Agmatine, a cationic endogenous polyamine in the central nervous system, is obtained from the decarboxylation of arginine. Agmatine exerts neuroprotective properties, according to a growing body of experimental data. This review aims to describe the present understanding of the involvement of agmatine in the central nervous system and highlight its potential as a new pharmacological therapy as a neuroprotective agent. A few molecular pathways for agmatine’s neuroprotective properties are also highlighted. Several studies have shown that agmatine has neuroprotective properties in a variety of neurological conditions, including stroke and traumatic brain damage. The prevention of brain edema, blood-brain barrier protection, anti-oxidation, anti-apoptosis, and anti-inflammation is some of the proposed neuroprotective mechanisms of agmatine. Agmatine is extremely effective in treating neurological diseases, as evidenced by its safety and low occurrence of side effects. However, the majority of the studies on agmatine that is now accessible were conducted using different experimental models; further, clinical trials are required before agmatine may be used extensively in clinical settings.

1. Kim, J.H.; Yenari, M.A.; Giffard, R.G.; Cho, S.W.; Park, K.A.; Lee, J.E. Agmatine Reduces Infarct Area in a Mouse Model of Transient Focal Cerebral Ischemia and Protects Cultured Neurons from Ischemia-like Injury. Exp. Neurol., 2004, 189(1), 122–130.

2. Taksande B.G.; Chopde, C.T.; Umekar, M.J.; Kotagale, N.R. Agmatine Attenuates Hyperactivity and Weight Loss Associated with Activity-based Anorexia in Female Rats. Pharmacol. Biochem. Behav., 2015, 132, 136–141.

3. Kim, J.H.; Lee, Y.W.; Park, K.A.; Lee, W.T.; Lee, J.E. Agmatine Attenuates Brain Edema through Reducing the Expression of Aquaporin-1 after Cerebral Ischemia. J. Cereb. Blood Flow Metab., 2010, 30(5), 943–949.

4. Li, G.; Regunathan, S.; Barrow, C.J.; Eshraghi, J.; Cooper, R.; Reis, D.J. Agmatine: An Endogenous Clonidine-displacing Substance in the Brain. Science, 1994, 263, 966–969.

5. Raasch, W.; Regunathan, S.; Li, G.; Reis, D.J. Agmatine, the Bacterial Amine, is Widely Distributed in Mammalian Tissues. Life Sci., 1995, 56(26), 2319–2330.

6. Otake, K.; Ruggiero, D.A.; Regunathan, S.; Wang, H.; Milner, T.A.; Reis, D.J. Regional Localization of Agmatine in the Rat Brain: An Immunocytochemical Study. Brain Res., 1998, 787(1), 1–14.

7. Taksande, B.G.; Kotagale, N.R.; Patel, M.R.; Shelkar, G.P.; Ugale, R.R.; Chopde, C.T. Agmatine, an Endogenous Imidazoline Receptor Ligand Modulates Ethanol Anxiolysis and Withdrawal Anxiety in Rats. Eur. J. Pharmacol., 2010, 637(1–3), 89–101.

8. Reis, D.J.; Regunathan, S.; Agmatine: A novel neurotransmitter? In: Advances in Pharmacology. Vol. 42. Academic Press, United States, 1997. p645–649.

9. Taksande, B.G.; Sharma, O.; Aglawe, M.M.; Kale, M.B.; Gawande, D.Y.; Umekar. M.J.; Kotagale, N.R. Acute Orexigenic Effect of Agmatine Involves Interaction between Central α2- adrenergic and GABAergic Receptors. Biomed. Pharmacother., 2017, 93, 939–947.

10. Kotagale, N.R.; Ali, M.T.; Chopde, C.T.; Umekar, M.J.; Taksande, B.G. Agmatine Inhibits Nicotine Withdrawal Induced Cognitive Deficits in Inhibitory Avoidance Task in Rats: Contribution of α2-adrenoceptors. Pharmacol. Biochem. Behav., 2018, 167, 42–49.

