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.
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References
Li G, Regunathan S, Barrow CJ, et al. Agmatine: an endogenous clonidine-displacing substance in the brain. Science 1994; 263: 966–9
Satriano J. Arginine pathways and the inflammatory response: interregulation of nitric oxide and polyamines: review article. Amino Acids 2004; 26: 321–9
Zhu M, Iyo A, Piletz J, et al. Expression of human arginine decarboxylase, the biosynthetic enzyme for agmatine. Biochim Biophys Acta 2004; 1670: 156–64
Reis DJ, Regunathan S. Is agmatine a novel neurotransmitter in brain? Trends Pharmacol Sci 2000; 21: 187–93
Coleman CS, Hu G, Pegg AE. Putrescine biosynthesis in mammalian tissues. Biochem J 2004; 379: 849–55
Iyo AH, Zhu MY, Ordway GA, et al. Expression of arginine decarboxylase in brain regions and neuronal cells. J Neurochem 2006; 96: 1042–50
Goracke-Postle CJ, Nguyen HO, Stone LS, et al. Release of tritiated agmatine from spinal synaptosomes. Neuroreport 2006; 17: 13–7
Reis DJ, Yang XC, Milner TA. Agmatine containing axon terminals in rat hippocampus form synapses on pyramidal cells. Neurosci Lett 1998; 250: 185–8
Su R, Wei X, Zheng J, et al. Anticonvulsive effect of agmatine in mice. Pharmacol Biochem Behav 2004; 77: 345–9
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: 33–40
Zhu MY, Wang WP, Bissette G. Neuroprotective effects of agmatine against cell damage caused by glucocorticoids in cultured rat hippocampal neurons. Neuroscience 2006; 1414) 2019–27
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: 713–9
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: 210–6
Halaris A, Piletz J. Relevance of imidazoline receptors and agmatine to psychiatry: a decade of progress. Ann N Y Acad Sci 2003; 1009: 1–20
Aricioglu F, Regunathan S. Agmatine attenuates stress- and lipopolysaccharide-induced fever in rats. Physiol Behav 2005; 85: 370–5
Reis DJ, Piletz JE. The imidazoline receptor in control of blood pressure by clonidine and allied drugs. Am J Physiol 1997; 273: R1569–71
Eglen RM, Hudson AL, Kendall DA, et al. ‘Seeing through a glass darkly’: casting light on imidazoline ‘I’ sites. Trends Pharmacol Sci 1998; 19: 381–90
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: 663–72
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: 295–313
Aricioglu F, Regunathan S, Piletz J. Is agmatine an endogenous factor against stress?Ann N Y Acad Sci 2003; 1009: 127–32
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): 1079-87
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): 21–8
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: 1317–26
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: 544–9
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: 247–9
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: 24–9
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: 20–9
Piletz J, May P, Wang G, et al. Agmatine crosses the blood-brain barrier. Ann N Y Acad Sci 2003; 1009: 64–74
Zomkowski AD, Hammes L, Lin J, et al. Agmatine produces antidepressant-like effects in two models of depression in mice. Neuroreport 2002; 13: 387–91
Aricioglu F, Altunbas H. Is agmatine an endogenous anxiolytic/ antidepressant agent? Ann N Y Acad Sci 2003; 1009: 136–40
Li Y, Gong Z, Cao J, et al. Antidepressant-like effect of agmatine and its possible mechanism. Eur J Pharmacol 2003; 469: 81–8
Lavinsky D, Arteni N, Netto C. Agmatine induces anxiolysis in the elevated plus maze task in adult rats. Behav Brain Res 2003; 141: 19–24
Stewart LS, McKay BE. Acquisition deficit and time-dependent retrograde amnesia for contextual fear conditioning in agmatine-treated rats. Behav Pharmacol 2000; 11: 93–7
Uzbay IT, Yesilyurt O, Celik T, et al. Effects of agmatine on ethanol withdrawal syndrome in rats. Behav Brain Res 2000; 107: 153–9
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: 191–7
Wei X, Su R, Lu X, et al. Inhibition by agmatine on morphine-induced conditioned place preference in rats. Eur J Pharmacol 2005; 515: 99–106
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: 1370–6
Tabor CW, Tabor H. Polyamines. Annu Rev Biochem 1984; 53: 749–90
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: 75–81
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: G375–81
Iyer R, Kim H, Tsoa R, et al. Cloning and characterization of human agmatinase. Mol Genet Metab 2002; 75: 209–18
Morris S. Recent advances in arginine metabolism. Curr Opin Clin Nutr Metab Care 2004; 7: 45–51
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: 235–45
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: 581–7
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: 281–5
Askalany A, Yamakura T, Petrenko A, et al. Effect of agmatine on heteromeric N-methyl-d-aspartate receptor channels. Neurosci Res 2005; 52: 387–92
Loring RH. Agmatine acts as an antagonist of neuronal nicotinic receptors. Br J Pharmacol 1990; 99: 207–11
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: 245–52
Otake K, Ruggiero DA, Regunathan S, et al. Regional localization of agmatine in the rat brain: an immunocytochemical study. Brain Res 1998; 787: 1–14
Sastre M, Regunathan S, Reis DJ. Uptake of agmatine into rat brain synaptosomes: possible role of cation channels. J Neurochem 1997; 69: 2421–6
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: 44–51
