Neuroprotective Effect of Agmatine in Ischemic Vascular Events

Main Article Content

Lisbeth Miranda-Mosqueda Stacy Ruiz-Oropeza Claudia Gomez-Acevedo

Abstract

Ischemic cerebrovascular diseases are leading cause of mortality and disability worldwide. Given the need for a pharmacological treatment for these diseases, agmatine has gained great interest due to its neuroprotective properties.


This article explores these properties of agmatine in ischemic events and their underlying mechanisms. Agmatine, considered as a neuromodulator, exerts its effects through its interaction with various molecular targets, including glutamate receptors, nitric oxide synthase, and metalloproteinases. Its ability to cross the blood-brain barrier and its role in neurotransmission processes postulate agmatine as a potential candidate for neuroprotection. Agmatine has a positive effect in the central nervous system to counteract excitotoxicity, oxidative stress, inflammation, alteration of the blood-brain barrier and energy disorders during ischemic events. This review describes the multiple interactions of agmatine within the ischemic cascade known to date, showing its ability to mitigate free radical formation, attenuate excitotoxicity, modulate inflammatory responses, stabilize the blood-brain barrier, and preserve mitochondrial function.


These properties position agmatine as a promising therapeutic agent for ischemic cerebrovascular diseases.

Keywords: agmatine, neuroprotection, ischemic events, blood-brain barrier, excitotoxicity, oxidative stress, inflammation, mitochondrial function

Article Details

How to Cite
MIRANDA-MOSQUEDA, Lisbeth; RUIZ-OROPEZA, Stacy; GOMEZ-ACEVEDO, Claudia. Neuroprotective Effect of Agmatine in Ischemic Vascular Events. Medical Research Archives, [S.l.], v. 12, n. 1, jan. 2024. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/4928>. Date accessed: 03 mar. 2024. doi: https://doi.org/10.18103/mra.v12i1.4928.
Section
Review Articles

