Neuroprotective Effect of Agmatine in Ischemic Vascular Events
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Jan 30, 2024
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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: 15 may 2024.
doi: https://doi.org/10.18103/mra.v12i1.4928.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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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
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