Agmatine transport into spinal nerve terminals is modulated by polyamine analogs

Goracke-Postle, Cory J.; Overland, Aaron C.; Stone, Laura S.; Fairbanks, Carolyn A.

doi:10.1111/j.1471-4159.2006.04193.x

Cited by 18 publications

(13 citation statements)

References 53 publications

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“…Evidence suggests that agmatine plays a role as a neurotransmitter (Reis and Regunathan 2000). Consistently, agmatine was released from purified spinal nerve terminals upon depolarisation (Goracke-Postle et al 2007). Thus, Agm may serve to locally inactivate neuromodulatory effects of synaptically released agmatine.…”

Section: Introductionmentioning

confidence: 93%

Synaptic localisation of agmatinase in rat cerebral cortex revealed by virtual pre-embedding

et al. 2011

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Light microscopic evidence suggested a synaptic role for agmatinase, an enzyme capable of inactivating the putative neurotransmitter and endogenous anti-depressant agmatine. Using electron microscopy and an alternative pre-embedding approach referred to as virtual pre-embedding, agmatinase was localised pre- and postsynaptically, to dendritic spines, spine and non-spine terminals, and dendritic profiles. In dendritic spines, labelling displayed a tendency towards the postsynaptic density. These results further strengthen a synaptic role for agmatine and strongly suggest a regulatory role for synaptically expressed agmatinase.

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Section: Introductionmentioning

confidence: 93%

Synaptic localisation of agmatinase in rat cerebral cortex revealed by virtual pre-embedding

et al. 2011

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“…As a putative inhibitor of glutamate neurotransmission, agmatine is distinct in that it may exert dual activity upon the NMDA receptor and/or its downstream signal transduction mediator, nitric-oxide synthase. Furthermore, agmatine is reported to have an uptake mechanism into purified nerve terminals (Sastre et al, 1997;GorackePostle et al, 2006GorackePostle et al, , 2007a and is also released from these structures by either K ϩ or evoked depolarization Goracke-Postle et al, 2006, 2007b or capsaicin exposure (Goracke-Postle et al 2007b). Consequently, the agmatinergic modulation of glutamatergic neuromodulation may be of neuronal origin.…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested ) that agmatine meets several criteria characteristic of an endogenous neuromodulator, including synthesis of agmatine in the brain , localization to neurons and synaptic vesicles (Otake et al, 1998;Goracke-Postle et al, 2006), transport into nerve terminals (Sastre et al, 1997;Goracke-Postle et al, 2006, 2007a, release by depolarization Goracke-Postle et al, 2006, 2007b, transport into astrocytes (Regunathan et al, 1995), and enzymatic degradation by CNS agmatinase (Sastre et al, 1996). An important criterion yet to be tested includes a demonstration that endogenous agmatine performs the same physiological function as does exogenously administered agmatine.…”

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confidence: 99%

Immunoneutralization of Agmatine Sensitizes Mice to μ-Opioid Receptor Tolerance

Wade

Eskridge

Nguyen

et al. 2009

J Pharmacol Exp Ther

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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 -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.

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“…Radiolabeled agmatine was first shown to be uptaken and packaged into synaptic vesicles and released upon membrane depolarization (Goracke-Postle et al, 2006, Goracke-Postle et al, 2007). Immunolabeled agmatine was co-localized with vasopressin and oxytocin in neurons of the rat hypothalamic paraventricular and supraoptic nuclei (Gorbatyuk et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Putative Agmatinase Inhibitor for Hypoxic-Ischemic New Born Brain Damage

et al. 2013

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Agmatine is an endogenous brain metabolite, decarboxylated arginine, which has neuroprotective properties when injected intraperitoneally (i.p.) into rat pups following hypoxic-ischemia. A previous screen for compounds based on rat brain lysates containing agmatinase with assistance from computational chemistry, led to piperazine-1-carboxamidine as a putative agmatinase inhibitor. Herein, the neuroprotective properties of piperazine-1-carboxamidine are described both in vitro and in vivo. Organotypic entorhinal-hippocampal slices were firstly prepared from seven-day-old rat pups and exposed in vitro to atmospheric oxygen depletion for 3 hrs. Upon reoxygenation the slices were treated with piperazine-1-carboxamidine or agmatine (50 μg/ml agents), or saline, and 15 hours later propidium iodine was used to stain. Piperazine-1-carboxamidine or agmatine produced substantial in vitro protection compared to post-reoxygenated saline-treated controls. An in vivo model involved surgical right carotid ligation followed by exposure to hypoxic ischemia (8% oxygen) for 2.5 hours. Piperazine-1-carboxamidine at 50 mg/kg i.p. was given 15 minutes post-reoxygenation and continued twice daily for 3 days. Cortical agmatine levels were elevated (+28.5%) following piperazine-1-carboxamidine treatment with no change in arginine or its other major metabolites. Histological staining with anti-Neun monoclonal antibody also revealed neuroprotection of CA1–3 layers of the hippocampus. Until endpoint at 22 days of age, no adverse events were observed in treated pups' body weights, rectal temperatures, or prompted ambulation. Piperazine-1-carboxamidine therefore appears to be a neuroprotective agent of a new category, agmatinase inhibitor.

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Agmatine transport into spinal nerve terminals is modulated by polyamine analogs

Cited by 18 publications

References 53 publications

Synaptic localisation of agmatinase in rat cerebral cortex revealed by virtual pre-embedding

Synaptic localisation of agmatinase in rat cerebral cortex revealed by virtual pre-embedding

Immunoneutralization of Agmatine Sensitizes Mice to μ-Opioid Receptor Tolerance

Putative Agmatinase Inhibitor for Hypoxic-Ischemic New Born Brain Damage

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