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CNS Drugs

, Volume 21, Issue 11, pp 885–900 | Cite as

Agmatine

Metabolic Pathway and Spectrum of Activity in Brain
  • Angelos Halaris
  • John Plietz
Leading Article

Abstract

Agmatine is an endogenous neuromodulator that, based on animal studies, has the potential for new drug development. As an endogenous aminoguanidine compound (1-amino-4-guanidinobutane), it is structurally unique compared with other monoamines. Agmatine was long thought to be synthesised only in lower life forms, until its biosynthetic pathway (decarboxylation of arginine) was described in the mammalian brain in 1994. Human arginine decarboxylase has been cloned and shown to have 48% identity to ornithine decarboxylase. In neurons of the brain and spinal cord, agmatine is packaged into synaptic vesicles and released upon neuronal depolarisation. Other evidence of a neuromodulation role for agmatine is the presence of a specific cellular uptake mechanism and a specific metabolic enzyme (agmatinase; which forms putrescine).

Initially, agmatine was conceptualised as an endogenous clonidine-displacing substance of imidazoline receptors; however, it has now been established to have affinity for several transmembrane receptors, such as α2-adrenergic, imidazoline I1 and glutamatergic NMDA receptors. In addition to activity at these receptors, agmatine irreversibly inhibits neuronal nitric oxide synthase and downregulates inducible nitric oxide synthase.

Endogenous agmatine is induced in response to stress and/or inflammation. Stressful conditions that induce agmatine include hypoxic-ischaemia and cold-restraint stress of ulcerogenic proportion. Induction of agmatine in the brain seems to occur in astrocytes, although neurons also synthesise agmatine. The effects of injected agmatine in animals include anticonvulsant-, antineurotoxic- and antidepressant-like actions. Intraperitoneal or intracerebroventricular injections of agmatine rapidly elicit antidepressant-like behavioural changes in the rodent forced swim test and tail suspension test. Intraperitoneal injections of agmatine into rats and mice also elicit acute anxiolytic-like behavioural changes in the elevated plus-maze stress test. In an animal model of acute stress disorder, intraperitoneal agmatine injections diminish contextual fear learning. Furthermore, intraperitoneal injections of agmatine reduce alcohol and opioid dependence by diminishing behaviour in a rat conditioned place preference paradigm.

Based on these findings, agmatine appears to be an endogenous neuromodulator of mental stress. The possible roles and/or beneficial effects of agmatine in stress-related disorders, such as depression, anxiety and post-traumatic stress disorder, merit further investigation.

Keywords

Morphine Quantitative Structure Activity Relationship Conditioned Place Preference Forced Swim Test Agmatine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

The authors have no commercial interests in agmatine or related products; however, John Piletz is principal co-inventor on US patent 20005/0220707 entitled ‘Mammalian agmatinase inhibitory substance’ (awarded November 2005). The patent currently has no royalties or licensee, but it could have commercial value in the future. No sources of funding were used to assist in the preparation of this review.

