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Carolyn A. Fairbanks - One of the best experts on this subject based on the ideXlab platform.

  • OCT2 and MATE1 provide bidirectional Agmatine transport.
    Molecular Pharmaceutics, 2010
    Co-Authors: Tate Winter, William F. Elmquist, Carolyn A. Fairbanks
    Abstract:

    Agmatine is a biogenic amine (l-arginine metabolite) of potential relevance to several central nervous system (CNS) conditions. The identities of transporters underlying Agmatine and polyamine disposition in mammalian systems are not well-defined. The SLC-family organic cation transporters (OCT) OCT1 and OCT2 and multidrug and toxin extrusion transporter-1 (MATE1) are transport systems that may be of importance for the cellular disposition of Agmatine and putrescine. We investigated the transport of [(3)H]Agmatine and [(3)H]putrescine in human embryonic kidney (HEK293) cells stably transfected with hOCT1, hOCT2, and hMATE1. Agmatine transport by hOCT1 and hOCT2 was concentration-dependent, whereas only hOCT2 demonstrated pH-dependent transport. hOCT2 exhibited a greater affinity for Agmatine (K(m) = 1.84 ± 0.38 mM) than did hOCT1 (K(m) = 18.73 ± 4.86 mM). Putrescine accumulation was pH- and concentration-dependent in hOCT2-HEK cells (K(m) = 11.29 ± 4.26 mM) but not hOCT1-HEK cells. Agmatine accumulation, in contrast to putrescine, was significantly enhanced by hMATE1 overexpression, and was saturable (K(m) = 240 ± 31 μM; V(max) = 192 ± 10 pmol/min/mg of protein). Intracellular Agmatine was also trans-stimulated (effluxed) from hMATE1-HEK cells in the presence of an inward proton-gradient. The hMATE1-mediated transport of Agmatine was inhibited by polyamines, the prototypical substrates MPP+ and paraquat, as well as guanidine and arcaine, but not l-arginine. These results suggest that Agmatine disposition may be influenced by hOCT2 and hMATE1, two transporters critical in the renal elimination of xenobiotic compounds.

  • Potassium- and capsaicin-induced release of Agmatine from spinal nerve terminals.
    Journal of neurochemistry, 2007
    Co-Authors: Cory J. Goracke-postle, Aaron C. Overland, Laura S. Stone, Maureen S. Riedl, Carolyn A. Fairbanks
    Abstract:

    Agmatine (decarboxylated arginine) was originally identified in the CNS as an imidazoline receptor ligand. Further studies demonstrated that Agmatine antagonizes NMDA receptors and inhibits nitric oxide synthase. Intrathecally administered Agmatine inhibits opioid tolerance and hyperalgesia evoked by inflammation, nerve injury, and intrathecally administered NMDA. These actions suggest an anti-glutamatergic role for Agmatine in the spinal cord. We have previously reported that radiolabeled Agmatine is transported into spinal synaptosomes in an energy- and temperature-dependent manner. In the present study, we demonstrate that Agmatine is releasable from purified spinal nerve terminals upon depolarization. When exposed to either elevated potassium or capsaicin, tritiated Agmatine (but not its precursor L-arginine or its metabolite putrescine) is released in a calcium-dependent manner. Control experiments confirmed that the observed release was specific to depolarization and not due to permeabilization of or degradation of synaptosomes. That capsaicin-evoked stimulation results in Agmatine release implicates the participation of primary afferent nerve terminals. Radiolabeled Agmatine also accumulates in purified spinal synaptosomal vesicles in a temperature-dependent manner, suggesting that the source of releasable Agmatine may be vesicular in origin. These results support the proposal that Agmatine may serve as a spinal neuromodulator involved in pain processing.

  • Agmatine transport into spinal nerve terminals is modulated by polyamine analogs
    Journal of Neurochemistry, 2007
    Co-Authors: Cory J. Goracke-postle, Aaron C. Overland, Laura S. Stone, Carolyn A. Fairbanks
    Abstract:

    Agmatine (decarboxylated arginine) is an endogenous amine found in the CNS that antagonizes NMDA receptors and inhibits nitric oxide synthase. Intrathecally administered Agmatine inhibits hyperalgesia evoked by inflammation, nerve injury and intrathecally administered NMDA. These actions suggest an antiglutamatergic neuromodulatory role for Agmatine in the spinal cord. Such a function would require a mechanism of regulated clearance of Agmatine such as neuronal or glial uptake. Consistent with this concept, radiolabeled Agmatine has been shown to accumulate in synaptosomes, but the mechanism of this transport has not been fully characterized. The present study describes an Agmatine uptake system in spinal synaptosomes that appears driven by a polyamine transporter. [(3)H]Agmatine uptake was Ca(2+), energy and temperature dependent. [(3)H]Agmatine transport was not moderated by L-arginine, L-glutamate, glycine, GABA, norepinephrine or serotonin. In contrast, [(3)H]Agmatine uptake was concentration dependently inhibited by unlabeled putrescine and by unlabeled spermidine (at significantly higher concentrations). Similarly, [(3)H]putrescine uptake was inhibited in a concentration-dependent manner by unlabeled Agmatine and spermidine. The polyamine analogs paraquat and methylglyoxal bis (guanylhydrazone) inhibited, whereas the polyamine transport enhancer difluoromethylornithine increased, [(3)H]Agmatine transport. Taken together, these results suggest that Agmatine transport into spinal synaptosomes may be governed by a polyamine transport mechanism.

  • Release of tritiated Agmatine from spinal synaptosomes.
    NeuroReport, 2006
    Co-Authors: Cory J. Goracke-postle, Laura S. Stone, Hoang Oanh X. Nguyen, Carolyn A. Fairbanks
    Abstract:

    Intrathecal Agmatine (decarboxylated arginine) moderates induction of neuropathic pain, spinal cord injury, and opioid tolerance in rodents. An endogenous central nervous system molecule and N-methyl-D-aspartate receptor antagonist/nitric oxide synthase inhibitor, Agmatine may be a neuromodulator. We evaluated depolarization-induced release of Agmatine from purified spinal nerve terminals (synaptosomes). Agmatine immunoreactivity was observed colocalized or closely apposed to some synaptophysin-and/or synaptotagmin-labeled structures. A temperature- and concentration-dependent uptake of [ 3 H]-Agmatine into synaptosomes was observed, consistent with an uptake mechanism. Potassium-induced depolarization resulted in release of [ 3 H]- Agmatine from the synaptosomes in a Ca 2+ -dependent manner, consistent with a neuromodulatory function. These results agree with previous reports of Agmatine uptake into synaptosomes of the brain and extend those results to include stimulated release and a spinal site of activity.

  • Pharmacodynamic and pharmacokinetic studies of Agmatine after spinal administration in the mouse.
    Journal of Pharmacology and Experimental Therapeutics, 2005
    Co-Authors: John C. Roberts, Brent Grocholski, Kelley F. Kitto, Carolyn A. Fairbanks
    Abstract:

    Agmatine is an endogenous decarboxylation product of arginine that has been previously shown to antagonize the N-methyl-d-aspartate (NMDA) receptor and inhibit nitric-oxide synthase. Many neuropharmacological studies have shown that exogenous administration of Agmatine prevents or reverses biological phenomena dependent on central nervous system glutamatergic systems, including opioid-induced tolerance, opioid self-administration, and chronic pain. However, the central nervous system (CNS) pharmacokinetic profile of Agmatine remains minimally defined. The present study determined the spinal cord pharmacokinetics and acute pharmacodynamics of intrathecally administered Agmatine in mice. After a single bolus intrathecal injection, Agmatine concentrations in spinal cord (cervical, thoracic, and lumbosacral) tissue and serum were quantified by an isocratic high-performance liquid chromatography fluorescence detection system. Agmatine persisted at near maximum concentrations in all levels of the spinal cord for several hours with a half-life of approximately 12 h. Initial Agmatine concentrations in serum were 10% those in CNS. However, the serum half-life was less than 10 min after intrathecal injection of Agmatine, consistent with previous preliminary pharmacokinetic reports of systemically administered Agmatine. The pharmacodynamic response to Agmatine in the NMDA-nociceptive behavior and thermal hyperalgesia tests was assessed. Whereas MK-801 (dizocilpine maleate) inhibits these two responses with equal potency, Agmatine inhibits the thermal hyperalgesia with significantly increased potency compared with the nociceptive behavior, suggesting two sites of action. In contrast to the pharmacokinetic results, the Agmatine inhibition of both behaviors had a duration of only 10 to 30 min. Collectively, these results suggest the existence of a currently undefined Agmatinergic extracellular clearance process in spinal cord.

Soundar Regunathan - One of the best experts on this subject based on the ideXlab platform.

