Radioligand binding studies reveal agmatine is a more selective antagonist for a polyamine-site on the NMDA receptor than arcaine or ifenprodil

Gibson, D. Alex; Harris, Barton R.; Rogers, Dennis T.; Littleton, John M.

doi:10.1016/s0006-8993(02)03198-0

Cited by 46 publications

(22 citation statements)

References 23 publications

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“…Finally, the antidepressant-like effects of putrescine were attenuated by arcaine, an antagonist of the NMDA receptor polyamine-binding site. Similar results were observed when putrescine was co-administered with agmatine, a more selective antagonist of the NMDA polyaminebinding site [24]. Together, these findings suggest that putrescine's antidepressant-like effects may be achieved through the inhibition of NMDA receptors.…”

Section: -Role Of Polyamines In Cnssupporting

confidence: 72%

“…Systemic injection of agmatine has been shown to substantially increase cortical agmatine concentration in rats [22], even though other studies suggest that 99% of the injected agmatine is rapidly metabolized by peripheral tissues [23]. This is interesting as agmatine is believed to function as a CNS neurotransmitter by binding to NMDA receptors [24], as well as acetylcholine, imidazoline, and serotonin receptors [15]. Furthermore, agmatine has been shown to have antidepressant, anxiolytic, anticonvulsant, anti-inflammatory, and neuro-protective properties [25,26,27].…”

Section: -Role Of Polyamines In Cnsmentioning

confidence: 99%

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Suicide and the Polyamine System

Gross¹,

Turecki

2013

CNSNDDT

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Suicide is a significant worldwide public health problem. Understanding the neurobiology is important as it can help us to better elucidate underlying etiological factors and provide opportunities for intervention. In recent years, many lines of research have suggested that the polyamine system may be dysregulated in suicidal behaviors. Initial research in animals provided evidence of a dysfunctional polyamine stress response system, while later work using post-mortem human brain tissue has suggested that molecular mechanisms may be at play in the suicide brain. In this review, we will describe the research that suggests the presence of alterations in the polyamine system in mental disorders and behavioral phenotypes, with particular attention to work on suicide. In addition, we will also describe potential avenues for future work. KeywordsEpigenetics; Major Depressive Disorder; Neurobiology; Polyamines; Polyamine Stress Response; Spermidine/Spermine-N 1 -Acetyltransferase; Suicide -IntroductionSuicide, most often associated with major depressive disorder (MDD) [1], is an important cause of premature death around the world [2]. According to the World Health Organization (www.who.int, 2012), approximately one million people die by suicide annually, and the rate of suicide attempts is 20 times greater than that of suicide completion (www.who.int, 2012). As such, suicidal behaviors (SB) are an important source of public health concern. The etiology of suicide is complex [3], and commonly understood as resulting from the interaction of predisposing (distal) and precipitant (proximal) factors [4]. Biological alterations resulting from a combination of genetic and environmental risk factors underlie predisposition to suicide, but the exact molecular mechanisms at play remain largely unclear. As such, it is important that we gain a better understanding of the molecular processes associated with suicide in order to identify new avenues for prevention and intervention.Over the past several decades, molecular studies of suicide and MDD have focused on the monoamine system. Beginning in the late 1960s, research into the neurobiology of suicide

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Section: -Role Of Polyamines In Cnssupporting

confidence: 72%

Section: -Role Of Polyamines In Cnsmentioning

confidence: 99%

Suicide and the Polyamine System

Gross¹,

Turecki

2013

CNSNDDT

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“…Agmatine, a polyamine precursor, is known to inhibit the NMDAR via binding at the polyamine site (Gibson et al, 2002). Exogenous administration of agmatine attenuates glutamate-induced neurotoxicity in cell cultures of rat cerebellum (Olmos et al, 1999), hippocampus (Wang et al, 2006), and cortex .…”

Section: Introductionmentioning

confidence: 99%

Agmatine reduces balance deficits in a rat model of third trimester binge-like ethanol exposure