References

  1. 1.
    Li G, Regunathan S, Barrow CJ, et al. Agmatine: an endogenous clonidine-displacing substance in the brain. Science 1994; 263: 966–9PubMedCrossRefGoogle Scholar
  2. 2.
    Satriano J. Arginine pathways and the inflammatory response: interregulation of nitric oxide and polyamines: review article. Amino Acids 2004; 26: 321–9PubMedCrossRefGoogle Scholar
  3. 3.
    Zhu M, Iyo A, Piletz J, et al. Expression of human arginine decarboxylase, the biosynthetic enzyme for agmatine. Biochim Biophys Acta 2004; 1670: 156–64PubMedCrossRefGoogle Scholar
  4. 4.
    Reis DJ, Regunathan S. Is agmatine a novel neurotransmitter in brain? Trends Pharmacol Sci 2000; 21: 187–93PubMedCrossRefGoogle Scholar
  5. 5.
    Coleman CS, Hu G, Pegg AE. Putrescine biosynthesis in mammalian tissues. Biochem J 2004; 379: 849–55PubMedCrossRefGoogle Scholar
  6. 6.
    Iyo AH, Zhu MY, Ordway GA, et al. Expression of arginine decarboxylase in brain regions and neuronal cells. J Neurochem 2006; 96: 1042–50PubMedCrossRefGoogle Scholar
  7. 7.
    Goracke-Postle CJ, Nguyen HO, Stone LS, et al. Release of tritiated agmatine from spinal synaptosomes. Neuroreport 2006; 17: 13–7PubMedCrossRefGoogle Scholar
  8. 8.
    Reis DJ, Yang XC, Milner TA. Agmatine containing axon terminals in rat hippocampus form synapses on pyramidal cells. Neurosci Lett 1998; 250: 185–8PubMedCrossRefGoogle Scholar
  9. 9.
    Su R, Wei X, Zheng J, et al. Anticonvulsive effect of agmatine in mice. Pharmacol Biochem Behav 2004; 77: 345–9PubMedCrossRefGoogle Scholar
  10. 10.
    Riazi K, Honar H, Homayoun H, et al. The synergistic anticon-vulsant effect of agmatine and morphine: possible role of alpha 2-adrenoceptors. Epilepsy Res 2005; 65: 33–40PubMedCrossRefGoogle Scholar
  11. 11.
    Zhu MY, Wang WP, Bissette G. Neuroprotective effects of agmatine against cell damage caused by glucocorticoids in cultured rat hippocampal neurons. Neuroscience 2006; 1414) 2019–27PubMedCrossRefGoogle Scholar
  12. 12.
    Gilad GM, Gilad VH, Finberg JP, et al. Neurochemical evidence for agmatine modulation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity. Neurochem Res 2005; 30: 713–9PubMedCrossRefGoogle Scholar
  13. 13.
    Wang WP, Iyo AH, Miguel-Hidalgo J, et al. Agmatine protects against cell damage induced by NMDA and glutamate in cultured hippocampal neurons. Brain Res 2006; 1084: 210–6PubMedCrossRefGoogle Scholar
  14. 14.
    Halaris A, Piletz J. Relevance of imidazoline receptors and agmatine to psychiatry: a decade of progress. Ann N Y Acad Sci 2003; 1009: 1–20PubMedCrossRefGoogle Scholar
  15. 15.
    Aricioglu F, Regunathan S. Agmatine attenuates stress- and lipopolysaccharide-induced fever in rats. Physiol Behav 2005; 85: 370–5PubMedCrossRefGoogle Scholar
  16. 16.
    Reis DJ, Piletz JE. The imidazoline receptor in control of blood pressure by clonidine and allied drugs. Am J Physiol 1997; 273: R1569–71PubMedGoogle Scholar
  17. 17.
    Eglen RM, Hudson AL, Kendall DA, et al. ‘Seeing through a glass darkly’: casting light on imidazoline ‘I’ sites. Trends Pharmacol Sci 1998; 19: 381–90PubMedCrossRefGoogle Scholar
  18. 18.
    Raasch W, Schafer U, Qadri F, et al. Agmatine, an endogenous ligand at imidazoline binding sites, does not antagonize the clonidine-mediated blood pressure reaction. Br J Pharmacol 2002; 135: 663–72PubMedCrossRefGoogle Scholar
  19. 19.