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: 1761–5
Auguet M, Viossat I, Marin JG, et al. Selective inhibition of inducible nitric oxide synthase by agmatine. Jpn J Pharmacol 1995; 69: 285–7
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: 129–33
Abe K, Abe Y, Saito H. Agmatine suppresses nitric oxide production in microglia. Brain Res 2000; 872: 141–8
Abe K, Abe Y, Saito H. Agmatine induces glutamate release and cell death in cultured rat cerebellar granule neurons. Brain Res 2003; 990: 165–71
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: 313–20
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): 234–9
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: 1226–33
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): 277–82
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: 87–92
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: 138–41
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: 253–63
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: 279–83
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: 677–84
Zhao D, Ren L. Non-adrenergic inhibition at prejunctional sites by agmatine of purinergic vasoconstriction in rabbit saphenous artery. Neuropharmacology 2005; 48: 597–606
Wang H, Regunathan S, Youngson C, et al. An antibody to agmatine localizes the amine in bovine adrenal chromaffin cells. Neurosci Lett 1995; 183: 17–21
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: 1272–82
Briaud S, Zhang BL, Sannajust F. Central actions of agmatine in conscious spontaneously hypertensive rats. Clin Exp Hypertens 2005; 27: 619–27
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): 1722–32
Sener A, Lebrun P, Blachier F, et al. Stimulus-secretion coupling of arginine-induced insulin release: insulinotropic action of agmatine. Biochem Pharmacol 1989; 38: 327–30
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: 165–8
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: 507–16
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: 410–9
Gilad VH, Rabey JM, Kimiagar Y, et al. The polyamine stress response: tissue-, endocrine-, and developmental-dependent regulation. Biochem Pharmacol 2001; 61: 207–13
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: 637–49
Gilad GM, Gilad VH. Brain polyamine stress response: recurrence after repetitive Stressor and inhibition by lithium. J Neurochem 1996; 67: 1992–6
Elgun S, Kumbasar H. Increased serum arginase activity in depressed patients. Prog Neuropsychopharmacol Biol Psychiatry 2000; 24: 227–32
Halaris A, Zhu H, Feng Y, et al. Plasma agmatine and platelet imidazoline receptors in depression. Ann N Y Acad Sci 1999; 881: 445–51
Sastre M, Galea E, Feinstein D, et al. Metabolism of agmatine in macrophages: modulation by lipopolysaccharide and inhibitory cytokines. Biochem J 1998; 330: 1405–9
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: 33–6
Feng Y, Piletz JE, Leblanc MH. Agmatine suppresses nitric oxide production and attenuates hypoxic-ischemic brain injury in neonatal rats. Pediatr Res 2002; 52: 606–11
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: 465
Aricioglu-Kartei F, Reis D, Regunathan S. Agmatine and morphine tolerance/dependance: molecular mechanisms of interactions [abstract]. Soc Neurosci Abstr 2001; 27: 685
Gilad GM, Salame K, Rabey JM, et al. Agmatine treatment is neuroprotective in rodent brain injury models. Life Sci 1996; 58: 41–6
Gilad GM, Gilad VH. Accelerated functional recovery and neuroprotection by agmatine after spinal cord ischemia in rats. Neurosci Lett 2000; 296: 97–100
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: 10584–9
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: 413–28
Aricioglu F, Korcegez E, Bozkurt A, et al. Effect of agmatine on acute and mononeuropathic pain. Ann N Y Acad Sci 2003; 1009: 106–15
Kolesnikov Y, Jain S, Pasternak GW. Modulation of opioid analgesia by agmatine. Eur J Pharmacol 1996; 296: 17–22
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: 232–8
Aricioglu-Kartal F, Uzbay IT. Inhibitory effect of agmatine on naloxone-precipitated abstinence syndrome in morphine dependent rats. Life Sci 1997; 61: 1775–81
McKay B, Lado W, Martin L, et al. Learning and memory in agmatine-treated rats. Pharmacol Biochem Behav 2002; 72: 551–7
McKay B, Persinger M. Combined effects of complex magnetic fields and agmatine for contextual fear learning deficits in rats. Life Sci 2003; 72: 2489–98
Porsolt RD, Anton G, Blavet N, et al. Behavioural despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol 1978; 47: 379–91
Porsolt RD, Deniel M, Jalfre M. Forced swimming in rats: hypothermia, immobility and the effects of imipramine. Eur J Pharmacol 1979; 57: 431–6
Gilad GM, Gilad VH, Eliyayev Y, et al. Developmental regulation of the brain polyamine-stress-response. Int J Dev Neurosci 1998; 16: 271–8
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: 52–63
Piletz J, Huang M, Lee K, inventors. Jackson State University, assignee. Mammalian agmatinase inhibitory substance. US patent application 20050220707; 2004 Apr 5
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.
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Halaris, A., Plietz, J. Agmatine. CNS Drugs 21, 885–900 (2007). https://doi.org/10.2165/00023210-200721110-00002
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DOI: https://doi.org/10.2165/00023210-200721110-00002