References

1. Halaris A, Plietz J. Agmatine: Metabolic pathway and spectrum of activity in the brain. CNS Drugs. 2007;21(11):885-900. DOI: 10.2165/00023210-200721110-00002
2. Haenisch B, Kügelgen I, Bönisch H, Göthert, Sauerbruch T, Schepke M, Marklein G, Höfling K, Schröder D, Molderings GJ. Regulatory mechanisms underlying agmatine homeostasis in humans. Am J Physiol Gastrointest Liver Physiol. 2008;295:G1104-G1110. DOI: 10.1152/ajpgi.90374.2008
3. Piletz JE, Aricioglu F, Cheng JT, Fairbanks CA, Gilad VH. Agmatine: Clinical applications after 100 years in translation. Drug Discov Today. 2013;18:880-93. DOI: 10.1016/j.drudis.2013.05.017
4. Bergin DH, Jing Y, Williams G, Mockett BG. Safety and neurochemical profiles of acute and sub chronic oral treatment with agmatine sulfate. Sci Rep. 2019;9(1):12669. DOI: 10.1038/s41598-019-49078-0
5. Molderings G, Bruss M, Bonisch H. Identification and pharmacological characterization of a specific agmatine transport system in human tumor cell lines. Ann NY Acad Sci. 2003;1009:75- 81. DOI: 10.1196/annals.1304.008
6. Rosenberg ML, Tohidi V, Sherwoowd K, Gayen S. Evidence for dietary agmatine sulfate effectiveness in neuropathies associated with painful small fiber neuropathy. A pilot open-label consecutive case series study. Nutrients. 2020;12(2):576. DOI: 10.3390/nu12020576
7. Li G, Regunathan S, Barrow CJ, Eshraghi J, Cooper R, Reis DJ. Agmatine: an endogenous clonidine-displacing substance in the brain. Science. 1994;263:966-969.DOI: 10.1126/science.7906055
8. Demady DR, Jianmongkol S, Vuletich JL, Bender AT, Osawa Y. Agmatine enhances the NADPH oxidase activity of neuronal NO synthase and leads to oxidative inactivation of the enzyme. Mol Pharmacol.2001;59:24-29. DOI: 10.1124/mol.59.1.24
9. Gibson DA, Harris BR, Rogers DT, Littleton JM. Radioligand binding studies reveal agmatine is a more selective antagonist for a polyamine-site on the NMDA receptor than arcaine or ifenprodil. Brain Res. 2002; 952:71-77. DOI: 10.1016/s0006-8993(02)03198-0
10. Wade CL, Eskridge LL, Nguyen HOX, Kitto KF, Stone LS, Wilcox G, Fairbanks CA Immunoneutralization of agmatine sensitizes mice to μ-opioid receptor tolerance. J Pharmacol Exp Ther. 2009; 331:539-546. DOI: 10.1124/jpet.109.155424
11. Ahn SS, Kim SH, Lee JE, Ahn KJ. Effects of agmatine on blood-brain-barrier stabilization assessed by permeability MRI in a rat model of transient cerebral ischemia. Am J Neuroradiol. 2015;36:283-8. Doi:10.3174/ajnr.A4113
12. Kim H, Kim MM. Effect of agmatine sulfate on modulation of matrix metalloproteinases via P13K/Akt-1 in HT1080 cells. Anticancer Res 2017;37(11):6303-09.
Doi: 10.21873/anticanres.12081
13. 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. DOI: 10.1203/00006450-200210000-00023
14. Condello S, Curro M, Ferlazzo N, Caccamo D, Satriano J, Ientile R. Agmatine effects on mitocondrial membrane potential and NF-kappaB activation protect against rotenone-induced cell damage in human neuronal-like SH-SY5Y cells. J Neurochem. 2011;116:67-75. DOI: 10.1111/j.1471-4159.2010.07085.x
15. Hong S, Lee JE, Kim CY, Seong GJ. Agmatine protects retinal ganglion cells from hypoxia induced apoptosis in transformed rat retinal ganglion cell line. BMC Neurosci. 2007;8:81-8. DOI: 10.1186/1471-2202-8-81
16. Fairbanks CA, Schreiber KL, Brewer KL, Yu CG. Agmatine reverses pain induced by inflammation, neuoropathy and spinal cord injury. Proc Natl Acad Sci USA. 2000;97:10584-89. DOI: 10.1073/pnas.97.19.10584
17. Arndt MA, Battaglia V, Parisi E, Lortie MJ, Isome M, Baskerville C. The arginine metabolite agmatine protects mitochondrial function and confers resistance to cellular apoptosis. Am J Physiol Cell Physiol. 2009;296(6):C141119.
Doi: 10.1152/ajpcell.00529.2008