  • Agmatine Levels in the Cerebrospinal Fluid of Normal Human Volunteers
    Journal of Pain & Palliative Care Pharmacotherapy, 2009
    Co-Authors: Soundar Regunathan, Damon Dozier, Ramarao Takkalapalli, William J. Phillips
    Abstract:

    Agmatine is an amine formed by the decarboxylation of l-arginine by the enzyme arginine decarboxylase. The fact that exogenous Agmatine modulates morphine analgesia and dependence raises the question of whether the biosynthesis of endogenous Agmatine is regulated during chronic pain. As a first step to understand the biological role of Agmatine in human neurological and psychiatric conditions, this study was aimed to determine the levels of cerebrospinal fluid (CSF) Agmatine in normal individuals. The levels of Agmatine in the CSF and blood were measured by high-performance liquid chromatography (HPLC) method. Samples of CSF and blood were collected from a total of 10 participants for this study. The CSF Agmatine levels ranged from 24.3 to 54.0 ng/mL, whereas the plasma Agmatine levels were from 8.4 to 65.1 ng/mL. The mean values with standard error for blood and CSF Agmatine were 33.8 ± 16.6 and 40.4 ± 9.1, respectively. The statistical analysis of these 10 samples indicated no correlation between blood ...

  • Repeated immobilization stress alters rat hippocampal and prefrontal cortical morphology in parallel with endogenous Agmatine and arginine decarboxylase levels.
    Neurochemistry international, 2008
    Co-Authors: Mengyang Zhu, Soundar Regunathan, Yangzheng Feng, Weiping Wang, Jingjing Huang, Garth Bissette
    Abstract:

    Agmatine, an endogenous amine derived from decarboxylation of L-arginine catalyzed by arginine decarboxylase, has been proposed as a neurotransmitter or neuromodulator in the brain. In the present study, we examined whether Agmatine has neuroprotective effects against repeated immobilization-induced morphological changes in brain tissues and possible effects of immobilization stress on endogenous Agmatine levels and arginine decarboxylase expression in rat brains. Sprague-Dawley rats were subjected to 2h immobilization stress daily for 7 days. This paradigm significantly increased plasma corticosterone levels, and the glutamate efflux in the hippocampus as measured by in vivo microdialysis. Immunohistochemical staining with beta-tubulin III showed that repeated immobilization caused marked morphological alterations in the hippocampus and medial prefrontal cortex that were prevented by simultaneous treatment with Agmatine (50mg/kg/day), i.p.). Likewise, endogenous Agmatine levels measured by high-performance liquid chromatography in the prefrontal cortex, hippocampus, striatum and hypothalamus were significantly increased by immobilization, as compared to controls. The increased endogenous Agmatine levels, ranging from 92 to 265% of controls, were accompanied by a significant increase of arginine decarboxylase protein levels in the same regions. These results demonstrate that the administration of exogenous Agmatine protects the hippocampus and medial prefrontal cortex against neuronal insults caused by repeated immobilization. The parallel increase in endogenous brain Agmatine and arginine decarboxylase protein levels triggered by repeated immobilization indicates that the endogenous Agmatine system may play an important role in adaptation to stress as a potential neuronal self-protection mechanism.

  • Repeated immobilization stress alters rat hippocampal and prefrontal cortical morphology in parallel with endogenous Agmatine and arginine decarboxylase levels.
    Neurochemistry International, 2008
    Co-Authors: Mengyang Zhu, Soundar Regunathan, Yangzheng Feng, Weiping Wang, Jingjing Huang, Garth Bissette
    Abstract:

    Abstract Agmatine, an endogenous amine derived from decarboxylation of l -arginine catalyzed by arginine decarboxylase, has been proposed as a neurotransmitter or neuromodulator in the brain. In the present study, we examined whether Agmatine has neuroprotective effects against repeated immobilization-induced morphological changes in brain tissues and possible effects of immobilization stress on endogenous Agmatine levels and arginine decarboxylase expression in rat brains. Sprague–Dawley rats were subjected to 2 h immobilization stress daily for 7 days. This paradigm significantly increased plasma corticosterone levels, and the glutamate efflux in the hippocampus as measured by in vivo microdialysis. Immunohistochemical staining with β-tubulin III showed that repeated immobilization caused marked morphological alterations in the hippocampus and medial prefrontal cortex that were prevented by simultaneous treatment with Agmatine (50 mg/kg/day), i.p.). Likewise, endogenous Agmatine levels measured by high-performance liquid chromatography in the prefrontal cortex, hippocampus, striatum and hypothalamus were significantly increased by immobilization, as compared to controls. The increased endogenous Agmatine levels, ranging from 92 to 265% of controls, were accompanied by a significant increase of arginine decarboxylase protein levels in the same regions. These results demonstrate that the administration of exogenous Agmatine protects the hippocampus and medial prefrontal cortex against neuronal insults caused by repeated immobilization. The parallel increase in endogenous brain Agmatine and arginine decarboxylase protein levels triggered by repeated immobilization indicates that the endogenous Agmatine system may play an important role in adaptation to stress as a potential neuronal self-protection mechanism.

