine (4-aminobutylguanidine), a dicationic molecule at physiological pH, exerts relevant modulatory actions at many different molecular target sites in mammalian cells, having been suggested that the administration of this compound may have therapeutic interest. Several plasma membrane transporters have been implicated in agmatine uptake by mammalian cells. Here we report that in kidney-derived COS-7 cell line, at physiological agmatine levels, the general polyamine transporter participates in the plasma membrane translocation of agmatine, with an apparent Km of 44 ± 7 µM and Vmax of 17.3 ± 3.3 nmol h(-1) mg(-1) protein, but that at elevated concentrations, agmatine can be also taken up by other transport systems. In the first case, the physiological polyamines (putrescine, spermidine and spermine), several diguanidines and bis(2-aminoimidazolines) and the polyamine transport inhibitor AMXT-1501 markedly decreased agmatine uptake. In cells transfected with any of the three ornithine decarboxylase antizymes (AZ1, AZ2 and AZ3), agmatine uptake was dramatically reduced. On the contrary, transfection with antizyme inhibitors (AZIN1 and AZIN2) markedly increased the transport of agmatine. Furthermore, whereas putrescine uptake was significantly decreased in cells transfected with ornithine decarboxylase (ODC), the accumulation of agmatine was stimulated, suggesting a trans-activating effect of intracellular putrescine on agmatine uptake. All these results indicate that ODC and its regulatory proteins (antizymes and antizyme inhibitors) may influence agmatine homeostasis in mammalian tissues.


Subject(s)
Agmatine/metabolism , Carboxy-Lyases/genetics , Carrier Proteins/genetics , Ornithine Decarboxylase Inhibitors/pharmacology , Ornithine Decarboxylase/genetics , Agmatine/antagonists & inhibitors , Animals , Biological Transport/drug effects , COS Cells , Carboxy-Lyases/metabolism , Carrier Proteins/metabolism , Chlorocebus aethiops , Dose-Response Relationship, Drug , Furans/pharmacology , Genetic Vectors/chemistry , Genetic Vectors/metabolism , Guanidine/analogs & derivatives , Guanidine/pharmacology , Humans , Hydrogen-Ion Concentration , Kinetics , Ornithine Decarboxylase/metabolism , Putrescine/pharmacology , Spermidine/pharmacology , Spermine/pharmacology , Transfection
6.
Pharmacol Biochem Behav ; 107: 42-7, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23583442

ABSTRACT

Although bupropion has been widely used in the treatment of depression, the precise mechanism of its therapeutic actions is not fully understood. The present study investigated the role of agmatine in an antidepressant like effect of bupropion in mouse forced swim test. The antidepressant like effect of bupropion was potentiated by pretreatment with agmatine (10-20mg/kg, ip) and by the drugs known to increase endogenous agmatine levels in brain viz., l-arginine (40 µg/mouse, icv), an agmatine biosynthetic precursor, ornithine decarboxylase inhibitor, dl-α-difluoromethyl ornithine hydrochloride, DFMO (12.5 µg/mouse, icv), diamine oxidase inhibitor, aminoguanidine (6.5 µg/mouse, icv) and agmatinase inhibitor, arcaine (50 µg/mouse, icv) as well as imidazoline I1 receptor agonists, moxonidine (0.25mg/kg, ip) and clonidine (0.015 mg/kg, ip) and imidazoline I2 receptor agonist, 2-(2-benzofuranyl)-2-imidazoline hydrochloride, 2-BFI (5mg/kg, ip). Conversely, prior administration of I1 receptor antagonist, efaroxan (1mg/kg, ip) and I2 receptor antagonist, idazoxan (0.25mg/kg, ip) blocked the antidepressant like effect of bupropion and its synergistic combination with agmatine. These results demonstrate involvement of agmatine in the antidepressant like effect of bupropion and suggest agmatine and imidazoline receptors as a potential therapeutic target for the treatment of depressive disorders.


