Agmatine has been functionally characterized as an important hormone and co-neurotransmitter in mammals. Given its ability in binding Imidazoline sites, a regolatory site of monoaminoxydase, it has been suggested to be involved in many neurological aspects. However, its inhibitory effect on this enzyme still remains an unanswered question. This present study is aimed to asses whether different experimental conditions could affect the agmatine action on monoaminoxydase activity. We demonstrate that the monoaminoxydase inhibition by agmatine is obtained under alkaline conditions and a long time of incubation. No inhibitiory action was found for shorter times of reaction at elevated pH, or at neutral condition and long time of incubation. No inhibition was also detected by substituting the monoamineoxydase substrate tyramine with kynuramine, however, while in these conditions a remarkable inhibition was shown by two aminoxydase inhibitors tranylcypromine and idazoxan. Herein, we discuss a mechanism model and the functional consequences of agmatine action on monoaminoxydase.
1. Raacsh W, Schafer U, Chun J & Dominiak P. Biological significance of agmatine, an endogenous ligand at imidazoline binding sites. Br J Pharmacol. 2001; 133, 755-780.
2. Aricioglu-kartal F & Uzbay IT. Inhibitory effect of agmatine on naloxone-precipitated abstinence syndrome in morphine dependent rats. Life Sci.1997; 61, 1775-1881.
3. Regunathan S, Youngson C, RaascH W, Wang H & Reis DJ. Imidazoline receptors and agmatine in blood vessels: a novel system inhibiting vascular smooth muscle proliferation. J Pharmacol Exp Ther. 1996; 276, 1272-1282.
4. Gilad GM, Gilad VH & Rabey JM. Arginine and ornithine decarboxylation in rodent brain: coincidental changes during development and after ischemia. Neurosi Lett 1996; 216, 33-36.
5. Olmos G, Degregorio-Rocasolano N, Paz RM, Gasull T, Assumpcio BM, Trullas R, Villarroel A, Lerma J & Garcia-Sevilla JA. 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; 127,1317-1326.
6. Reis DJ & Regunathan S. Is agmatine a novel neurotransmitter in brain? TiPS. 2000; 21, 187-193.
7. Goracke-Postle CJ, Overland AC, Riedl MS, Stone LS, Fairbanks CA. Potassium-and capsaicin-induced release of agmatine from spinal nerve terminals. J. Neurochem. 2007 Sep;102(6):1738-48.
8. Li G, Regunathan S, Barrow CJ, Eshraghi J, Cooper R, & Reis DJ. Agmatine: an endogenous clonidine-displacing substance in the brain. Science. 1994; 263:966-9.
9. Tesson F, Prip-Buus C, Lemoine A, Pegorier JP, Parini A. Subcellular distribution of imidazoline-guanidinium-receptive sites in human and rabbit liver. Major localization to the mitochondrial outer membrane. J Biol Chem. 1991; 266:155-60.
10. Tesson F, Prip-Buus C, Lemoine A, Pegorier JP & Parini A. Characterization of mitochondrial imidazoline-guanidinium receptive sites (IGRS) in liver. Am J Hypertens. 1995; 5, 805-825.
11. Raddatz R, Parini A & Lanier SM. Localization of the imidazoline binding domain on monoamine oxidase. B Mol Pharmacol 1997; 52, 549-553.
12. Raddatz R, Savic SL, Bakthavachalam V, Lesnik J, Jasper JR, Mcgrath CR, Parini A, Lanier SM. Imidazoline-binding domains on monoamine oxidase B and subpopulations of enzyme. J Pharmacol Exp Ther 2000; 292, 1135-1145.
13. Head GA, & Mayorov DN. Imidazoline receptors, novel agents and therapeutic potential. Cardiovasc Hematol Agents Med Chem. 2006; 4:17-32.
14. Raasch W, Muhle H, & Dominiak P. Modulation of MAO activity by imidazoline and guanidine derivatives. Ann N Y Acad Sci. 1999; 881:313-31.
15. Jones TZ, Giurato L, Guccione S. & Ramsay RR. Interactions of imidazoline ligands with the active site of purified monoamine oxidase A. FEBS J. 2007; 274, 1567-1575.
16. Holt A. & Baker GB. Metabolism of agmatine (clonidine-displacing substance) by diamine oxidase and the possible implications for studies of imidazoline receptors. Prog Brain Res. 1995; 106, 187-197.
17. Su RB, Li J, Li X. & Qin BY. Down-regolation of MAO-B activity and imidazoline receptors in rat brain following chromic treatment of morphine. Acta Pharmacol. Sin. 2001; 22, 639-644.
18. Ozaita A, Olmos G, Boronat MA, Lizcano JM, Unzeta M. & Garcia-Sevilla JA. Inhibition of monoamine oxidase A and B activities by imidazol(ine)/guanidine drugs, nature of the interaction and distinction from I2-imidazoline receptors in rat liver. Br J Pharmacol. 1997; 121, 901-912.
19. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976; 72:248-54.
20. Weissbach H, Smith TE, Daly JW, Witkop B, & Udenfriend S. A rapid spectrophotometric assay of mono-amine oxidase based on the rate of disappearance of kynuramine. J Biol Chem. 1960; 235:1160-3.
21. Holt A, Palcic MM. A peroxidase-coupled continuous absorbance plate-reader assay for flavin monoamine oxidases, copper-containing amine oxidases and related enzymes. Nat Protoc. 2006; 1(5):2498-505.
22. Holt A., Sharman D.F., Baker G.B., & Palcic M.M. (1997). A continuous spectrophotometric assay for monoamine oxidase and related enzymes in tissue homogenates. Anal Biochem. 244:384-92.
23. Tipton KF. Inhibition of monoamine oxidase by substituted hydrazines. Biochem J. 1992; 128:913-9.
24. Kim H, Sablin SO, & Ramsay RR. Inhibition of monoamine oxidase A by beta-carboline derivatives. Arch Biochem Biophys. 1997; 337:137-42.
25. Zomkowski AD, Hammes L, Lin J, Calixto JB, Santos AR, Rodrigues AL. Agmatine produces antidepressant-like effects in two models of depression in mice. Neuroreport. 2002; 13(4):387-91.
26. Shopsin B. The clinical antidepressant effect of exogenous agmatine is not reversed by parachlorophenylalanine: a pilot study. Acta Neuropsychiatr. 2013; 25(2):113-8. doi: 10.1111/j.1601-5215.2012.00675.x.
27. Laube G, Bernstein HG. Agmatine: multifunctional arginine metabolite and magic bullet in clinical neuroscience? Biochem J. 2017; 474(15):2619-2640.