  • chronic treatment with glucocorticoids alters rat hippocampal and prefrontal cortical morphology in parallel with endogenous Agmatine and arginine decarboxylase levels
    Journal of Neurochemistry, 2007
    Co-Authors: Mengyang Zhu, Weiping Wang, Jingjing Huang, Soundar Regunathan
    Abstract:

    In the present study, we examined the possible effect of chronic treatment with glucocorticoids on the morphology of the rat brain and levels of endogenous Agmatine and arginine decarboxylase (ADC) protein, the enzyme essential for Agmatine synthesis. Seven-day treatment with dexamethasone, at a dose (10 and 50 mug/kg/day) associated to stress effects contributed by glucocorticoids, did not result in obvious morphologic changes in the medial prefrontal cortex and hippocampus, as measured by immunocytochemical staining with beta-tubulin III. However, 21-day treatment (50 mug/kg/day) produced noticeable structural changes such as the diminution and disarrangement of dendrites and neurons in these areas. Simultaneous treatment with Agmatine (50 mg/kg/day) prevented these morphological changes. Further measurement with HPLC showed that endogenous Agmatine levels in the prefrontal cortex and hippocampus were significantly increased after 7-day treatments with dexamethasone in a dose-dependent manner. On the contrary, 21-day treatment with glucocorticoids robustly reduced Agmatine levels in these regions. The treatment-caused biphasic alterations of endogenous Agmatine levels were also seen in the striatum and hypothalamus. Interestingly, treatment with glucocorticoids resulted in a similar change of ADC protein levels in most brain areas to endogenous Agmatine levels: an increase after 7-day treatment versus a reduction after 21-day treatment. These results demonstrated that Agmatine has neuroprotective effects against structural alterations caused by glucocorticoids in vivo. The parallel alterations in the endogenous Agmatine levels and ADC expression in the brain after treatment with glucocorticoids indicate the possible regulatory effect of these stress hormones on the synthesis and metabolism of Agmatine in vivo.

  • Agmatine: biological role and therapeutic potentials in morphine analgesia and dependence.
    The AAPS Journal, 2006
    Co-Authors: Soundar Regunathan
    Abstract:

    Agmatine is an amine that is formed by decarboxylation of L-arginine by the enzyme arginine decarboxylase (ADC) and hydrolyzed by the enzyme agmatinase to putrescine. Agmatine binds to several target receptors in the brain and has been proposed as a novel neuromodulator. In animal studies, Agmatine potentiated morphine analgesia and reduced dependence/withdrawal. While the exact mechanism is not clear, the interactions with N-methyl-D-aspartate (NMDA) receptors, alpha2-adrenergic receptors, and intracellular cyclic adenosine monophosphate (cAMP) signaling have been proposed as possible targets. Like other monoamine transmitter molecules, Agmatine is rapidly metabolized in the periphery and has poor penetration into the brain, which limits the use of Agmatine itself as a therapeutic agent. However, the development of agmatinase inhibitors will offer a useful method to increase endogenous Agmatine in the brain as a possible therapeutic approach to potentiate morphine analgesia and reduce dependence/withdrawal. This review provides a succinct discussion of the biological role/therapeutic potential of Agmatine during morphine exposure/pain modulation, with an extensive amount of literature cited for further details.

Garth Bissette - One of the best experts on this subject based on the ideXlab platform.

  • Repeated immobilization stress alters rat hippocampal and prefrontal cortical morphology in parallel with endogenous Agmatine and arginine decarboxylase levels.
    Neurochemistry International, 2008
    Co-Authors: Mengyang Zhu, Soundar Regunathan, Yangzheng Feng, Weiping Wang, Jingjing Huang, Garth Bissette
    Abstract:

    Abstract Agmatine, an endogenous amine derived from decarboxylation of l -arginine catalyzed by arginine decarboxylase, has been proposed as a neurotransmitter or neuromodulator in the brain. In the present study, we examined whether Agmatine has neuroprotective effects against repeated immobilization-induced morphological changes in brain tissues and possible effects of immobilization stress on endogenous Agmatine levels and arginine decarboxylase expression in rat brains. Sprague–Dawley rats were subjected to 2 h immobilization stress daily for 7 days. This paradigm significantly increased plasma corticosterone levels, and the glutamate efflux in the hippocampus as measured by in vivo microdialysis. Immunohistochemical staining with β-tubulin III showed that repeated immobilization caused marked morphological alterations in the hippocampus and medial prefrontal cortex that were prevented by simultaneous treatment with Agmatine (50 mg/kg/day), i.p.). Likewise, endogenous Agmatine levels measured by high-performance liquid chromatography in the prefrontal cortex, hippocampus, striatum and hypothalamus were significantly increased by immobilization, as compared to controls. The increased endogenous Agmatine levels, ranging from 92 to 265% of controls, were accompanied by a significant increase of arginine decarboxylase protein levels in the same regions. These results demonstrate that the administration of exogenous Agmatine protects the hippocampus and medial prefrontal cortex against neuronal insults caused by repeated immobilization. The parallel increase in endogenous brain Agmatine and arginine decarboxylase protein levels triggered by repeated immobilization indicates that the endogenous Agmatine system may play an important role in adaptation to stress as a potential neuronal self-protection mechanism.