    Reis DJ, Li G, Regunathan S. Endogenous ligands of imidazoline receptors: classic and immunoreactive clonidine-displacing substance and agmatine. Ann N Y Acad Sci 1995; 763: 295–313PubMedCrossRefGoogle Scholar
  20. 20.
    Aricioglu F, Regunathan S, Piletz J. Is agmatine an endogenous factor against stress?Ann N Y Acad Sci 2003; 1009: 127–32PubMedCrossRefGoogle Scholar
  21. 21.
    Wu N, Su R, Xu B, et al. IRAS, a candidate for I(l)-imidazoline receptor, mediates inhibitory effect of agmatine on cellular morphine dependence. Biochem Pharmacol 2005; 70 (7): 1079-87Google Scholar
  22. 22.
    Wu N, Su RB, Liu Y, et al. Modulation of agmatine on calcium signal in morphine-dependent CHO cells by activation of IRAS, a candidate for imidazoline I1 receptor. Eur J Pharmacol 2006; 548(1-3): 21–8PubMedCrossRefGoogle Scholar
  23. 23.
    Olmos G, DeGregorio-Rocasolano N, Paz Regalado M, et al. Protection by imidazol(ine) drugs and agmatine of glutamate-induced neurotoxicity in cultured cerebellar granule cells through blockade of NMDA receptor. Br J Pharmacol 1999; 127: 1317–26PubMedCrossRefGoogle Scholar
  24. 24.
    Yang XC, Reis DJ. Agmatine selectively blocks the N-methyl-D-aspartate subclass of glutamate receptor channels in rat hippocampal neurons. J Pharmacol Exp Ther 1999; 288: 544–9PubMedGoogle Scholar
  25. 25.
    Galea E, Regunathan S, Eliopoulos V, et al. Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous polyamine formed by decarboxylation of arginine. Biochem J 1996; 316: 247–9PubMedGoogle Scholar
  26. 26.
    Demady DR, Jianmongkol S, Vuletich JL, et al. Agmatine enhances the NADPH oxidase activity of neuronal NO synthase and leads to oxidative inactivation of the enzyme. Mol Pharmacol 2001; 59: 24–9PubMedGoogle Scholar
  27. 27.
    Regunathan S, Piletz J. Regulation of inducible nitric oxide synthase and agmatine synthesis in macrophages and astrocytes. Ann N Y Acad Sci 2003 Dec; 1009: 20–9PubMedCrossRefGoogle Scholar
  28. 28.
    Piletz J, May P, Wang G, et al. Agmatine crosses the blood-brain barrier. Ann N Y Acad Sci 2003; 1009: 64–74PubMedCrossRefGoogle Scholar
  29. 29.
    Zomkowski AD, Hammes L, Lin J, et al. Agmatine produces antidepressant-like effects in two models of depression in mice. Neuroreport 2002; 13: 387–91PubMedCrossRefGoogle Scholar
  30. 30.
    Aricioglu F, Altunbas H. Is agmatine an endogenous anxiolytic/ antidepressant agent? Ann N Y Acad Sci 2003; 1009: 136–40PubMedCrossRefGoogle Scholar
  31. 31.
    Li Y, Gong Z, Cao J, et al. Antidepressant-like effect of agmatine and its possible mechanism. Eur J Pharmacol 2003; 469: 81–8PubMedCrossRefGoogle Scholar
  32. 32.
    Lavinsky D, Arteni N, Netto C. Agmatine induces anxiolysis in the elevated plus maze task in adult rats. Behav Brain Res 2003; 141: 19–24PubMedCrossRefGoogle Scholar
  33. 33.
    Stewart LS, McKay BE. Acquisition deficit and time-dependent retrograde amnesia for contextual fear conditioning in agmatine-treated rats. Behav Pharmacol 2000; 11: 93–7PubMedCrossRefGoogle Scholar
  34. 34.
    Uzbay IT, Yesilyurt O, Celik T, et al. Effects of agmatine on ethanol withdrawal syndrome in rats. Behav Brain Res 2000; 107: 153–9PubMedCrossRefGoogle Scholar
  35. 35.
    Aricioglu F, Means A, Regunathan S. Effect of agmatine on the development of morphine dependence in rats: potential role of cAMP system. Eur J Pharmacol 2004; 504: 191–7PubMedCrossRefGoogle Scholar