Subject(s)
Agmatine/pharmacology , Antidepressive Agents/pharmacology , Bupropion/pharmacology , Immobility Response, Tonic/drug effects , Immobility Response, Tonic/physiology , Agmatine/administration & dosage , Agmatine/antagonists & inhibitors , Animals , Antidepressive Agents/administration & dosage , Arginine/administration & dosage , Arginine/pharmacology , Benzofurans/pharmacology , Biguanides/administration & dosage , Biguanides/pharmacology , Bupropion/administration & dosage , Bupropion/antagonists & inhibitors , Clonidine/pharmacology , Dose-Response Relationship, Drug , Drug Interactions , Eflornithine/administration & dosage , Eflornithine/pharmacology , Guanidines/administration & dosage , Guanidines/pharmacology , Idazoxan/pharmacology , Imidazoles/pharmacology , Injections, Intraventricular , Male , Mice , Motor Activity/drug effects
7.
Behav Pharmacol ; 24(2): 87-94, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23399882

ABSTRACT

The present study investigated the effect of agmatine on acquisition and expression of ethanol conditioned place preference (CPP) and its modulation by imidazoline agents. Swiss albino mice were treated intraperitoneally with saline or agmatine (20-40 mg/kg) before injection of ethanol (1.25 mg/kg) during conditioning days or on a test day (20-120 mg/kg), to observe the effect on acquisition or expression of CPP, respectively. Agmatine inhibited the acquisition but not the expression of ethanol CPP. Furthermore, both the I1 receptor antagonist, efaroxan (9 mg/kg) and the I2 receptor antagonist, BU224 (5 mg/kg) attenuated the agmatine-induced inhibition of the ethanol CPP acquisition. In contrast, the I2 receptor agonist, 2-BFI (5 mg/kg) and I1 receptor agonist, moxonidine (0.4 mg/kg) alone, or a combination of their subeffective doses, significantly attenuated the effect of agmatine (20 mg/kg) on acquisition of ethanol CPP. Agmatine or imidazoline agents alone produced neither place preference nor aversion, and at the doses used in the present study did not affect locomotor activity. Thus, agmatine attenuates the acquisition of ethanol CPP at least in part by imidazoline (I1 or I2) receptors. In future studies, agmatine or agents acting at the imidazoline receptors could be explored for their therapeutic potential in ethanol dependence.


Subject(s)
Agmatine/therapeutic use , Alcoholism/prevention & control , Imidazoline Receptors/agonists , Molecular Targeted Therapy , Monoamine Oxidase/metabolism , Neurotransmitter Agents/therapeutic use , Agmatine/administration & dosage , Agmatine/adverse effects , Agmatine/antagonists & inhibitors , Alcohol Deterrents/administration & dosage , Alcohol Deterrents/adverse effects , Alcohol Deterrents/antagonists & inhibitors , Alcohol Deterrents/therapeutic use , Alcoholism/drug therapy , Alcoholism/metabolism , Alcoholism/physiopathology , Animals , Anti-Anxiety Agents/administration & dosage , Anti-Anxiety Agents/adverse effects , Anti-Anxiety Agents/antagonists & inhibitors , Anti-Anxiety Agents/therapeutic use , Behavior, Addictive/etiology , Behavior, Addictive/prevention & control , Behavior, Animal/drug effects , Conditioning, Classical/drug effects , Dose-Response Relationship, Drug , Drug Therapy, Combination/adverse effects , Imidazoline Receptors/antagonists & inhibitors , Imidazoline Receptors/metabolism , Injections, Intraperitoneal , Male , Mice , Monoamine Oxidase/chemistry , Monoamine Oxidase Inhibitors/pharmacology , Motor Activity/drug effects , Neurotransmitter Agents/administration & dosage , Neurotransmitter Agents/adverse effects , Neurotransmitter Agents/antagonists & inhibitors
8.
Fundam Clin Pharmacol ; 27(5): 498-509, 2013 Oct.
Article in English | MEDLINE | ID: mdl-22681550