  • Repeated immobilization stress alters rat hippocampal and prefrontal cortical morphology in parallel with endogenous Agmatine and arginine decarboxylase levels.
    Neurochemistry international, 2008
    Co-Authors: Mengyang Zhu, Soundar Regunathan, Yangzheng Feng, Weiping Wang, Jingjing Huang, Garth Bissette
    Abstract:

    Agmatine, an endogenous amine derived from decarboxylation of L-arginine catalyzed by arginine decarboxylase, has been proposed as a neurotransmitter or neuromodulator in the brain. In the present study, we examined whether Agmatine has neuroprotective effects against repeated immobilization-induced morphological changes in brain tissues and possible effects of immobilization stress on endogenous Agmatine levels and arginine decarboxylase expression in rat brains. Sprague-Dawley rats were subjected to 2h immobilization stress daily for 7 days. This paradigm significantly increased plasma corticosterone levels, and the glutamate efflux in the hippocampus as measured by in vivo microdialysis. Immunohistochemical staining with beta-tubulin III showed that repeated immobilization caused marked morphological alterations in the hippocampus and medial prefrontal cortex that were prevented by simultaneous treatment with Agmatine (50mg/kg/day), i.p.). Likewise, endogenous Agmatine levels measured by high-performance liquid chromatography in the prefrontal cortex, hippocampus, striatum and hypothalamus were significantly increased by immobilization, as compared to controls. The increased endogenous Agmatine levels, ranging from 92 to 265% of controls, were accompanied by a significant increase of arginine decarboxylase protein levels in the same regions. These results demonstrate that the administration of exogenous Agmatine protects the hippocampus and medial prefrontal cortex against neuronal insults caused by repeated immobilization. The parallel increase in endogenous brain Agmatine and arginine decarboxylase protein levels triggered by repeated immobilization indicates that the endogenous Agmatine system may play an important role in adaptation to stress as a potential neuronal self-protection mechanism.

  • neuroprotective effects of Agmatine against cell damage caused by glucocorticoids in cultured rat hippocampal neurons
    Neuroscience, 2006
    Co-Authors: M Y Zhu, W P Wang, Garth Bissette
    Abstract:

    In the present study the neuroprotective effects of Agmatine against neuronal damage caused by glucocorticoids were examined in cultured rat hippocampal neurons. Spectrophotometric measurements of lactate dehydrogenase activities, β-tubulin III immunocytochemical staining, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick-end-labeling assay (TUNEL) labeling and caspase-3 assays were carried out to detect cell damage or possible involved mechanisms. Our results show that dexamethasone and corticosterone produced a concentration-dependent increase of lactate dehydrogenase release in 12-day hippocampal cultures. Addition of 100 μM Agmatine into media prevented the glucocorticoid-induced increase of lactate dehydrogenase release, an effect also shared with the specific N-methyl-d-aspartate receptor antagonist MK801 and glucocorticoid receptor antagonists mifepristone and spironolactone. Arcaine, an analog of Agmatine with similar structure as Agmatine, also blocked glucocorticoid-induced increase of lactate dehydrogenase release. Spermine and putrescine, the endogenous polyamine and metabolic products of Agmatine without the guanidino moiety of Agmatine, have no appreciable effect on glucocorticoid-induced injuries, indicating a structural relevance for this neuroprotection. Immunocytochemical staining with β-tubulin III confirmed the substantial neuronal injuries caused by glucocorticoids and the neuroprotective effects of Agmatine against these neuronal injuries. TUNEL labeling demonstrated that Agmatine significantly reduced TUNEL-positive cell numbers induced by exposure of cultured neurons to dexamethasone. Moreover, exposure of hippocampal neurons to dexamethasone significantly increased caspase-3 activity, which was inhibited by co-treatment with Agmatine. Taken together, these results demonstrate that Agmatine can protect cultured hippocampal neurons from glucocorticoid-induced neurotoxicity, through a possible blockade of the N-methyl-d-aspartate receptor channels or a potential anti-apoptotic property.

Joseph Satriano - One of the best experts on this subject based on the ideXlab platform.