11. Gilad, G.M.; Salame, K.; Rabey, J.M.; Gilad, V.H. Agmatine Treatment is Neuroprotective in Rodent Brain Injury Models. Life Sci., 1995, 58(2), 41–46.

12. Aglawe, M.M.; Taksande, B.G.; Kuldhariya, S.S.; Chopde, C.T.; Umekar, M.J.; Kotagale, N.R. Participation of Central Imidazoline Binding Sites in Antinociceptive Effect of Ethanol and Nicotine in Rats. Fundam. Clin. Pharmacol., 2014, 28(3), 284–293.

13. Kolesnikov, Y.; Jain, S.; Pasternak, G.W. Modulation of Opioid Analgesia by Agmatine. Eur. J. Pharmacol. 1996, 296(1), 17–22.

14. Kotagale, N.R.; Chopde, C.T.; Umekar, M.J.; Taksande, B.G. Chronic Agmatine Treatment Prevents Behavioral Manifestations of Nicotine Withdrawal in Mice. Eur. J. Pharmacol., 2015, 754, 190–198.

15. Bence, A.K.; Worthen, D.R.; Stables, J.P.; Crooks, P.A. An in vivo Evaluation of the Antiseizure Activity and Acute Neurotoxicity of Agmatine. Pharmacol. Biochem. Behav., 2003, 74(3), 771–775.

16. Li, Y.F.; Gong, Z.H.; Cao, J.B.; Wang, H.L.; Luo, Z.P.; Li, J. Antidepressant-like Effect of Agmatine and its Possible Mechanism. Eur. J. Pharmacol., 2003, 469(1–3), 81–88.

17. Kale, M.; Nimje, N.; Aglawe, M.M.; Umekar, M.; Taksande, B.; Kotagale, N. Agmatine Modulates Anxiety and Depression-like Behaviour in Diabetic Insulin-resistant Rats. Brain Res., 2020, 1747, 147045.

18. Kotagale, N.; Rahmatkar, S.; Chauragade, S.; Dixit, M.; Umekar, M.; Chopde, C.; Taksande, B. Involvement of Hippocampal Agmatine in β1-42 Amyloid Induced Memory Impairment, Neuroinflammation and BDNF Signaling Disruption in Mice. Neurotoxicology, 2020, 80, 1–11.

19. Matheus, F.C.; Aguiar A.S. Jr.; Castro, A.A.; Villarinho, J.G.; Ferreira, J.; Figueiredo, C.P.; Walz, R.; Santos, A.R.; Tasca, C.I.; Prediger, R.D. Neuroprotective Effects of Agmatine in Mice Infused with a Single Intranasal Administration of 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP). Behav. Brain Res., 2012, 235(2), 263–272.

20. Loring, R.H. Agmatine Acts as an Antagonist of Neuronal Nicotinic Receptors. Br. J. Pharmacol., 1990, 99(1), 207–211.

21. Reis, D.J.; Yang, X.C.; Milner, T.A. Agmatine Containing Axon Terminals in Rat Hippocampus form Synapses on Pyramidal Cells. Neurosci. Lett., 1998, 250(3), 185–188.

22. Yang, X.C.; Reis, D.J. Agmatine Selectively Blocks the N-methyl- D-aspartate Subclass of Glutamate Receptor Channels in Rat Hippocampal Neurons. J. Pharmacol. Exp. Ther., 1999, 288(2), 544–549.

23. Kotagale, N.; Deshmukh, R.; Dixit, M.; Fating, R.; Umekar, M.; Taksande, B. Agmatine Ameliorates Manifestation of Depression-like Behavior and Hippocampal Neuroinflammation in Mouse Model of Alzheimer’s Disease. Brain Res. Bull., 2020, 160, 56–64.

24. Marde, V.S.; Tiwari, P.L.; Wankhede, N.L.; Taksande, B.G.; Upaganlawar A.B.; Umekar, M.J.; Kale, M.B. Neurodegenerative Disorders Associated with Genes of Mitochondria. Future J. Pharm. Sci., 2021, 7(1), 66.