  36. 36.
    Wei X, Su R, Lu X, et al. Inhibition by agmatine on morphine-induced conditioned place preference in rats. Eur J Pharmacol 2005; 515: 99–106PubMedCrossRefGoogle Scholar
  37. 37.
    Fullerton CS, Ursano RJ, Wang L. Acute stress disorder, post-traumatic stress disorder, and depression in disaster or rescue workers. Am J Psychiatry 2004; 161: 1370–6PubMedCrossRefGoogle Scholar
  38. 38.
    Tabor CW, Tabor H. Polyamines. Annu Rev Biochem 1984; 53: 749–90PubMedCrossRefGoogle Scholar
  39. 39.
    Molderings G, Bruss M, Bonisch H, et al. Identification and pharmacological characterization of a specific agmatine transport system in human tumor cell lines. Ann N Y Acad Sci 2003; 1009: 75–81PubMedCrossRefGoogle Scholar
  40. 40.
    Mistry SK, Burwell TJ, Chambers RM, et al. Cloning of human agmatinase: an alternate path for polyamine synthesis induced in liver by hepatitis B virus. Am J Physiol Gastrointest Liver Physiol 2002; 282: G375–81PubMedGoogle Scholar
  41. 41.
    Iyer R, Kim H, Tsoa R, et al. Cloning and characterization of human agmatinase. Mol Genet Metab 2002; 75: 209–18PubMedCrossRefGoogle Scholar
  42. 42.
    Morris S. Recent advances in arginine metabolism. Curr Opin Clin Nutr Metab Care 2004; 7: 45–51PubMedCrossRefGoogle Scholar
  43. 43.
    Gorbatyuk OS, Milner TA, Wang G, et al. Localization of agmatine in vasopressin and oxytocin neurons of the rat hypothalamic paraventricular and supraoptic nuclei. Exp Neurol 2001; 171: 235–45PubMedCrossRefGoogle Scholar
  44. 44.
    Piletz JE, Chikkala DN, Ernsberger P. Comparison of the properties of agmatine and endogenous clonidine-displacing substance at imidazoline and alpha-2 adrenergic receptors. J Pharmacol Exp Ther 1995; 272: 581–7PubMedGoogle Scholar
  45. 45.
    Zheng J, Weng X, Gai X, et al. Mechanism underlying blockade of voltage-gated calcium channels by agmatine in cultured rat hippocampal neurons. Acta Pharmacol Sin 2004; 25: 281–5PubMedGoogle Scholar
  46. 46.
    Askalany A, Yamakura T, Petrenko A, et al. Effect of agmatine on heteromeric N-methyl-d-aspartate receptor channels. Neurosci Res 2005; 52: 387–92PubMedCrossRefGoogle Scholar
  47. 47.
    Loring RH. Agmatine acts as an antagonist of neuronal nicotinic receptors. Br J Pharmacol 1990; 99: 207–11PubMedCrossRefGoogle Scholar
  48. 48.
    Molderings GJ, Schmidt K, Bonisch H, et al. Inhibition of 5-HT3 receptor function by imidazolines in mouse neuroblastoma cells: potential involvement of sigma 2 binding sites. Naunyn Schmiedebergs Arch Pharmacol 1996; 354: 245–52PubMedCrossRefGoogle Scholar
  49. 49.
    Otake K, Ruggiero DA, Regunathan S, et al. Regional localization of agmatine in the rat brain: an immunocytochemical study. Brain Res 1998; 787: 1–14PubMedCrossRefGoogle Scholar
  50. 50.
    Sastre M, Regunathan S, Reis DJ. Uptake of agmatine into rat brain synaptosomes: possible role of cation channels. J Neurochem 1997; 69: 2421–6PubMedCrossRefGoogle Scholar
  51. 51.
    Molderings G, Heinen A, Menzel S, et al. Gastrointestinal uptake of agmatine: distribution in tissues and organs and pathophysiologic relevance. Ann N Y Acad Sci 2003; 1009: 44–51PubMedCrossRefGoogle Scholar
  52. 52.
    Sastre M, Regunathan S, Galea E, et al. Agmatinase activity in rat brain: a metabolic pathway for the degradation of agmatine. J Neurochem 1996; 67: 1761–5PubMedCrossRefGoogle Scholar
