Skip to content
2000
Volume 26, Issue 1
  • ISSN: 1871-5249
  • E-ISSN: 1875-6166

Abstract

Objective

Major Depressive Disorder (MDD) is a psychiatric disorder that has a tight connection to stressful experiences, decreased levels of endogenous antioxidants and enhanced levels of oxidative stress. We drafted this research to define the results of combining agmatine and melatonin on stress-induced depression in mice.

Methods

Experimental groups included the non-stressed group treated with vehicle (ethanol at a concentration of 0.0005%), stressed vehicle (ethanol at a concentration of 0.0005%)-treated group, group treated with fluoxetine (10 mg/kg/day), group treated with melatonin (10 mg/kg/day), group treated with agmatine (1 mg/kg/day), group receiving a combination of melatonin (10 mg/kg/day) and agmatine (1 mg/kg/day). The animals were subjected to restraint stress for two hours daily for a duration of one week, concurrently with the daily oral administration of agents through drinking water. Open field test and forced swimming test were operated on the 8th day. The oxidative stress markers were measured in the mice hippocampus.

Results

Stress led to the elevation of immobility time. The combination group showed a significant effect in comparison to the agmatine and melatonin groups. The combination of melatonin and agmatine was successful in the elevation of hippocampus catalase activity; and this effect was comparable in the fluoxetine group. We observed enhancement of superoxide dismutase activity in treatment groups and reduction in levels in melatonin, agmatine and combination groups.

Conclusion

A combination of agmatine and melatonin improves stress-induced depression more effectively than each alone, which may result from suppressing oxidative stress.

© 2026 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cnsamc/10.2174/0118715249347833250307041355
2025-03-25
2026-03-01