ABSTRACT

Potentiation of opioid analgesia by endothelin-A (ET(A)) receptor antagonist, BMS182874, and imidazoline receptor/α2-adrenoceptor agonists such as clonidine and agmatine are well known. It is also known that agmatine blocks morphine hyperthermia in rats. However, the effect of agmatine on morphine or oxycodone hypothermia in mice is unknown. The present study was carried out to study the role of α2-adrenoceptors, imidazoline, and ET(A) receptors in morphine and oxycodone hypothermia in mice. Body temperature was determined over 6 h in male Swiss Webster mice treated with morphine, oxycodone, agmatine, and combination of agmatine with morphine or oxycodone. Yohimbine, idazoxan, and BMS182874 were used to determine involvement of α2-adrenoceptors, imidazoline, and ET(A) receptors, respectively. Morphine and oxycodone produced significant hypothermia that was not affected by α2-adrenoceptor antagonist yohimbine, imidazoline receptor/α2 adrenoceptor antagonist idazoxan, or ET(A) receptor antagonist, BMS182874. Agmatine did not produce hypothermia; however, it blocked oxycodone but not morphine-induced hypothermia. Agmatine-induced blockade of oxycodone hypothermia was inhibited by idazoxan and yohimbine. The blockade by idazoxan was more pronounced compared with yohimbine. Combined administration of BMS182874 and agmatine did not produce changes in body temperature in mice. However, when BMS182874 was administered along with agmatine and oxycodone, it blocked agmatine-induced reversal of oxycodone hypothermia. This is the first report demonstrating that agmatine does not affect morphine hypothermia in mice, but reverses oxycodone hypothermia. Imidazoline receptors and α2-adrenoceptors are involved in agmatine-induced reversal of oxycodone hypothermia. Our findings also suggest that ET(A) receptors may be involved in blockade of oxycodone hypothermia by agmatine.


Subject(s)
Agmatine/therapeutic use , Hypothermia/prevention & control , Imidazoline Receptors/metabolism , Morphine/adverse effects , Oxycodone/adverse effects , Receptor, Endothelin A/metabolism , Receptors, Adrenergic, alpha-2/metabolism , Adrenergic alpha-2 Receptor Agonists/administration & dosage , Adrenergic alpha-2 Receptor Agonists/therapeutic use , Adrenergic alpha-2 Receptor Antagonists/adverse effects , Agmatine/administration & dosage , Agmatine/antagonists & inhibitors , Animals , Body Temperature Regulation/drug effects , Dansyl Compounds/adverse effects , Dose-Response Relationship, Drug , Endothelin A Receptor Antagonists , Hypothermia/chemically induced , Idazoxan/adverse effects , Imidazoline Receptors/agonists , Imidazoline Receptors/antagonists & inhibitors , Male , Mice , Oxycodone/antagonists & inhibitors , Receptors, Adrenergic, alpha-2/chemistry , Yohimbine/adverse effects
9.
Pharmacol Biochem Behav ; 103(3): 550-60, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23103903

ABSTRACT

The potentiation of oxycodone antinociception by BMS182874 (endothelin-A (ET(A)) receptor antagonist) and agmatine (imidazoline receptor/α(2)-adrenoceptor agonist) is well-documented. It is also known that imidazoline receptors but not α(2)-adrenoceptors are involved in potentiation of oxycodone antinociception by agmatine and BMS182874 in mice. However, the involvement of specific imidazoline receptor subtypes (I(1), I(2), or both) in this interaction is not clearly understood. The present study was conducted to determine the involvement of imidazoline I(1) and I(2) receptors in agmatine- and BMS182874-induced potentiation of oxycodone antinociception in mice. Antinociceptive (tail flick and hot-plate) latencies were determined in male Swiss Webster mice treated with oxycodone, agmatine, BMS182874, and combined administration of oxycodone with agmatine or BMS182874. Efaroxan (imidazoline I(1) receptor antagonist) and BU224 (imidazoline I(2) receptor antagonist) were used to determine the involvement of I(1) and I(2) imidazoline receptors, respectively. Oxycodone produced significant antinociceptive response in mice which was not affected by efaroxan but was blocked by BU224. Agmatine-induced potentiation of oxycodone antinociception was blocked by BU224 but not by efaroxan. Similarly, BMS182874-induced potentiation of oxycodone antinociception was blocked by BU224 but not by efaroxan. This is the first report demonstrating that BMS182874- or agmatine-induced enhancement of oxycodone antinociception is blocked by BU224 but not by efaroxan. We conclude that imidazoline I(2) receptors but not imidazoline I(1) receptors are involved in BMS182874- and agmatine-induced potentiation of oxycodone antinociception in mice.