  53. 53.
    Auguet M, Viossat I, Marin JG, et al. Selective inhibition of inducible nitric oxide synthase by agmatine. Jpn J Pharmacol 1995; 69: 285–7PubMedCrossRefGoogle Scholar
  54. 54.
    Feng Y, LeBlanc MH, Regunathan S. Agmatine reduces extracellular glutamate during pentylenetetrazole-induced seizures in rat brain: a potential mechanism for the anticonvulsive effects. Neurosci Lett 2005; 390: 129–33PubMedCrossRefGoogle Scholar
  55. 55.
    Abe K, Abe Y, Saito H. Agmatine suppresses nitric oxide production in microglia. Brain Res 2000; 872: 141–8PubMedCrossRefGoogle Scholar
  56. 56.
    Abe K, Abe Y, Saito H. Agmatine induces glutamate release and cell death in cultured rat cerebellar granule neurons. Brain Res 2003; 990: 165–71PubMedCrossRefGoogle Scholar
  57. 57.
    Satriano J, Schwartz D, Ishizuka S, et al. Suppression of inducible nitric oxide generation by agmatine aldehyde: beneficial effects in sepsis. J Cell Physiol 2001; 188: 313–20PubMedCrossRefGoogle Scholar
  58. 58.
    Khoshnoodi MA, Motiei-Langroudi R, Tahsili-Fahadan P, et al. Involvement of nitric oxide system in enhancement of morphine-induced conditioned place preference by agmatine in male mice. Neurosci Lett 2006; 399(3): 234–9PubMedCrossRefGoogle Scholar
  59. 59.
    Roberts J, Grocholski B, Kitto K, et al. Pharmacodynamic and pharmacokinetic studies of agmatine after spinal administration in the mouse. J Pharmacol Exp Ther 2005; 314: 1226–33PubMedCrossRefGoogle Scholar
  60. 60.
    Feng Y, Halaris AE, Piletz JE. Determination of agmatine in brain and plasma using high-performance liquid chromatography with fluorescence detection [published erratum appears in J Chromatogr B Biomed Sci Appl 1997 Aug 15; 696 (1): 173]. J Chromatogr B Biomed Sci Appl 1997; 691(2): 277–82PubMedCrossRefGoogle Scholar
  61. 61.
    Zhang W, Kaye D. Simultaneous determination of arginine and seven metabolites in plasma by reversed-phase liquid chromatography with a time-controlled ortho-phthaldialdehyde precolumn derivatization. Anal Biochem 2004; 326: 87–92PubMedCrossRefGoogle Scholar
  62. 62.
    Zhao S, Wang B, Yuan H, et al. Determination of agmatine in biological samples by capillary electrophoresis with optical fiber light-emitting-diode-induced fluorescence detector. J Chromatogr A 2006; 1123: 138–41PubMedCrossRefGoogle Scholar
  63. 63.
    Dias Elpo Zomkowski A, Oscar Rosa A, Lin J, et al. Evidence for serotonin receptor subtypes involvement in agmatine antidepressant like-effect in the mouse forced swimming test. Brain Res 2004; 1023: 253–63PubMedCrossRefGoogle Scholar
  64. 64.
    Zomkowski A, Santos A, Rodrigues A. Evidence for the involvement of the opioid system in the agmatine antidepressant-like effect in the forced swimming test. Neurosci Lett 2005; 381: 279–83PubMedCrossRefGoogle Scholar
  65. 65.
    Gonzalez C, Regunathan S, Reis DJ, et al. Agmatine, an endogenous modulator of noradrenergic neurotransmission in the rat tail artery. Br J Pharmacol 1996; 119: 677–84PubMedCrossRefGoogle Scholar
  66. 66.
    Zhao D, Ren L. Non-adrenergic inhibition at prejunctional sites by agmatine of purinergic vasoconstriction in rabbit saphenous artery. Neuropharmacology 2005; 48: 597–606PubMedCrossRefGoogle Scholar
  67. 67.
    Wang H, Regunathan S, Youngson C, et al. An antibody to agmatine localizes the amine in bovine adrenal chromaffin cells. Neurosci Lett 1995; 183: 17–21PubMedCrossRefGoogle Scholar