25. Arndt, M.A.; Battaglia, V.; Parisi, E.; Lortie, M.J.; Isome, M.; Baskerville, C.; Pizzo, D.P.; Ientile, R.; Colombatto, S.; Toninello, A.; Satriano, J. The Arginine Metabolite Agmatine Protects Mitochondrial Function and Confers Resistance to Cellular Apoptosis. Am. J. Physiol. Cell Physiol., 2009, 296(6), C1411–C1419.

26. Taksande, B.G.; Nambiar, S.; Patil, S.; Umekar, M.J.; Aglawe, M.M.; Kotagale, N.R. Agmatine Reverses Ethanol Consumption in Rats: Evidences for an Interaction with Imidazoline Receptors. Pharmacol. Biochem. Behav., 2019, 186, 172779.

27. Piletz, J.E.; Aricioglu, F.; Cheng, J.T.; Fairbanks, C.A.; Gilad, V.H.; Haenisch, B.; Halaris, A.; Hong, S.; Lee, J.E.; Li, J.; Liu, P. Agmatine: Clinical Applications after 100 Years in Translation. Drug Discov. Today, 2013, 18(17–18), 880–893.

28. Greenberg, S.; George, J.; Wollman, Y.; Shapira, I.; Laniado, S.; Keren, G. The Effect of Agmatine Administration on Ischemic-reperfused Isolated Rat Heart. J. Cardiovasc. Pharmacol. Ther., 2001, 6(1), 37–45.

29. Satriano, J.; Cunard, R.; Peterson, O.W.; Dousa, T.; Gabbai, F.B.; Blantz, R.C. Effects on Kidney Filtration Rate by Agmatine Requires Activation of Ryanodine Channels for Nitric Oxide Generation. Am. J. Physiol. Renal Physiol., 2008, 294(4), F795–F800.

30. Taksande, B.G.; Faldu, D.S.; Dixit, M.P.; Sakaria, J.N.; Aglawe, M.M.; Umekar, M.J.; Kotagale, N.R. Agmatine Attenuates Chronic Unpredictable Mild Stress Induced Behavioral Alteration in mice. Eur. J. Pharmacol., 2013, 720(1–3), 115–120.

31. Gilad, G.M.; Gilad, V.H. Long-term (5 years), High Daily Dosage of Dietary Agmatine--Evidence of Safety: A Case Report. J. Med. Food., 2014, 17(11), 1256–1259.

32. Gilad, G.M.; Gilad, V.H. Accelerated Functional Recovery and Neuroprotection by Agmatine after Spinal Cord Ischemia in Rats. Neurosci. Lett., 2000, 296(2–3), 97–100.

33. Jiang, X.; Pu, H.; Hu, X.; Wei, Z.; Hong, D.; Zhang, W.; Gao, Y.; Chen, J.; Shi, Y. A Post-stroke Therapeutic Regimen with Omega-3 Polyunsaturated Fatty Acids that Promotes White Matter Integrity and Beneficial Microglial Responses after Cerebral Ischemia. Transl Stroke Res., 2016, 7(6), 548–561.

34. Ji, B.; Zhou, F.; Han, L.; Yang, J.; Fan, H.; Li, S.; Li, J.; Zhang, X.; Wang, X.; Chen, X.; Xu, Y. Sodium Tanshinone IIA Sulfonate Enhances Effectiveness Rt-PA Treatment in Acute Ischemic Stroke Patients Associated with Ameliorating Blood-brain Barrier Damage. Transl. Stroke Res., 2017, 8(4), 334–340.

35. Xu, W.; Gao, L.; Li, T.; Shao, A.; Zhang, J. Neuroprotective Role of Agmatine in Neurological Diseases. Curr. Neuropharmacol., 2018, 16(9), 1296–1305.

36. Taksande, B.G.; Kotagale, N.R.; Gawande, D.Y.; Bharne, A.P.; Chopde, C.T.; Kokare, D.M. Neuropeptide Y in the Central Nucleus of Amygdala Regulates the Anxiolytic Effect of Agmatine in Rats. Eur. Neuropsychopharmacol., 2014, 24(6), 955–963.

