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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 aminamine (l-argiarginine 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 catication 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-argiarginine. 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-argiarginine 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-argiarginine, 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.

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

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:

    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.

  • 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 aminamine 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, Roland C. Blantz, Carolyn J. Kelly, 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.

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.