Subject(s)
Agmatine/pharmacology , Analgesics, Opioid/pharmacology , Dansyl Compounds/pharmacology , Imidazoline Receptors/metabolism , Oxycodone/pharmacology , Agmatine/antagonists & inhibitors , Analgesics, Opioid/antagonists & inhibitors , Animals , Benzofurans/pharmacology , Drug Synergism , Imidazoles/pharmacology , Imidazoline Receptors/agonists , Imidazoline Receptors/antagonists & inhibitors , Male , Mice , Oxycodone/antagonists & inhibitors , Pain Measurement
10.
Arzneimittelforschung ; 61(4): 229-33, 2011.
Article in English | MEDLINE | ID: mdl-21650081

ABSTRACT

Agmatine (CAS 2482-00-0), an amine formed by decarboxylation of L-arginine, interacts with several targets like alpha2-adrenergic, imidazoline and N-methyl-D-aspartic acid (NMDA) receptors and besides it is involved in the nitric oxide mediated effects. It has also been proposed that it possesses vasodilator effects and increases glomerular filtration rate in rats. The aim of this study was to supply evidence for the effects of agmatine in a rat model of hemorrhagic shock and explain the possible mechanisms of action. The iliac arteries and veins of Sprague-Dawley rats were catheterized under urethane anesthesia and around 2 ml/100 g blood was withdrawn within 20 min until the mean arterial blood pressure was stabilized around 25 mmHg. The rats were either pretreated with physiological saline, yohimbine (an alpha2-adrenergic receptor antagonist) or L-arginine (a nitric oxide donor) intravenously before administration of agmatine (300 microg/kg). Agmatine restored blood pressure in rats pretreated with physiological saline where all rats survived. Pretreatment with L-arginine abolished the increase in blood pressure produced by agmatine and the 1 h survival rate decreased to 67% (p < 0.01). Yohimbine pretreatment also suppressed agmatine induced restoration of blood pressure; however, the survival rate was found to be 17% for 3 min. No statistically significant effect was observed in the heart rate responses. These results may suggest that agmatine may increase survival through alpha2-adrenergic receptors and restores blood pressure through nitric oxide and adrenergic mechanisms in rats bled to hemorrhage.


Subject(s)
Agmatine/therapeutic use , Hemorrhage/drug therapy , Adrenergic alpha-Agonists/therapeutic use , Agmatine/antagonists & inhibitors , Animals , Blood Pressure/drug effects , Dose-Response Relationship, Drug , Heart Rate/drug effects , Hemorrhage/mortality , Hemorrhage/physiopathology , Nitric Oxide/physiology , Nitric Oxide Donors/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Adrenergic, alpha-2/drug effects , Shock, Hemorrhagic/drug therapy , Shock, Hemorrhagic/physiopathology , Survival , Yohimbine/therapeutic use
11.
Pharmacol Biochem Behav ; 96(2): 125-9, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20451544

ABSTRACT

Agmatine is an endogenous amine derived from l-arginine that potentiates morphine analgesia and inhibits naloxone precipitated abstinent symptoms in morphine dependent rats. In this study, the effects of agmatine on long-term potentiation (LTP) in the lateral perforant path (LPP)-granule cell synapse of the rat dentate gyrus (DG) on saline or morphine-treated rats were investigated. Population spikes (PS), evoked by stimulation of the LPP, was recorded from DG region. Acute agmatine (2.5-10mg/kg, s.c.) treatment facilitated hippocampal LTP. Acute morphine (30mg/kg, s.c.) treatment significantly attenuated hippocampal LTP and agmatine (10mg/kg, s.c.) restored the amplitude of PS that was attenuated by morphine. Chronic morphine treatment resulted in the enhancement of hippocampal LTP, agmatine co-administered with morphine significantly attenuated the enhancement of morphine on hippocampal LTP. Imidazoline receptor antagonist idazoxan (5mg/kg, i.p.) reversed the effect of agmatine. These results suggest that agmatine attenuated the effect of morphine on hippocampal LTP, possibly through activation of imidazoline receptor.