  • From This Site

    /content/journals/cnsamc/10.2174/0118715249347833250307041355
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. YanS. XuC. YangM. ZhangH. ChengY. XueZ. HeZ. WangT. BaiS. WangG. WuJ. TongZ. CaiX. The expression of agmatinase manipulates the affective state of rats subjected to chronic restraint stress.Neuropharmacology202322910947610.1016/j.neuropharm.2023.109476 36849038
     [Google Scholar]
  2. McEwenB.S. The neurobiology of stress: from serendipity to clinical relevance.Brain Res.20008861-217218910.1016/S0006‑8993(00)02950‑4 11119695
     [Google Scholar]
  3. BathinaK.C. ten ThijM. Lorenzo-LuacesL. RutterL.A. BollenJ. Individuals with depression express more distorted thinking on social media.Nat. Hum. Behav.20215445846610.1038/s41562‑021‑01050‑7 33574604
     [Google Scholar]
  4. AndradeL. Caraveo-anduagaJ.J. BerglundP. BijlR.V. GraafR.D. VolleberghW. DragomireckaE. KohnR. KellerM. KesslerR.C. KawakamiN. KiliçC. OffordD. Bedirhan UstunT. WittchenH.U. The epidemiology of major depressive episodes: Results from the International Consortium of Psychiatric Epidemiology (ICPE) surveys.Int. J. Methods Psychiatr. Res.200312132110.1002/mpr.138 12830306
     [Google Scholar]
  5. Al-harbiK.S. Treatment-resistant depression: Therapeutic trends, challenges, and future directions.Patient Prefer. Adherence2012636938810.2147/PPA.S29716 22654508
     [Google Scholar]
  6. CarusoG. GrassoM. FidilioA. TorrisiS.A. MussoN. GeraciF. TropeaM.R. PriviteraA. TasceddaF. PuzzoD. SalomoneS. DragoF. LeggioG.M. CaraciF. Antioxidant activity of fluoxetine and vortioxetine in a non-transgenic animal model of alzheimer’s disease.Front. Pharmacol.20211280954110.3389/fphar.2021.809541 35002742
     [Google Scholar]
  7. SakhaeeE. OstadhadiS. KhanM.I. YousefiF. Norouzi-JavidanA. AkbarianR. ChamanaraM. ZolfaghariS. The role of NMDA receptor and nitric oxide/cyclic guanosine monophosphate pathway in the antidepressant-like effect of dextromethorphan in mice forced swimming test and tail suspension test.Biomed. Pharmacother.20178562763410.1016/j.biopha.2016.11.073
     [Google Scholar]
  8. LiuT. ZhongS. LiaoX. ChenJ. HeT. LaiS. JiaY. A meta-analysis of oxidative stress markers in depression.PLoS One20151010e013890410.1371/journal.pone.0138904 26445247
     [Google Scholar]
  9. MehrzadiS. HosseiniA. HassaniS. AzimiradF. HosseinzadehA. Evaluating the antidepressant-like properties of melatonin and vitamin D3 combination in mice subjected to restraint stress: Investigating the involvement of Oxidative stress.Curr. Drug Ther.202419447047910.2174/1574885518666230811121026
     [Google Scholar]
  10. BakuninaN. ParianteC.M. ZunszainP.A. Immune mechanisms linked to depression via oxidative stress and neuroprogression.Immunology2015144336537310.1111/imm.12443 25580634
     [Google Scholar]
  11. Quera SalvaM.A. HartleyS. BarbotF. AlvarezJ.C. LofasoF. GuilleminaultC. Circadian rhythms, melatonin and depression.Curr. Pharm. Des.201117151459147010.2174/138161211796197188 21476953
     [Google Scholar]
  12. WonE. NaK.S. KimY.K. Associations between melatonin, neuroinflammation, and brain alterations in depression.Int. J. Mol. Sci.202123130510.3390/ijms23010305 35008730
     [Google Scholar]
  13. TononA.C. PilzL.K. MarkusR.P. HidalgoM.P. ElisabetskyE. Melatonin and depression: A translational perspective from animal models to clinical studies.Front. Psychiatry20211263898110.3389/fpsyt.2021.638981 33897495
     [Google Scholar]
  14. Ashkenazy-FrolingerT. Kronfeld-SchorN. JuettenJ. EinatH. It is darkness and not light: Depression-like behaviors of diurnal unstriped Nile grass rats maintained under a short photoperiod schedule.J. Neurosci. Methods2010186216517010.1016/j.jneumeth.2009.11.013 19932714
     [Google Scholar]
  15. DubocovichM.L. MarkowskaM. Functional MT1 and MT2 melatonin receptors in mammals.Endocr. J.200527210111010.1385/ENDO:27:2:101 16217123
     [Google Scholar]
  16. LaunayJ.M. LemaîtreB.J. HussonH.P. DreuxC. HartmannL. Da PradaM. Melatonin synthesis by rabbit platelets.Life Sci.198231141487149410.1016/0024‑3205(82)90010‑8 7144437
     [Google Scholar]
  17. DubocovichM.L. DelagrangeP. KrauseD.N. SugdenD. CardinaliD.P. OlceseJ. International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors.Pharmacol. Rev.201062334338010.1124/pr.110.002832 20605968