  • Agmatine effects on mitochondrial membrane potential andnf κb activation protect against rotenone induced cell damage in human neuronal like sh sy5y cells
    Journal of Neurochemistry, 2011
    Co-Authors: Salvatore Condello, Joseph Satriano, Monica Curro, Nadia Ferlazzo, Daniela Caccamo, Riccardo Ientile
    Abstract:

    Agmatine, an endogenous arginine metabolite, has been proposed as a novel neuromodulator that plays protective roles in the CNS in several models of cellular damage. However, the mechanisms involved in these protective effects in neurodegenerative diseases are poorly understood. The present study was undertaken to investigate the effects of Agmatine on cell injury induced by rotenone, commonly used in establishing in vivo and in vitro models of Parkinson's disease, in human-derived dopaminergic neuroblastoma cell line (SH-SY5Y). We report that Agmatine dose-dependently suppressed rotenone-induced cellular injury through a reduction of oxidative stress. Similar effects were obtained by spermine, suggesting a scavenging effect for these compounds. However, unlike spermine, Agmatine also prevented rotenone-induced nuclear factor-κB nuclear translocation and mitochondrial membrane potential dissipation. Furthermore, rotenone-induced increase in apoptotic markers, such as caspase 3 activity, Bax expression and cytochrome c release, was significantly attenuated with Agmatine treatment. These findings demonstrate mitochondrial preservation with Agmatine in a rotenone model of apoptotic cell death, and that the neuroprotective action of Agmatine appears because of suppressing apoptotic signalling mechanisms. Thus, Agmatine may have therapeutic potential in the treatment of Parkinson's disease by protecting dopaminergic neurons.

  • The antiproliferative effects of Agmatine correlate with the rate of cellular proliferation
    American Journal of Physiology-Cell Physiology, 2007
    Co-Authors: Masato Isome, Mark Lortie, Yasuko Murakami, Eva Parisi, Senya Matsufuji, Joseph Satriano
    Abstract:

    Polyamines are small cationic molecules required for cellular proliferation. Agmatine is a biogenic amine unique in its capacity to arrest proliferation in cell lines by depleting intracellular polyamine levels. We previously demonstrated that Agmatine enters mammalian cells via the polyamine transport system. As polyamine transport is positively correlated with the rate of cellular proliferation, the current study examines the antiproliferative effects of Agmatine on cells with varying proliferative kinetics. Herein, we evaluate Agmatine transport, intracellular accumulation, and its effects on antizyme expression and cellular proliferation in nontransformed cell lines and their transformed variants. H-ras- and Src-transformed murine NIH/3T3 cells (Ras/3T3 and Src/3T3, respectively) that were exposed to exogenous Agmatine exhibit increased uptake and intracellular accumulation relative to the parental NIH/3T3 cell line. Similar increases were obtained for human primary foreskin fibroblasts relative to a human fibrosarcoma cell line, HT1080. Agmatine increases expression of antizyme, a protein that inhibits polyamine biosynthesis and transport. Ras/3T3 and Src/3T3 cells demonstrated augmented increases in antizyme protein expression relative to NIH/3T3 in response to Agmatine. All transformed cell lines were significantly more sensitive to the antiproliferative effects of Agmatine than nontransformed lines. These effects were attenuated in the presence of exogenous polyamines or inhibitors of polyamine transport. In conclusion, the antiproliferative effects of Agmatine preferentially target transformed cell lines due to the increased Agmatine uptake exhibited by cells with short cycling times.

  • suppression of inducible nitric oxide generation by Agmatine aldehyde beneficial effects in sepsis
    Journal of Cellular Physiology, 2001
    Co-Authors: Joseph Satriano, Carolyn J. Kelly, Roland C. Blantz, Mark Lortie, Doron Schwartz, Shunji Ishizuka, Scott C Thomson, Francis B Gabbai
    Abstract:

    The induction of inducible nitric oxide synthase (iNOS) serves an important immuno-protective function in inflammatory states, but ungoverned nitric oxide (NO) generation can contribute to a number of pathologic consequences. Delineation of the mechanisms that can downregulate iNOS-generated NO in inflammation could have therapeutic relevance. Here we show that Agmatine, a metabolite of arginine, inhibits iNOS mediated nitric oxide generation in cytokine stimulated cell culture preparations. This effect was not cell type specific. Increased diamine oxidase (DAO) and decreased aldehyde dehydrogenase (AldDH) activities are also representative of inflammatory settings. Increasing the conversion of Agmatine to an aldehyde form by addition of purified DAO or suppression of aldehyde breakdown by inhibition of AldDH activity increases the inhibitory effects of Agmatine in an additive fashion. Inhibitors of DAO, but not monoamine oxidase (MAO), decreased the inhibitory effects of Agmatine, as did the addition of AldDH or reacting aldehydes with phenylhydrazine. We examined rats given lipopolysaccharide (LPS) to evaluate the potential effects of Agmatine in vivo. Endotoxic rats administered Agmatine prevented the decreases in blood pressure and renal function normally associated with sepsis. Agmatine treatment also increased the survival of LPS treated mice. Our data demonstrate the capacity of Agmatine aldehyde to suppress iNOS mediated NO generation, and indicate a protective function of Agmatine in a model of endotoxic shock. How Agmatine may aid in coordinating the early NO phase and the later repair phase responses in models of inflammation is discussed. © 2001 Wiley-Liss, Inc.