Subject(s)
Agmatine/pharmacology , Hippocampus/drug effects , Long-Term Potentiation/drug effects , Morphine/pharmacology , Agmatine/antagonists & inhibitors , Animals , Dentate Gyrus/drug effects , Dentate Gyrus/physiology , Drug Interactions , Hippocampus/physiology , Idazoxan/pharmacology , Imidazoline Receptors/agonists , Imidazoline Receptors/antagonists & inhibitors , Male , Morphine/administration & dosage , Rats , Rats, Wistar
12.
J Pharmacol Exp Ther ; 331(2): 539-46, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19684255

ABSTRACT

Systemically or centrally administered agmatine (decarboxylated arginine) prevents, moderates, or reverses opioid-induced tolerance and self-administration, inflammatory and neuropathic pain, and sequelae associated with ischemia and spinal cord injury in rodents. These behavioral models invoke the N-methyl-D-aspartate (NMDA) receptor/nitric-oxide synthase cascade. Agmatine (AG) antagonizes the NMDA receptor and inhibits nitric-oxide synthase in vitro and in vivo, which may explain its effect in models of neural plasticity. Agmatine has been detected biochemically and immunohistochemically in the central nervous system. Consequently, it is conceivable that agmatine operates in an anti-glutamatergic manner in vivo; the role of endogenous agmatine in the central nervous system remains minimally defined. The current study used an immunoneutralization strategy to evaluate the effect of sequestration of endogenous agmatine in acute opioid analgesic tolerance in mice. First, intrathecal pretreatment with an anti-AG IgG (but not normal IgG) reversed an established pharmacological effect of intrathecal agmatine: antagonism of NMDA-evoked behavior. This result justified the use of anti-AG IgG to sequester endogenous agmatine in vivo. Second, intrathecal pretreatment with the anti-AG IgG sensitized mice to induction of acute spinal tolerance of two micro-opioid receptor-selective agonists, [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin and endomorphin-2. A lower dose of either agonist that, under normal conditions, produces moderate or no tolerance was tolerance-inducing after intrathecal pretreatment of anti-AG IgG (but not normal IgG). The effect of the anti-AG IgG lasted for at least 24 h in both NMDA-evoked behavior and the acute opioid tolerance. These results suggest that endogenous spinal agmatine may moderate glutamate-dependent neuroplasticity.


Subject(s)
Agmatine/antagonists & inhibitors , Agmatine/pharmacology , Antibodies, Blocking/pharmacology , Receptors, Opioid, mu/drug effects , Agmatine/immunology , Analgesics, Opioid/pharmacology , Animals , Arginine/pharmacology , Behavior, Animal/drug effects , Dose-Response Relationship, Drug , Drug Tolerance , Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology , Excitatory Amino Acid Agonists , Guinea Pigs , Immunoglobulin G/biosynthesis , Immunoglobulin G/pharmacology , Immunohistochemistry , Injections, Spinal , Male , Mice , N-Methylaspartate , Oligopeptides/pharmacology , Pain Measurement/drug effects , Rats , Rats, Sprague-Dawley , Spinal Cord/drug effects
13.
Neuropharmacology ; 57(4): 415-24, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19589348

