Agmatine: an Endogenous Clonidine-Displacing Substance in the Brain

Li, Gen; Regunathan, S.; Barrow, Colin J.; Eshraghi, Jamshid; Cooper, Raymond; Reis, Donald J.

doi:10.1126/science.7906055

Cited by 682 publications

(434 citation statements)

References 31 publications

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“…In light of mentioned findings we have studied the possible involvement of a 2 -adrenoceptors, known to mediate some physiologic effects of agmatine (Li et al, 1994;Roerig, 2003;Zomkowski et al, 2002;Ruiz-Durantez et al, 2003). UK 14 304, which is a highly selective a 2 -adrenoceptor agonist (Cambridge, 1981) with low affinity for I 1 receptors (I 1 /a 2 affinity ratio ¼ 0.01; Bricca et al, 1993;Ernsberger et al, 1992), was used to support our hypothesis that agmatine enhances the effects of morphine on producing CPP via a mechanism involving a 2 -adrenoceptors.…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that agmatine acts as an endogenous agonist at imidazoline receptors and as a noncatecholamine ligand at a 2 -adrenergic receptors (Li et al, 1994;Piletz et al, 1995). Agmatine and a 2 -adrenoceptors have important functional interactions, including the potentiating effect on morphineinduced analgesia (Fairbanks et al, 2000;Yesilyurt and Uzbay, 2001), agonistic activity in prejunctional rat tail artery (Gonzalez et al, 1996), and multiple effects on sympathetic neurotransmission in rat vas deferens (Jurkiewicz et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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Agmatine Potentiates Morphine-Induced Conditioned Place Preference in Mice: Modulation by Alpha(2)-Adrenoceptors

Tahsili-Fahadan

Yahyavi-Firouz-Abadi

Khoshnoodi

et al. 2005

Neuropsychopharmacol

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The effects of agmatine, an endogenous polyamine metabolite formed by decarboxylation of L-arginine, and its combination with morphine on conditioned place preference (CPP) has been investigated in male mice. Our data show that subcutaneous administration of morphine (1-7.5 mg/kg) significantly increases the time spent in the drug-paired compartment in a dose-dependent manner. Intraperitoneal administration of agmatine (1-40 mg/kg) alone does not induce either CPP or conditioned place aversion, while combination of agmatine and subeffective doses of morphine leads to potent rewarding effects. Lower doses of morphine (0.1, 0.05, and 0.01 mg/kg) are able to induce CPP in mice pretreated with agmatine 1, 5, and 10 mg/kg, respectively. Concomitant intraperitoneal administration of UK 14 304 (0.5 mg/kg), a highly selective a 2 -agonist, with per se noneffective dose of morphine (0.5 mg/kg) and also its combination with noneffective doses of agmatine (1 mg/kg) plus morphine (0.05 mg/kg) produces significant CPP. UK 14 304 (0.05, 0.5 mg/kg) alone, or in combination with agmatine (1, 5 mg/kg) have had no effect. We have further investigated the possible involvement of the a 2 -adrenoceptors in the potentiating effect of agmatine on morphine-induced place preference. Selective a 2 -antagonists, yohimbine (0.005 mg/kg) and RX821002 (0.1, 0.5 mg/kg), block the CPP induced by concomitant administration of agmatine (5 mg/kg) and morphine (0.05 mg/kg). Yohimbine (0.001-0.05 mg/kg) or RX821002 (0.05-0.5 mg/kg) alone or in combination with morphine (0.05 mg/kg) or agmatine (5 mg/kg) fail to show any significant place preference or aversion. Our results indicate that pretreatment of animals with agmatine enhances the rewarding properties of morphine via a mechanism which may involve a 2 -adrenergic receptors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Agmatine Potentiates Morphine-Induced Conditioned Place Preference in Mice: Modulation by Alpha(2)-Adrenoceptors

Tahsili-Fahadan

Yahyavi-Firouz-Abadi

Khoshnoodi

et al. 2005

Neuropsychopharmacol

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“…In the past decade, accumulating evidence indicated agmatine's several levels of pharmacological and physiological importance. Agmatine is present in the brain and other tissues of mammals (Lortie et al, 1996;Li et al, 1994). In neuronal tissues, agmatine is present in axon terminals associated with synaptic vesicles (Reis et al, 1998) and can be taken up into synaptosomes via a Na + -independent system (Sastre et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

“…In neuronal tissues, agmatine is present in axon terminals associated with synaptic vesicles (Reis et al, 1998) and can be taken up into synaptosomes via a Na + -independent system (Sastre et al, 1997). Agmatine has been reported to act as a ligand of the imidazoline receptor (Li et al, 1994). It inhibits all isoforms of nitric oxide synthase (NOS; Galea et al, 1996) and blocks nicotinic receptor (Loring, 1990), voltage-gated Ca 2+ channels and Nmethyl-D-aspartate (NMDA) receptor channels (Yang and Reis, 1999).…”