  • An emerging role for Agmatine
    Kidney International, 1999
    Co-Authors: Joseph Satriano, Carolyn J. Kelly, Roland C. Blantz
    Abstract:

    An emerging role for Agmatine. Polyamines, required components of proliferation, are autoregulated by the protein antizyme. To date, Agmatine is the only molecule other than the polyamines that can induce antizyme, and thus influence cell homeostasis and growth. Agmatine has effectively suppressed proliferation in immortalized and transformed cell lines. An increased sensitivity to the anti-proliferative effects of Agmatine observed in Ras transformed versus native cells paralleled an increase in Agmatine uptake in the transformed cells. We hypothesize that Agmatine may target transformed cells via selective transporters.

  • Agmatine a bioactive metabolite of arginine production degradation and functional effects in the kidney of the rat
    Journal of Clinical Investigation, 1996
    Co-Authors: Mark Lortie, Joseph Satriano, Scott C Thomson, W F Novotny, Orjan W Peterson, Volker Vallon, K Malvey, M Mendonca, Paul A Insel, Roland C. Blantz
    Abstract:

    Until recently, conversion of arginine to Agmatine by arginine decarboxylase (ADC) was considered important only in plants and bacteria. In the following, we demonstrate ADC activity in the membrane-enriched fraction of brain, liver, and kidney cortex and medulla by radiochemical assay. Diamine oxidase, an enzyme shown here to metabolize Agmatine, was localized by immunohistochemistry in kidney glomeruli and other nonrenal cells. Production of labeled Agmatine, citrulline, and ornithine from [3H]arginine was demonstrated and endogenous Agmatine levels (10(-6)M) in plasma ultrafiltrate and kidney were measured by HPLC. Microperfusion of Agmatine into renal interstitium and into the urinary space of surface glomeruli of Wistar-Fromter rats produced reversible increases in nephron filtration rate (SNGFR) and absolute proximal reabsorption (APR). Renal denervation did not alter SNGFR effects but prevented APR changes. Yohimbine (an alpha 2 antagonist) microperfusion into the urinary space produced opposite effects to that of Agmatine. Microperfusion of urinary space with BU-224 (microM), a synthetic imidazoline2 (I2) agonist, duplicated Agmatine effects on SNGFR but not APR whereas an I1 agonist had no effect. Agmatine effects on SNGFR and APR are not only dissociable but appear to be mediated by different mechanisms. The production and degradation of this biologically active substance derived from arginine constitutes a novel endogenous regulatory system in the kidney.

Donald J. Reis - One of the best experts on this subject based on the ideXlab platform.

  • Is Agmatine a novel neurotransmitter in brain
    Trends in Pharmacological Sciences, 2000
    Co-Authors: Donald J. Reis, S. Regunathan
    Abstract:

    Abstract Recent evidence suggests that Agmatine, which is an intermediate in polyamine biosynthesis, might be an important neurotransmitter in mammals. Agmatine is synthesized in the brain, stored in synaptic vesicles in regionally selective neurons, accumulated by uptake, released by depolarization, and inactivated by agmatinase. Agmatine binds to α 2 -adrenoceptors and imidazoline binding sites, and blocks NMDA receptor channels and other ligand-gated cationic channels. Furthermore, Agmatine inhibits nitric oxide synthase, and induces the release of some peptide hormones. As a result of its ability to inhibit both hyperalgesia and tolerance to, and withdrawal from, morphine, and its neuroprotective activity, Agmatine has potential as a treatment of chronic pain, addictive states and brain injury.

  • Agmatine selectively blocks then methyl d aspartate subclass of glutamate receptor channels in rat hippocampal neurons
    Journal of Pharmacology and Experimental Therapeutics, 1999
    Co-Authors: Xiancheng Yang, Donald J. Reis
    Abstract:

    We investigated in rat hippocampus neurons whether 4-(aminobutyl)guanidine (Agmatine), formed by decarboxylation ofl-arginine by arginine decarboxylase and metabolized to urea and putrescine, can modulate the function of N -methyl-d-aspartate (NMDA) receptor channels. In cultured hippocampal neurons studied by whole-cell patch clamp, extracellular-applied Agmatine produced a voltage- and concentration-dependent block of NMDA but not α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid nor kainate currents. Analysis of the voltage dependence of the block suggests that Agmatine binds at a site located within the NMDA channel pore with a dissociation constant of 952 μM at 0 mV and an electric distance of 0.62. We also tested effects of several Agmatine analogs. Arcaine (1,4-butyldiguanidine) also produced a similar voltage-dependent block of the NMDA current, whereas putrescine (1,4-butyldiamine) had little effect, suggesting that the guanidine group of Agmatine is the active moiety when blocking the NMDA channel. Moreover, spermine (an endogenous polyamine) potentiated the NMDA current even in the presence of blocker Agmatine or arcaine, suggesting that the guanidine-containing compounds Agmatine and arcaine interact with the NMDA channel at a binding site different from that of spermine. Our results indicate that in hippocampal neurons Agmatine selectively modulates the NMDA subclass of glutamate receptor channels mediated by the interaction between the guanidine group and the channel pore. The results support other data that Agmatine may function as an endogenous neurotransmitter/neuromodulator in brain.

  • Agmatine selectively blocks the n methyl d aspartate subclass of glutamate receptor channels in rat hippocampal neurons
    Journal of Pharmacology and Experimental Therapeutics, 1999
    Co-Authors: Xiancheng Yang, Donald J. Reis
    Abstract:

    We investigated in rat hippocampus neurons whether 4-(aminobutyl)guanidine (Agmatine), formed by decarboxylation ofl-arginine by arginine decarboxylase and metabolized to urea and putrescine, can modulate the function of N -methyl-d-aspartate (NMDA) receptor channels. In cultured hippocampal neurons studied by whole-cell patch clamp, extracellular-applied Agmatine produced a voltage- and concentration-dependent block of NMDA but not α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid nor kainate currents. Analysis of the voltage dependence of the block suggests that Agmatine binds at a site located within the NMDA channel pore with a dissociation constant of 952 μM at 0 mV and an electric distance of 0.62. We also tested effects of several Agmatine analogs. Arcaine (1,4-butyldiguanidine) also produced a similar voltage-dependent block of the NMDA current, whereas putrescine (1,4-butyldiamine) had little effect, suggesting that the guanidine group of Agmatine is the active moiety when blocking the NMDA channel. Moreover, spermine (an endogenous polyamine) potentiated the NMDA current even in the presence of blocker Agmatine or arcaine, suggesting that the guanidine-containing compounds Agmatine and arcaine interact with the NMDA channel at a binding site different from that of spermine. Our results indicate that in hippocampal neurons Agmatine selectively modulates the NMDA subclass of glutamate receptor channels mediated by the interaction between the guanidine group and the channel pore. The results support other data that Agmatine may function as an endogenous neurotransmitter/neuromodulator in brain.

  • inhibition of mammalian nitric oxide synthases by Agmatine an endogenous polyamine formed by decarboxylation of arginine
    Biochemical Journal, 1996
    Co-Authors: Elena Galea, S. Regunathan, Vassily Eliopoulos, Douglas L Feinstein, Donald J. Reis
    Abstract:

    Agmatine, decarboxylated arginine, is a metabolic product of mammalian cells. Considering the close structural similarity between L-arginine and Agmatine, we investigated the interaction of Agmatine and nitric oxide synthases (NOSs), which use L-arginine to generate nitric oxide (NO) and citrulline. Brain, macrophages and endothelial cells were respectively used as sources for NOS isoforms I, II and III. Enzyme activity was measured by the production of nitrites or L-citrulline. Agmatine was a competitive NOS inhibitor but not an NO precursor. Ki values were approx. 660 microM (NOS I), 220 microM (NOS II) and 7.5 mM (NOS III). Structurally related polyamines did not inhibit NOS activity. Agmatine, therefore, may be an endogenous regulator of NO production in mammals.

  • An antibody to Agmatine localizes the amine in bovine adrenal chromaffin cells
    Neuroscience Letters, 1995
    Co-Authors: H Wang, S. Regunathan, Charlotte Youngson, S. Bramwell, Donald J. Reis
    Abstract:

    Abstract Agmatine, a newly identified amine in mammalian brain, is an endogenous ligand for imidazoline and α 2 -adrenergic receptors. We sought to develop a polyclonal antibody to Agmatine suitable for immunocytochemistry. Agmatine was conjugated to keyhole limpet hemocyanin and injected into rabbits. The polyclonal antiserum so generated dose-dependently recognized the Agmatine conjugate but not carrier protein by dot blot. Its reaction with the conjugate was selectively antagonized by Agmatine but not related compounds. The antiserum, but not pre-immune or pre-adsorbed antiserum, selectively stained cultured adrenal chromaffin cells. Our results indicate that Agmatine immunoreactivity is contained in a sub-population of adrenal chromaffin cells and, thus, these antibodies are useful for immunocytochemical localization of the amine in mammalian tissues.