ABSTRACT

Recent findings demonstrated the dysregulation of imidazoline receptor binding sites in major depression and their normalization by chronic treatment with antidepressants including selective serotonin reuptake inhibitors (SSRIs). Present study investigated the role of agmatine and imidazoline receptors in antidepressant like effect of SSRIs and imipramine in mouse forced swimming test (FST) paradigm. The antidepressant like effect of fluoxetine or paroxetine was potentiated by imidazoline I(1)/I(2) receptor agonist agmatine (5-10 mg/kg, ip), imidazoline I(1) receptor agonists, moxonidine (0.25-0.5 mg/kg, ip) and clonidine (0.015-0.03 mg/kg, ip), imidazoline I(2) receptor agonist, 2-(2-benzofuranyl)-2-imidazoline (5-10 mg/kg, ip) as well as by the drugs known to increase endogenous agmatine levels in brain viz., L-arginine, an agmatine biosynthetic precursor (40 microg/mouse, icv), ornithine decarboxylase inhibitor, difluoromethyl ornithine (12.5 microg/mouse, icv), diamine oxidase inhibitor, aminoguanidine (6.5 microg/mouse, icv) and agmatinase inhibitor, arcaine (50 microg/mouse, icv). Conversely, prior administration of I(1) receptor antagonist, efaroxan (1 mg/kg, ip), I(2) receptor antagonist, idazoxan (0.25 mg/kg, ip) and arginine decarboxylase inhibitor, d-arginine (100 mg/kg, ip) blocked the antidepressant like effect of paroxetine (10 mg/kg, ip) and fluoxetine (20 mg/kg, ip). On the other hand, antidepressant like effect of imipramine was neither augmented nor attenuated by any of the above drugs. Mice pretreated with SSRIs but not imipramine and exposed to FST showed higher concentration of agmatine in brain as compared to saline control. This effect of SSRIs on agmatine levels was completely blocked by arginine decarboxylase inhibitor d-arginine but not by imidazoline receptor antagonists, efaroxan or idazoxan. These results demonstrate that modulation of imidazoline receptors by agmatine are implicated in the antidepressant like effect of SSRIs and may be projected as a potential therapeutic target for the treatment of depressive disorders.


Subject(s)
Agmatine/metabolism , Antidepressive Agents/pharmacology , Brain/drug effects , Depression/drug therapy , Imidazoline Receptors/metabolism , Selective Serotonin Reuptake Inhibitors/pharmacology , Agmatine/antagonists & inhibitors , Agmatine/pharmacology , Animals , Antidepressive Agents/administration & dosage , Arginine/metabolism , Carboxy-Lyases/antagonists & inhibitors , Dose-Response Relationship, Drug , Drug Synergism , Imidazoline Receptors/agonists , Imidazoline Receptors/antagonists & inhibitors , Male , Mice , Motor Activity/drug effects , Selective Serotonin Reuptake Inhibitors/administration & dosage , Stress, Psychological/drug therapy
14.
Life Sci ; 79(9): 854-60, 2006 Jul 24.
Article in English | MEDLINE | ID: mdl-16564552

ABSTRACT

The effect of the putative endogenous ligand for alpha(2)-adrenoceptors and imidazoline receptors agmatine was studied in sympathetic neurotransmission in the rat epididymal vas deferens. Tissues were obtained from N(varpi)-nitro-l-arginine methyl ester (l-NAME)-treated or normal animals and were contracted by electrical stimulation or by exogenous adenosine 5'-triphosphate (ATP). In the electrically stimulated epididymal end, agmatine produced an inhibitory effect on twitch contraction that was partially reversed in l-NAME-treated animals, whereas the inhibition produced by clonidine was not affected by l-NAME treatment. The nitric oxide (NO)-donor S-nitroso-N-acetyl-penicillamine (SNAP) also inhibited twitch contraction. Neither agmatine nor SNAP interfered with the responses induced by exogenous ATP in the epididymal end. Removal of the epithelium of the preparation did not modify the agmatine response. We conclude that a nitrergic pathway activated by agmatine plays a role in its inhibitory effect in rat vas deferens, but it remains to be investigated whether it results from a direct action on the enzyme NO-synthase or a receptor-mediated mechanism.


Subject(s)
Agmatine/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Muscle, Smooth, Vascular/drug effects , NG-Nitroarginine Methyl Ester/pharmacology , Adenosine Triphosphate/pharmacology , Adrenergic alpha-Agonists/pharmacology , Agmatine/pharmacology , Animals , Blood Pressure/drug effects , Clonidine/pharmacology , Dose-Response Relationship, Drug , Electric Stimulation , Epididymis/physiology , In Vitro Techniques , Male , Muscle Contraction/drug effects , Nitric Oxide/physiology , Nitric Oxide Donors/pharmacology , Rats , Rats, Wistar , S-Nitroso-N-Acetylpenicillamine/pharmacology , Synaptic Transmission/drug effects , Vas Deferens/drug effects
15.
Acta Pharmacol Sin ; 26(5): 616-22, 2005 May.
Article in English | MEDLINE | ID: mdl-15842783