18. Raasch W, Schäfer U, Chun J, Dominiak P. Biological significance of agmatine, an endogenous ligand at imidazoline binding sites. Br J Pharmacol. 2001;133(6):755-80. DOI: 10.1038/sj.bjp.0704153
19. Regunathan S, Piletz JE. Regulation of inducible nitric oxide synthase and agmatine synthesis in macrophages and astrocytes. Ann NY Acad Sci. 2003;1009:20-29. Doi: 10.1196/annals.1304.002
20. Yang XC, Reis DJ. Agmatine selectively blocks the N-methyl-D-aspartate subclass of glutamate receptor channels in rat hippocampal neurons. J Phamacol Exp Ther. 1999;288:544-9. PMID: 9918557
21. Yang MZ, Mun Ch, Choi YJ, Baik JH. Agmatine inhibits matrix metalloproteinase-9 via endotelial nitric oxide synthase in cerebral endothelial cells. Neurol Res.2007; 29(7):749-54. DOI: 10.1179/016164107X208103
22. Neis VB, Rosa PB, Olescowicz G, Rodrigues ALS. Therapeutic potential of agmatine for CNS disorders. Neurochem International. 2017;108:318-31. DOI: 10.1016/j.neuint.2017.05.006
23. Kosonen R, Barua S, Kim JY, Lee JE. Role of agmatine in the application of neural progenitor cell in central nervous system diseases: therapeutic potentials and effects. Anat Cell Biol 2021;54:143-51. DOI:10.5115/acb.21.089
24. Piletz JE, May PJ, Wang G (2003) Agmatine crosses the blood-brain barrier. Ann NY Acad Sci .2003;1009:64–74. DOI: 10.1196/annals.1304.007
25. Watts D, Pfaffenseller B, Wollenhaupt-Aguiar B, Paul Géa L, Cardoso TA, Kapczinski F. Agmatine as a potential therapeutic intervention in bipolar depression: the preclinical landscape. Expert Opin Ther Targets. 2019; 23(4):327-39. DOI: 10.1080/14728222.2019.1581764
26. Zhu M, Iyo A, Piletz J. Expression of human arginine descarboxylase, the biosynthetic enzyme for agmatine. Biochim Biophys Acta. 2004;1670:156-64.
Doi: 10.1016/j.bbagen.2003.11.006
27. Otake K, Ruggiero DA, Regunathan S. Regional localization of agmatine in the rat brain: an immunocytochemical study. Brain Res. 1998;787:1-14. DOI: 10.1016/s0006-8993(97)01200-6
28. Sastre M, Regunathan S, Reis DJ. Uptake of agmatine into rat brain synaptosomes: possible role of cation channels. J Neurochem. 1997;69:2421-6. DOI: 10.1046/j.1471-4159.1997.69062421.x
29. Reis DJ, Yang XC, Milner TA. Agmatine containing axon terminals in rat hippocampus from synapses on pyramidal cells. Neurosci Lett. 1998;250:185-8. DOI: 10.1016/s0304-3940(98)00466-2
30. Gorbatyuk OS, Milner TA, Wang G, Regunathan S, Reis DJ. Localization of agmatine in vasopressin and oxytocin neurons of the rat hypothalamic paraventricular and supraoptic nuclei. Exp Neurol. 2001;171(2):235- 45, DOI: 10.1006/exnr.2001.7746
31. Goracke-Postle CJ, Nguyen HO, Stone LS. Release of tritiated agmatine from spinal synaptosomes. Neuroreport. 2006;17:13-7. Doi: 10.1097/01.wnr.0000192739.38653.aa
32. Sastre M, Regunathan S, Galea E. Agmatinase activity in rat brain: a metabolic pathway for the degradation of agmatine. J Neurochem. 1996; 67:1761-5- DOI: 10.1046/j.1471-4159.1996.67041761.x
33. 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. PMID: 7853171
34. Gonzalez C, Regunathan S, Reis DJ. Agmatine, an endogenous modulator of noradrenergic neurotransmission in the rat tail artery. Br J Pharmacol. 1996;119:677-84. DOI: 10.1111/j.1476-5381.1996.tb15726.x
35. Zhao D, Ren L. Non-adrenergic inhibition at prejunctional sites by agmatine of purinergic vasoconstriction in rabbit saphenous artery. Neuropharmacology. 2005;48:597-606. DOI: 10.1016/j.neuropharm.2004.12.004
36. Zheng J, Weng X, Gai X. Mechanism underlying blockade of voltage-gated calcium channels by agmatine in cultured rat hippocampal neurons. Acta Pharmacol Sin. 2004; 25:281-5. PMID: 15000878
37. Keynan O, Mirovsky Y, Dekel S, Gilad VH, Gilad GM. Safety and efficacy of dietary agmatine sulfate in lumbar disc-associated radiculopathy. AN open-label, dose-escalating study followed by a randomized, double-blind, placebo-controlled trial. Pain Med. 2010;11(3):356-68. DOI: 10.1111/j.1526-4637.2010.00808.x