  68. 68.
    Regunathan S, Youngson C, Raasch W, et al. Imidazoline receptors and agmatine in blood vessels: a novel system inhibiting vascular smooth muscle proliferation. J Pharmacol Exp Ther 1996; 276: 1272–82PubMedGoogle Scholar
  69. 69.
    Briaud S, Zhang BL, Sannajust F. Central actions of agmatine in conscious spontaneously hypertensive rats. Clin Exp Hypertens 2005; 27: 619–27PubMedCrossRefGoogle Scholar
  70. 70.
    Tahsili-Fahadan P, Yahyavi-Firouz-Abadi N, Khoshnoodi MA, et al. Agmatine potentiates morphine-induced conditioned place preference in mice: modulation by alpha(2)-adrenoceptors. Neuropsychopharmacology 2006; 31(8): 1722–32PubMedCrossRefGoogle Scholar
  71. 71.
    Sener A, Lebrun P, Blachier F, et al. Stimulus-secretion coupling of arginine-induced insulin release: insulinotropic action of agmatine. Biochem Pharmacol 1989; 38: 327–30PubMedCrossRefGoogle Scholar
  72. 72.
    Kalra SP, Pearson E, Sahu A, et al. Agmatine, a novel hypothalamic amine, stimulates pituitary luteinizing hormone release in vivo and hypothalamic luteinizing hormone-releasing hormone release in vitro. Neurosci Lett 1995; 194: 165–8PubMedCrossRefGoogle Scholar
  73. 73.
    Molderings GJ, Gothert M. Inhibitory presynaptic imidazoline receptors on sympathetic nerves in the rabbit aorta differ from I1- and I2-imidazoline binding sites. Naunyn Schmiedebergs Arch Pharmacol 1995; 351: 507–16PubMedGoogle Scholar
  74. 74.
    Regunathan S, Feinstein DL, Reis DJ. Anti-proliferative and anti-inflammatory actions of imidazoline agents: are imidazoline receptors involved? Ann N Y Acad Sci 1999; 881: 410–9PubMedCrossRefGoogle Scholar
  75. 75.
    Gilad VH, Rabey JM, Kimiagar Y, et al. The polyamine stress response: tissue-, endocrine-, and developmental-dependent regulation. Biochem Pharmacol 2001; 61: 207–13PubMedCrossRefGoogle Scholar
  76. 76.
    Gilad GM, Gilad VH. Overview of the brain polyamine-stress-response: regulation, development, and modulation by lithium and role in cell survival. Cell Mol Neurobiol 2003; 23: 637–49PubMedCrossRefGoogle Scholar
  77. 77.
    Gilad GM, Gilad VH. Brain polyamine stress response: recurrence after repetitive Stressor and inhibition by lithium. J Neurochem 1996; 67: 1992–6PubMedCrossRefGoogle Scholar
  78. 78.
    Elgun S, Kumbasar H. Increased serum arginase activity in depressed patients. Prog Neuropsychopharmacol Biol Psychiatry 2000; 24: 227–32PubMedCrossRefGoogle Scholar
  79. 79.
    Halaris A, Zhu H, Feng Y, et al. Plasma agmatine and platelet imidazoline receptors in depression. Ann N Y Acad Sci 1999; 881: 445–51PubMedCrossRefGoogle Scholar
  80. 80.
    Sastre M, Galea E, Feinstein D, et al. Metabolism of agmatine in macrophages: modulation by lipopolysaccharide and inhibitory cytokines. Biochem J 1998; 330: 1405–9PubMedGoogle Scholar
  81. 81.
    Gilad GM, Gilad VH, Rabey JM. Arginine and ornithine decar-boxylation in rodent brain: coincidental changes during development and after ischemia. Neurosci Lett 1996; 216: 33–6PubMedCrossRefGoogle Scholar
  82. 82.
    Feng Y, Piletz JE, Leblanc MH. Agmatine suppresses nitric oxide production and attenuates hypoxic-ischemic brain injury in neonatal rats. Pediatr Res 2002; 52: 606–11PubMedCrossRefGoogle Scholar
  83. 83.