37. Taksande, B.G.; Kotagale, N.R.; Tripathi, S.J.; Ugale, R.R.; Chopde, C.T. Antidepressant like Effect of Selective Serotonin Reuptake Inhibitors Involve Modulation of Imidazoline Receptors by Agmatine. Neuropharmacology, 2009, 57(4), 415–424.

38. Feng, Y.; Piletz, J.E.; Leblanc, M.H. Agmatine Suppresses Nitric Oxide Production and Attenuates Hypoxic-ischemic Brain Injury in Neonatal Rats. Pediatr Res., 2002, 52(4), 606–611.

39. Jung, H.J.; Yang, M.Z.; Kwon, K.H.; Yenari, M.A.; Choi, Y.J.; Lee, W.T.; Park, K.A.; Lee, J.E. 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), 201–212.

40. Umare, M.D.; Wankhede, N.L.; Bajaj, K.K.; Trivedi, R.V.; Taksande, B.G.; Umekar, M.J.; Mahore J.G.; Kale, M.B. Interweaving of reactive oxygen species and major neurological and psychiatric disorders. In: Annales Pharmaceutiques Françaises. Elsevier, Masson, 2021.

41. Kotagale, N.; Rahangdale, S.; Borkar, A.; Singh, K.; Ikhar, A.; Takale, N.; Umekar, M.; Taksande, B. Possible Involvement of Agmatine in Neuropharmacological Actions of Metformin in Diabetic Mice. Eur J Pharmacol., 2021, 907:174255.

42. Shlosberg, D.; Benifla, M.; Kaufer, D.; Friedman, A. Blood-brain Barrier Breakdown as a Therapeutic Target in Traumatic Brain Injury. Nat. Rev. Neurol., 2010, 6(7), 393–403.

43. Kotagale, N.R.; Taksande, B.G.; Inamdar, N.N. Neuroprotective Offerings by agmatine. Neurotoxicology, 2019, 73, 228–245.

44. Kuo, J.R.; Lo, C.J.; Chang, C.P.; Lin, K.C.; Lin, M.T.; Chio, C.C. Agmatine-Promoted Angiogenesis, Neurogenesis, and Inhibition of Gliosis-reduced Traumatic Brain Injury in Rats. J. Trauma, 2011, 71(4), E87–E93.

45. Yu, C.G.; Marcillo, A.E.; Fairbanks, C.A.; Wilcox, G.L.; Yezierski, R.P. Agmatine Improves Locomotor Function and Reduces Tissue Damage Following Spinal Cord Injury. Neuroreport, 2000, 11(14), 3203–3207.

46. Kim, J.H.; Yenari, M.A.; Park, K.A.; Lee, J.E. The Multifaceted Effects of Agmatine on Functional Recovery After Spinal Cord Injury through Modulations of BMP-2/4/7 Expressions in Neurons and Glial Cells. PLoS One, 2013, 8(1), e53911.

47. Dixit, M.P.; Upadhya, M.A.; Taksande, B.G.; Raut, P.; Umekar, M.J.; Kotagale, N.R. Neuroprotective Effect of Agmatine in Mouse Spinal Cord Injury Model: Modulation by Imidazoline Receptors. J. Nat. Sci. Biol. Med., 2018, 9(2), 115–120.

48. Zhu, M.Y.; Piletz, J.E.; Halaris, A.; Regunathan, S. Effect of Agmatine Against Cell Death Induced by NMDA and Glutamate in Neurons and PC12 Cells. Cell. Mol. Neurobiol., 2003, 23(4), 865–872.

49. Wang, W.P.; Iyo, A.H.; Miguel-Hidalgo, J.; Regunathan, S.; Zhu, M.Y. Agmatine Protects Against Cell Damage Induced by NMDA and Glutamate in Cultured Hippocampal Neurons. Brain Res., 2006, 1084(1), 210–216.