Section: Introductionmentioning

confidence: 99%

Agmatine protects against cell damage induced by NMDA and glutamate in cultured hippocampal neurons

et al. 2006

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Agmatine is a polyamine and has been considered as a novel neurotransmitter or neuromodulator in the central nervous system. In the present study, the neuroprotective effect of agmatine against cell damage caused by N-methyl-D-aspartate (NMDA) and glutamate was investigated in cultured rat hippocampal neurons. Lactate dehydrogenase (LDH) activity assay, β-tubulin III immunocytochemical staining and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end-labeling (TUNEL) assay were conducted to detect cell damage. Exposure of 12-day neuronal cultures of rat hippocampus to NMDA or glutamate for 1 h caused a concentration-dependent neurotoxicity, as indicated by the significant increase in released LDH activities. Addition of 100 µM agmatine into media ablated the neurotoxicity induced by NMDA or glutamate, an effect also produced by the specific NMDA receptor antagonist dizocilpine hydrogen maleate (MK801). Arcaine, an analog of agmatine with similar structure as agmatine, fully prevented the NMDA-or glutamate-induced neuronal damage. Spermine and putrescine, the endogenous polyamine and metabolic products of agmatine without the guanidine moiety of agmatine, failed to show this effect, indicating a structural relevance for this neuroprotection. Immunocytochemical staining and TUNEL assay confirmed the findings in the LDH measurement. That is, agmatine and MK801 markedly attenuated NMDA-induced neuronal death and significantly reduced TUNEL-positive cell numbers induced by exposure of cultured hippocampal neurons to NMDA. Taken together, these results demonstrate that agmatine can protect cultured hippocampal neurons from NMDA-or glutamate-induced excitotoxicity, through a possible blockade of the NMDA receptor channels or a potential anti-apoptotic property.

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“…These modulators include SCH-202676 [21][22][23], amiloride analogues [24][25][26], agmatine [27]. The results suggested that for the P2Y 1 receptor, modes of interaction of orthosteric and allosteric binding sites might be different from that of other GPCRs.…”

Section: Discussionmentioning

confidence: 99%

2,2′-Pyridylisatogen tosylate antagonizes P2Y1 receptor signaling without affecting nucleotide binding

Gao¹,

Mamedova²,

Tchilibon³

et al. 2004

Biochemical Pharmacology

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The effect of 2,2′-pyridylisatogen tosylate (PIT) on the human P2Y 1 receptor and on other recombinant P2Y receptors has been studied. We first examined the modulation by PIT of the agonist-induced accumulation of inositol phosphates. PIT blocked 2-methylthio-ADP (2-MeSADP)-induced accumulation of inositol phosphates in 1321N1 astrocytoma cells stably expressing human P2Y 1 receptors in a non-competitive and concentration-dependent manner. The IC 50 for reduction of the maximal agonist effect was 0.14 μM. In contrast, MRS2179, a competitive P2Y 1 receptor antagonist, parallel-shifted the agonist concentration-response curve to the right. PIT also concentration-dependently blocked the P2Y 1 receptor signaling induced by the endogenous agonists, ADP and ATP. A simple structural analogue of PIT was synthesized and found to be inactive as a P2Y 1 receptor antagonist, suggesting that the nitroxyl group of PIT is a necessary structural component for P2Y 1 receptor antagonism. We next examined the possible modulation of the binding of the newly available antagonist radioligand for the P2Y 1 receptor, [ 3 H] MRS2279. It was found that PIT (0.01-10 μM) did not inhibit [ 3 H] MRS2279 binding to the human P2Y 1 receptor. PIT (10 μM) had no effect on the competition for [ 3 H] MRS2279 binding by agonists, ADP and ATP, suggesting that its antagonism of the P2Y 1 receptor may be allosteric. PIT had no significant effect on agonist activation of other P2Y receptors, including P2Y 2 , P2Y 4 , P2Y 6 , P2Y 11 and P2Y 12 receptors. Thus, PIT selectively and non-competitively blocked P2Y 1 receptor signaling without affecting nucleotide binding.

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Agmatine: an Endogenous Clonidine-Displacing Substance in the Brain

Cited by 682 publications

References 31 publications

Agmatine Potentiates Morphine-Induced Conditioned Place Preference in Mice: Modulation by Alpha(2)-Adrenoceptors

Agmatine Potentiates Morphine-Induced Conditioned Place Preference in Mice: Modulation by Alpha(2)-Adrenoceptors

Agmatine protects against cell damage induced by NMDA and glutamate in cultured hippocampal neurons

2,2′-Pyridylisatogen tosylate antagonizes P2Y1 receptor signaling without affecting nucleotide binding

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