38. Shopsin B. The clinical antidepressant effect of exogenous agmatine is not reversed by parachlorphenyalanine: a pilot study. Acta Neuropsychiatr 2013;25(2):113-8. DOI: 10.1111/j.1601-5215.2012.00675.x
39. Uzbay T, Goktalay G, Kayir H, Eker SS. Increased plasma agmatine levels in patients with schizophrenia. J Psychiatr Res. 2013;47(8):1054-60.
Doi: 10.1016/j.jpsychires.2013.04.004
40. Cunha AS, Matheus FC, Moretti M, Sampaio TB. Agmatine attenuates reserpine-induced oral dyskinesia in mice: Role of oxidative stress, nitric oxide and glutamate NMDA receptors. Behav Brain Res. 2016; 312:64-76. DOI: 10.1016/j.bbr.2016.06.014
41. Bergin DH, Liu P. Agmatine protects against β-amyloid 25-35-induced memory impairments in the rat. Neurosci. 2010;169(2):794-811. DOI: 10.1016/j.neuroscience.2010.05.004
42. Dixit MP, Rahmatkar SN, Raut P, Umekar MJ, Taksande BG, Kotagale NR. Evidences for agmatine alterations in Aβ1-42 induced memory impairment in mice. Neurosci Lett. 2021;1:740:135447
Doi: 10.1016/j.neulet.2020.135447
43. Borikar SP, Dongare SI, Danao KR. Reversal of lipopolysaccharide-induced learning and memory deficits by agmatine in mice. Int J Neurosci.2022;132(6):621-32. Doi: 10.1080/00207454.2020.1830086
44. Gilad GM, Salame K, Rabey JM, Gilad VH. Agmatine treatment is neuroprotective in rodent brain injury models. Life Sci. 1996; 58(2):41-46. DOI: 10.1016/0024-3205(95)02274-0
45. Gilad GM, Gilad VH. Accelerated functional recovery and neuroprotection by agmatine after spinal cord ischemia in rats. Neurosci Lett. 2000; 296:97-100. DOI: 10.1016/s0304-3940(00)01625-6
46. Mun CH, Lee WT, Park KA, Lee JE. Regulation of endothelial nitric oxide synthase by agmatine after transient global cerebral ischemia in rat brain. Anat Cell Biol. 2010;43(3):230-40. DOI: 10.5115/acb.2010.43.3.230
47. Barua S, Kim JY, Kim JH, Lee JE. Therapeutic effect of agmatine on neurological disease: Focus on ion channels and receptors. Neurochem Res. 2019; 44(4):735-50. DOI: 10.1007/s11064-018-02712-1
48. Milosevic K, Stevanovic I, Bozic ID, Milosevic A. Agmatine mitigates inflammation-related oxidative stress in BV-2 cells by inducing a pre-adaptative response. Int J Mol Sci. 2022; 23:3561. DOI: 10.3390/ijms23073561
49. Salas ML, Molina CMD, Sancho ST. Pathophysiology of the ischemic cascade and its influence on cerebral ischemia]. Revista Medica Sinergia. 2020;5(8):e555. DOI: 10.31434/rms.v5i8.555
50. Camacho A, Massieu L. Role of glutamate transporters in the clearance and release of glutamate during ischemia and its relation to neural death. Arch Med Res. 2006; 37(1):11-18. DOI: 10.1016/j.arcmed.2005.05.014
51. Weilinger NL, Maslieieva V, Bialecki J, Sridharan SS, Tang PL, Thompson RJ. Ionotropic receptors and ion channels in ischemic neuronal death and dysfunction. 2013; 34(1):39-48.
Doi: 10.1038/aps.2012.95
52. Brassai A, Suvanjeiev RG, Bán EG, Lakatos M. Role of synaptic and non-synaptic glutamate receptors in ischaemia induced neurotoxicity. Brain Res Bul. 2015;112:1-6. Doi: 10.1016/j.brainresbull.2014.12.007
53. Thompson BJ, Ronaldson PT. Drug delivery to the ischemic brain. Adv Pharmacol. 2014; 71:165- 202.
Doi: 10.1016/bs.apha.2014.06.013
54. 5Ahn SK, Hong S, Park YM, Lee WT, Park KA, Lee JE. Effects of agmatine on hypoxic microglia and activity of nitric oxide synthase. Brain Res. 2011; 373:48-54. DOI: 10.1016/j.brainres.2010.12.002
55. Kitagawa K, Matsumoto M, Tagaya M, Hata R, Ueda H, Ninobe M, Handa N, Fukunaga R, Kimura K, Mikoshiba K, Kamada T. Ischemic tolerance phenomenon found in the brain. Brain Res.1990; 528:21-4. Doi: 10.1016/0006-8993(90)90189-I