50. Marde, V.S.; Atkare, U.A.; Gawali, S.V.; Tiwari, P.L.; Badole, S.P.; Wankhede, N.L.; Taksande, B.G.; Upaganlawar, A.B.; Umekar, M.J.; Kale, M.B. Alzheimer’s Disease and Sleep Disorders: Insights into the Possible Disease Connections and the Potential Therapeutic Targets. Asian J. Psychiatr., 2022, 68, 102961.

51. Iizuka, Y.; Hong, S.; Kim, C.Y.; Kim, S.K.; Je Seong, G. Agmatine Pretreatment Protects Retinal Ganglion Cells (RGC-5 Cell Line) from Oxidative Stress in vitro. Biocell, 2008, 32(3), 245–250.

52. Wang, C.C.; Chio, C.C.; Chang, C.H.; Kuo, J.R.; Chang, C.P. Beneficial Effect of Agmatine on Brain Apoptosis, Astrogliosis, and Edema after Rat Transient Cerebral Ischemia. BMC Pharmacol., 2010, 10(1), 11.

53. Ahn, S.K.; Hong, S.; Park, Y.M.; Choi, J.Y.; Lee, W.T.; Park, K.A.; Lee, J.E. Protective Effects of Agmatine on Lipopolysaccharide-injured Microglia and Inducible Nitric Oxide Synthase Activity. Life Sci., 2012, 91(25–26), 1345–1350.

54. Abe, K.; Abe, Y.; Saito, H. Agmatine Induces Glutamate Release and Cell Death in Cultured Rat Cerebellar Granule Neurons. Brain Res., 2003, 990(1–2), 165–171.

55. Kotil, K.; Kuscuoglu, U.; Kirali, M.; Uzun, H.; Akçetin, M.; Bilge, T. Investigation of the Dose-dependent Neuroprotective Effects of Agmatine in Experimental Spinal Cord Injury: A Prospective Randomized and Placebo-control Trial. J. Neurosurg. Spine, 2006, 4(5), 392–399.

56. Hong, S.; Lee, J.E.; Kim, C.Y.; Seong, G.J. Agmatine Protects Retinal Ganglion Cells from Hypoxia-induced Apoptosis in Transformed Rat Retinal Ganglion Cell Line. BMC Neurosci., 2007, 8(1), 81.

57. Dastan, A.; Kocer, I.; Erdogan, F.; Ates, O.; Kızıltunc, A. Agmatine as Retinal Protection from Ischemia-reperfusion Injury in Guinea Pigs. Jpn. J. Ophthalmol., 2009, 53(3), 219–224.

58. Bennet, D.; Kim, S. Effects of Agmatine and Resveratrol on RGC-5 Cell Behavior under Light Stimulation. Environ. Toxicol. Pharmacol., 2014, 38(1), 84–97.

59. Zhu, M.Y.; Wang, W.P.; Bissette, G. Neuroprotective Effects of Agmatine against Cell Damage Caused by Glucocorticoids in Cultured Rat Hippocampal Neurons. Neuroscience, 2006, 141(4), 2019–2027.

60. Zhu, M.Y.; Wang, W.P.; Cai, Z.W.; Regunathan, S.; Ordway, G. Exogenous Agmatine has Neuroprotective Effects Against Restraint-induced Structural Changes in the Rat Brain. Eur. J. Neurosci., 2008, 27(6), 1320–1332.

61. Freitas, A.E.; Egea, J.; Buendía, I.; Navarro, E.; Rada, P.; Cuadrado, A.; Rodrigues, A.L.S.; López, M.G. Agmatine Induces Nrf2 and Protects Against Corticosterone Effects in Hippocampal Neuronal Cell Line. Mol. Neurobiol., 2015, 51(3), 1504–1519.

62. Taksande, B.G.; Chopde, C.T.; Umekar, M.J.; Kotagale, N.R. Agmatine Attenuates Lipopolysaccharide Induced Anorexia and Sickness Behavior in Rats. Pharmacol. Biochem. Behav., 2015, 132, 108–114.