    Fairbanks C, Kaminski L, Nguyen H, et al. Pre-treatment with antisera raised against agmatine sensitizes mice to plasticity-mediated events [abstract]. Soc Neurosci Abstr 2001; 27: 465Google Scholar
  84. 84.
    Aricioglu-Kartei F, Reis D, Regunathan S. Agmatine and morphine tolerance/dependance: molecular mechanisms of interactions [abstract]. Soc Neurosci Abstr 2001; 27: 685Google Scholar
  85. 85.
    Gilad GM, Salame K, Rabey JM, et al. Agmatine treatment is neuroprotective in rodent brain injury models. Life Sci 1996; 58: 41–6Google Scholar
  86. 86.
    Gilad GM, Gilad VH. Accelerated functional recovery and neuroprotection by agmatine after spinal cord ischemia in rats. Neurosci Lett 2000; 296: 97–100PubMedCrossRefGoogle Scholar
  87. 87.
    Fairbanks CA, Schreiber KL, Brewer KL, et al. Agmatine reverses pain induced by inflammation, neuropathy, and spinal cord injury. Proc Natl Acad Sci U S A 2000; 97: 10584–9PubMedCrossRefGoogle Scholar
  88. 88.
    Onal A, Delen Y, Ulker S, et al. Agmatine attenuates neuropathic pain in rats: possible mediation of nitric oxide and noradren-ergic activity in the brainstem and cerebellum. Life Sci 2003; 73: 413–28PubMedCrossRefGoogle Scholar
  89. 89.
    Aricioglu F, Korcegez E, Bozkurt A, et al. Effect of agmatine on acute and mononeuropathic pain. Ann N Y Acad Sci 2003; 1009: 106–15PubMedCrossRefGoogle Scholar
  90. 90.
    Kolesnikov Y, Jain S, Pasternak GW. Modulation of opioid analgesia by agmatine. Eur J Pharmacol 1996; 296: 17–22PubMedCrossRefGoogle Scholar
  91. 91.
    Li J, Li X, Pei G, et al. Effects of agmatine on tolerance to and substance dependence on morphine in mice. Chung Kuo Yao Li Hsueh Pao 1999; 20: 232–8PubMedGoogle Scholar
  92. 92.
    Aricioglu-Kartal F, Uzbay IT. Inhibitory effect of agmatine on naloxone-precipitated abstinence syndrome in morphine dependent rats. Life Sci 1997; 61: 1775–81PubMedCrossRefGoogle Scholar
  93. 93.
    McKay B, Lado W, Martin L, et al. Learning and memory in agmatine-treated rats. Pharmacol Biochem Behav 2002; 72: 551–7PubMedCrossRefGoogle Scholar
  94. 94.
    McKay B, Persinger M. Combined effects of complex magnetic fields and agmatine for contextual fear learning deficits in rats. Life Sci 2003; 72: 2489–98PubMedCrossRefGoogle Scholar
  95. 95.
    Porsolt RD, Anton G, Blavet N, et al. Behavioural despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol 1978; 47: 379–91PubMedCrossRefGoogle Scholar
  96. 96.
    Porsolt RD, Deniel M, Jalfre M. Forced swimming in rats: hypothermia, immobility and the effects of imipramine. Eur J Pharmacol 1979; 57: 431–6PubMedCrossRefGoogle Scholar
  97. 97.
    Gilad GM, Gilad VH, Eliyayev Y, et al. Developmental regulation of the brain polyamine-stress-response. Int J Dev Neurosci 1998; 16: 271–8PubMedCrossRefGoogle Scholar
  98. 98.
    Huang M, Regunathan S, Botta M, et al. Structure-activity analysis of guanidine group in agmatine for brain agmatinase. Ann N Y Acad Sci 2003; 1009: 52–63PubMedCrossRefGoogle Scholar
  99. 99.
    Piletz J, Huang M, Lee K, inventors. Jackson State University, assignee. Mammalian agmatinase inhibitory substance. US patent application 20050220707; 2004 Apr 5Google Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  1. 1.Department of Psychiatry and Behavioral Neurosciences, Loyola University Stritch School of MedicineLoyola University Chicago, Loyola University Medical CenterMaywoodUSA

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