56. Kim JH, Kim JY, Jung JY, Lee YW, Lee WT, Huh SK, Lee JE. Endogenous agmatine induced by ischemic preconditioning regulates ischemic tolerance following cerebral ischemia. Exp Neurobiol. 2017;26(6):380-9. DOI: 10.5607/en.2017.26.6.380
57. Kotagale NR, Taksande BG, Inamdar NN. Neuroprotective offerings by agmatine. Neurotoxicology. 2019; 73:2228-45. DOI: 10.1016/j.neuro.2019.05.001
58. Wang WP, Iyo AH, Miguel-Hidalgo J, Regunathan S, Zhu MY. Agmatine protects against cell damage induced by NMDA and glutamate in cultured hippocampal neurons. Brain Res. 2006; 1084: 210-6. DOI: 10.1016/j.brainres.2006.02.024
59. Cuenca-López MD, Brea D, Segura T, Galindo MF, Antón-Martínez D, Aguila J, Castillo J, Jordán J. La inflamación como agente terapéutico en el infarto cerebral: respuesta inflamatoria celular y mediadores inflamatorios. Rev Neurol. 2010;50(06):349-359. DOI: 10.33588/rn.5006.2009666
60. Shichita T, Ito M, Yoshimira A. Post-ischemic inflammation regulates neural damage and protection. Front Cell Neurosci. 2014;8:319-7. Doi: 10.3389/fncel.2014.00319
61. Lee WT, Hong S, Yoon SH, Kim JH, Park KA, Seong GJ, Lee JE. Neuroprotective effects of agmatine on oxygen-glucose deprived primary-cultured astrocytes and nuclear translocation of nuclear factor-kappa B. Brain Res. 2009;1281:64-70.
Doi: 10.1016/j.brainres.2009.05.046
62. Kim JM, Lee JE, Cheon SY, Lee JH, Kim SY, Kam EH, Koo BN. The anti-inflammatory effects of agmatine on transient focal cerebral ischemia in diabetic rats. J Neurosurg Anesthesiol. 2016; 28(3):203-13.
Doi: 10.1097/ANA.0000000000000195
63. Cui H, Lee JH, Kim JY, Koo BN, Lee JE. The neuroprotective effect of agmatine after focal cerebral ischemia in diabetic rats. J Neurosurg Anesthesiol. 2012;24(1), 39-50. DOI:10.1097/ANA.0b013e318235af18
64. Turan I, Ozacmak HS, Ozacmak VH, Barut F, Arasli M. Agmatine attenuates intestinal ischemia and reperfusion injury by reducing oxidative stress and inflammatory reaction in rats. Life Sci. 2017; 89:23-8. Doi: 10.1016/j.lfs.2017.08.032
65. Kim J, Sim AY, Barua S, Kim JY, Lee JE. Agmatine-IRF2BP22 interaction induces M2 phenotype of microglia by increasing IRF2-KLF4 signaling. Inflamm Res. 2023; 72(6):1203-1213.DOI: 10.1007/s00011-023-01741-z
66. Yang C, Hawkins KE, Doré S, Candelario-Jalil E. Neuroinflammatory mechanisms of blood brain barrier damage in ischemic stroke. Am J Physiol Cell Physiol. 2018;316:C135-C153. DOI: 10.1152/ajpcell.00136.2018
67. Jiang X, Andjelkovic AV, Zhu L, Yang T, Bennett MVL, Chen J, Keep RF, Shi Y. Blood-brain barrier dysfunction and recovery after ischemic stroke. Prog Neurobiol. 2018;163-164, 144–171. DOI: 10.1016/j.pneurobio.2017.10.001
68. Jung HJ, Yang MZ, Kwon KH, Yenari MA, Choi YJ, Lee WT, Park KA, Lee JE. Endogenous agmatine inhibits cerebral vascular matrix metalloproteinases expression by regulating activating transcription factor 3 and endothelial nitric oxide synthesis. Curr Neurovasc Res. 2010; 7(3):201-12. DOI: 10.2174/156720210792231804. PMID: 20560878.
69. Kim JH, Lee YW, Park KA, Lee WT, Lee JE. Agmatine attenuates brain edema through reducing the expression of aquaporin-1 after cerebral ischemia. J Cerebral Blood Flow & Metab. 2010; 30:943-49, Doi:10.1038/jcbfm.2009.260
70. Wang CC, Chio CC, Chang CH, Kuo JR, Chang CP. Beneficial effect of agmatine on brain apoptosis, astrogliosis and edema after rat transient cerebral ischemia. BMC Pharmacology. 2010;10:11-6. Doi: 10.1186/1471-2210-10-11
71. Battaglia V, Grancara S, Satriano J, Saccoccio S, Agostinelli E, Toninello A. Agmatine prevents the Ca2+-dependent induction of permeability transition in rat brain mitochondria. AminoAcids. 2010; 38:431-7. DOI: 10.1007/s00726-009-0402-0
72. Iadecola C (1999) Mechanisms of cerebral ischemic damage. In: Wlz W. (eds) Cerebral ischemia. Contemporary Neuroscience. Human Press, Totowa, NJ. DOI: 10.1007/978-1- 59259-479-5_1