ABSTRACT

AIM: To assess the inhibitory effect of agmatine on tumor growth in vivo and tumor cell proliferation in vitro. METHODS: The transplanted animal model, [3H]thymidine incorporation assay,3-[4,5-dimethythiazol-2-yl]-2,5-diphenyltetrazolium assay, and lactate dehydrogenase (LDH) release assay were performed. RESULTS: Agmatine, at doses of 5-40 mg/kg, suppressed the S180 sarcoma tumor growth dose-dependently in mice in vivo and the highest inhibitory ratio reached 31.3% in Kunming mice and 50.0% in Balb/c mice, respectively. Similar results were obtained in the transplanted B16 melanoma tumor model. Agmatine (1-1000 micromol/L) was able to attenuate the proliferation of cultured MCF-7 human breast cancer cells in vitro in a concentration-dependent manner and the highest inhibitory ratio reached 50.3% in the [3H]thymidine incorporation assay. Additionally, in the LDH release assay, spermine (20 micromol/L) and spermidine (20 micromol/L) increased the LDH release significantly, but agmatine (1-1000 micromol/L) did not, indicating that the inhibitory effect of agmatine on the proliferation of MCF was not related to cellular toxicity. In the [3H]thymidine incorporation assay, putrescine (12.5-100.0 micromol/L) could reverse the inhibitory effect of agmatine on the proliferation of MCF concentration-dependently, suggesting that the inhibitory effect of agmatine on the proliferation of MCF might be associated with a decreased level of the intracellular polyamines pool. CONCLUSION: Agmatine had significant inhibitory effect on transplanted tumor growth in vivo and proliferation of tumor cells in vitro, and the mechanism might be a result of inducing decrease of intracellular polyamine contents.


Subject(s)
Agmatine/pharmacology , Breast Neoplasms/pathology , Cell Proliferation/drug effects , Polyamines/metabolism , Sarcoma 180/pathology , Agmatine/antagonists & inhibitors , Animals , Cell Line, Tumor , Humans , L-Lactate Dehydrogenase/metabolism , Male , Melanoma, Experimental/pathology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Neoplasm Transplantation , Putrescine/pharmacology
16.
Biochim Biophys Acta ; 1619(2): 159-66, 2003 Jan 20.
Article in English | MEDLINE | ID: mdl-12527112

ABSTRACT

Agmatine has recently gained wide interest as a bioactive arginine metabolite with a multitude of physiological functions. This study evaluates the in vivo role of agmatine in the modulation of metabolism and intracellular level of polyamines. Here, we report that agmatine, administered to mice, differentially affects the renal and liver activity of the two key enzymes regulating polyamine biosynthesis and interconversion/degradation. Thus, agmatine exerts a negative regulation of ODC activity and protein content, and positive regulation of SSAT activity, having no effect on ODC and SSAT transcript level. Agmatine modulation of ODC and SSAT activities is noticeably augmented by the inhibitor of its catabolism, aminoguanidine. Antizyme and eIF4E protein content appears to be affected by agmatine only insignificantly and apparently do not contribute to agmatine-induced down-regulation of ODC content. The homeostasis of spermidine and spermine is preserved after agmatine injection, while the putrescine level decreases. Furthermore, when tested in a mouse kidney injury model, agmatine, partially but significantly, reduces [3H] thymidine incorporation into DNA. This is consistent with suppressed renal tubule epithelial cell proliferation. The findings provide in vivo evidence of a substantial role of agmatine as a modulator of polyamine biosynthesis and degradation and suggest its suppressive effect on cell proliferation.


Subject(s)
Agmatine/pharmacology , Cell Division/drug effects , Polyamines/metabolism , Proteins , Acetyltransferases/biosynthesis , Agmatine/antagonists & inhibitors , Animals , DNA Replication/drug effects , Disease Models, Animal , Epithelial Cells/drug effects , Eukaryotic Initiation Factor-4E/biosynthesis , Folic Acid Antagonists , Kidney Diseases/chemically induced , Kidney Diseases/metabolism , Mice , Ornithine Decarboxylase/biosynthesis , Polyamines/analysis , Protein Biosynthesis
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