63. Gawali, N.B.; Bulani, V.D.; Chowdhury, A.A.; Deshpande, P.S.; Nagmoti, D.M.; Juvekar, A.R. Agmatine Ameliorates Lipopolysaccharide Induced Depressive-like Behaviour in Mice by Targeting the Underlying Inflammatory and Oxido-nitrosative Mediators. Pharmacol. Biochem. Behav., 2016, 149, 1–8.

64. Taksande, B.G.; Gawande, D.Y.; Chopde, C.T.; Umekar, M.J.; Kotagale, N.R. Agmatine Ameliorates Adjuvant Induced Arthritis and Inflammatory Cachexia in Rats. Biomed. Pharmacother., 2017, 86, 271–278.

65. Sahin, C.; Albayrak, O.; Akdeniz, T.F.; Akbulut, Z.; Demirel, G.Y.; Aricioglu, F. Agmatine Reverses Sub-chronic Stress induced Nod-like Receptor Protein 3 (NLRP3) Activation and Cytokine Response in Rats. Basic Clin. Pharmacol. Toxicol., 2016, 119(4), 367–375.

66. Kotagale, N.; Dixit, M.; Garmelwar, H.; Bhondekar, S.; Umekar, M.; Taksande, B. Agmatine Reverses Memory Deficits Induced by Aβ1-42 Peptide in Mice: A Key Role of Imidazoline Receptors. Pharmacol. Biochem. Behav., 2020, 196, 172976.

67. Wankhede, N.L.; Kale, M.B.; Upaganlawar, A.B.; Taksande, B.G.; Umekar, M.J.; Behl, T.; Abdellatif, A.A.; Bhaskaran, P.M.; Dachani, S.R.; Sehgal, A.; Singh, S. Involvement of Molecular Chaperone in Protein-misfolding Brain Diseases. Biomed. Pharmacother., 2022, 147, 112647.

68. Alhadidi, Q.; Sayeed, M.S.B.; Shah, Z.A. The Interplay between Cofilin and Phospho-cofilin: Its Role in Maintaining Blood Brain Barrier Integrity. CNS Neurol. Disord. Drug Targets, 2017, 16(3), 279–290.

69. Agre, P.; King, L.S.; Yasui, M.; Guggino, W.B.; Ottersen, O.P.; Fujiyoshi, Y.; Engel, A.; Nielsen, S. Aquaporin water channels- -from atomic structure to clinical medicine. J. Physiol., 2002, 542(1), 3–16.

70. Taksande, B.G.; Khade, S.D.; Aglawe, M.M.; Gujar, S.; Chopde, C.T.; Kotagale, N.R. Agmatine Inhibits Behavioral Sensitization to Ethanol through Imidazoline Receptors. Alcohol. Clin. Exp. Res., 2019, 43(4), 747–757.

71. Dabhekar, S.V.; Chandurkar, P.A.; Kale, M.B.; Wankhede, N.L.; Taksande, B.G.; Umekar, M.J.; Upaganlawar, A.B. Herbal Medicine in the Treatment of Alzheimer’s Disease and Dementia: Phytoconstituent & Their Possible Pharmacological Activities. Depress Anxiety Open Access, 2022, 5, 1002.

72. Chandurkar, P.; Dhokne, M.; Wankhede, N.; Mangrulkar, S.; Taksande, B.; Upaganlawar, A.; Umekar, M.; Kale, M. Modulation of Mitochondrial Function in Elderly Brain: Involvement of Autophagy and Apoptosis. INNOSC Theranostics and Pharmacol. Sci., 2023, 4(2), 33–45.

73. Kale, M.B.; Bajaj, K.; Umare, M.; Wankhede, N.L.; Taksande, B.G.; Umekar, M.J.; Upaganlawar, A. Exercise and Nutraceuticals: Eminent Approach for Diabetic Neuropathy. Curr. Mol. Pharmacol., 2022, 15(1), 108–128.

74. Kotagale, N.; Taksande, B.; Inamdar, N. Is There a Rendezvous for SARS-CoV-2 and Agmatine. Coronaviruses, 2022, 3(3), 1–22.