Lewis

Wellmann

Barron

2007

Pharmacology Biochemistry and Behavior

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This study examined the effects of binge-like ethanol (ETOH) exposure in neonatal rats on a cerebellar-mediated balance task, and the ability of agmatine, an n-methyl-d-aspartate receptor (NMDAR) modulator, to reverse such effects. Five neonatal treatments groups were used, including ETOH (6.0 g/kg/day), AG (20 mg/kg), ETOH plus AG (6.0 g/kg/day and 20 mg/kg), a maltose control, and a non-treated control. Ethanol was administered via oral intubation twice daily for eight days, (AG was administered with the last ETOH intubation only). Two exposure periods were used; PND 1-8 or PND 8-15. On PND 31-33, balance performance on a single dowel was tested. Treatment with AG during withdrawal in ETOH exposed animals improved performance relative to ETOH alone among the PND 1-8 exposure period. ETOH exposure during the 2 nd postnatal week did not impair balance. These findings provide further support that exposure to ETOH during critical developmental periods can impair performance on a cerebellar-dependent balance task. Of perhaps greater significance, co-administration of agmatine reduced these deficits suggesting that NMDA modulation via polyamine blockade may provide a novel approach to attenuating damage associated with binge-like ETOH consumption.

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“…However, its low affinity along with its weak activity at I-BS, in comparison to selective I-BS compounds, raises doubt on its fidelity for these sites. Agmatine has been reported to interact with other target sites including N-methyl-D-aspartate (NMDA) receptor [77], 5-HT 3 receptor channel [78], nicotinic receptor [79], which in turn may explain its eclectic biological effects.…”

Section: Imidazoleacetic Acid Ribotide Agmatinementioning

confidence: 99%

Borne Identity: Leading Endogenous Suspects at Imidazoline Binding Sites

Ghazaleh¹,

Tyacke²,

Hudson³

2015

J Neurol Neurosci

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The imidazoline binding sites (I-BS) represent a heterogenous family of receptors/sites that stemmed from studies investigating the hypotensive effect of the imidazoline compound clonidine [1]. Structure-affinity relationship studies complemented by functional analyses characterised three types of I-BS, denoted I 1 -BS, I 2 -BS (I 2A and I 2B ) and I 3 -BS [2]. Extensive research has established the involvement of central I 1 -BS in cardiovascular function [3]. Other reported functions include alleviating symptoms associated with metabolic syndrome X [4] and Huntington's Disease [5], promoting natriuresis [6], regulating intraocular pressure [7], and modulating mRNA expression for phenylethanolamine N-methyl transferase (PNMT) [8]. Furthermore, the expression of these sites was shown to be altered in conditions such as depression [9] and dysphoric premenstrual syndrome [10] AbstractOver the past few years, a vast amount of research has shed light on the pharmacology of imidazoline binding sites (I-BS). To date, at least three classes of imidazoline binding sites have been characterised in accordance to their localisation, drug selectivity, proposed signalling pathways and functional roles. The existence of these sites raises the question as to whether an endogenous modulator exists. The identification of an endogenous extract denoted as clonidine displacing substance prompted the search for the active ingredient capable of mimicking the action of selective ligands at these sites. A number of candidates have been isolated and their functional activities have been assessed at these sites. Such endogenous ligands include agmatine, imidazoleacetic acid ribotide and the β-carboline harmane. As of yet, no consensus has been made to confirm the identity of the endogenous ligand at I-BS. The current review collates and reports what is known about these substances and their functional significance at I-BS.

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Radioligand binding studies reveal agmatine is a more selective antagonist for a polyamine-site on the NMDA receptor than arcaine or ifenprodil

Cited by 46 publications

References 23 publications

Suicide and the Polyamine System

Suicide and the Polyamine System

Agmatine reduces balance deficits in a rat model of third trimester binge-like ethanol exposure

Borne Identity: Leading Endogenous Suspects at Imidazoline Binding Sites

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