     [Google Scholar]
  18. FavaM. Daytime sleepiness and insomnia as correlates of depression.J. Clin. Psychiatry200465Suppl. 162732 15575802
     [Google Scholar]
  19. LamR.W. Sleep disturbances and depression: A challenge for antidepressants.Int. Clin. Psychopharmacol.200621Suppl. 1S25S2910.1097/01.yic.0000195658.91524.61 16436937
     [Google Scholar]
  20. TsunoN. BessetA. RitchieK. Sleep and depression.J. Clin. Psychiatry200566101254126910.4088/JCP.v66n1008 16259539
     [Google Scholar]
  21. OgłodekE.A. JustM.J. SzromekA.R. AraszkiewiczA. Melatonin and neurotrophins NT-3, BDNF, NGF in patients with varying levels of depression severity.Pharmacol. Rep.s2016685945
     [Google Scholar]
  22. NeisV.B. BettioL.E.B. MorettiM. RosaP.B. RibeiroC.M. FreitasA.E. GonçalvesF.M. LealR.B. RodriguesA.L.S. Acute agmatine administration, similar to ketamine, reverses depressive-like behavior induced by chronic unpredictable stress in mice.Pharmacol. Biochem. Behav.2016150-15110811410.1016/j.pbb.2016.10.004 27743829
     [Google Scholar]
  23. ValverdeA.P. CamargoA. RodriguesA.L.S. Agmatine as a novel candidate for rapid-onset antidepressant response.World J. Psychiatry2021111198199610.5498/wjp.v11.i11.981 34888168
     [Google Scholar]
  24. FengY. PiletzJ.E. LeblancM.H. Agmatine suppresses nitric oxide production and attenuates hypoxic-ischemic brain injury in neonatal rats.Pediatr. Res.200252460661110.1203/00006450‑200210000‑00023 12357058
     [Google Scholar]
  25. ZhuM.Y. PiletzJ.E. HalarisA. RegunathanS. Effect of agmatine against cell death induced by NMDA and glutamate in neurons and PC12 cells.Cell. Mol. Neurobiol.2003234/586587210.1023/A:1025069407173 14514037
     [Google Scholar]
  26. CaiS. Glycine/NMDA receptor antagonists as potential CNS therapeutic agents: ACEA-1021 and related compounds.Curr. Top. Med. Chem.20066765166210.2174/156802606776894465 16719807
     [Google Scholar]
  27. HuangZ. HuangP.L. PanahianN. DalkaraT. FishmanM.C. MoskowitzM.A. Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase.Science199426551801883188510.1126/science.7522345 7522345
     [Google Scholar]
  28. KaindlA.M. DegosV. PeineauS. GouadonE. ChhorV. LoronG. Le CharpentierT. JosserandJ. AliC. VivienD. CollingridgeG.L. LombetA. IssaL. ReneF. LoefflerJ.P. KavelaarsA. VerneyC. MantzJ. GressensP. Activation of microglial N‐methyl‐D‐aspartate receptors triggers inflammation and neuronal cell death in the developing and mature brain.Ann. Neurol.201272453654910.1002/ana.23626 23109148
     [Google Scholar]
  29. ZomkowskiA.D.E. HammesL. LinJ. CalixtoJ.B. SantosA.R.S. RodriguesA.L.S. Agmatine produces antidepressant-like effects in two models of depression in mice.Neuroreport200213438739110.1097/00001756‑200203250‑00005 11930146
     [Google Scholar]
  30. PorsoltR.D. BertinA. JalfreM. Behavioral despair in mice: A primary screening test for antidepressants.Arch. Int. Pharmacodyn. Ther.19772292327336 596982
     [Google Scholar]
  31. Yankelevitch-YahavR. FrankoM. HulyA. DoronR. The forced swim test as a model of depressive-like behavior.J. Vis. Exp.201525258710.3791/52587‑v
     [Google Scholar]
  32. BorsiniF. MeliA. Is the forced swimming test a suitable model for revealing antidepressant activity?Psychopharmacology (Berl.)198894214716010.1007/BF00176837 3127840
     [Google Scholar]
  33. KorczakD.J. PereiraS. KoulajianK. MatejcekA. GiaccaA. Type 1 diabetes mellitus and major depressive disorder: Evidence for a biological link.Diabetologia201154102483249310.1007/s00125‑011‑2240‑3 21789690
     [Google Scholar]
  34. Menezes ZanoveliJ. de MoraisH. Caroline da Silva DiasI. Karoline SchreiberA. Pasquini de SouzaC. Maria da CunhaJ. Depression associated with diabetes: From pathophysiology to treatment.Curr. Diabetes Rev.201612316517810.2174/1573399811666150515125349 25981499
     [Google Scholar]
  35. RebaiR. JasminL. BoudahA. The antidepressant effect of melatonin and fluoxetine in diabetic rats is associated with a reduction of the oxidative stress in the prefrontal and hippocampal cortices.Brain Res. Bull.201713414215010.1016/j.brainresbull.2017.07.013 28746841
     [Google Scholar]
  36. MunhozC.D. García-BuenoB. MadrigalJ.L. LepschL.B. ScavoneC. LezaJ.C. Stress-induced neuroinflammation: Mechanisms and new pharmacological targets.Rev. Bras. Pesqui. Med. Biol.2008411210371046
     [Google Scholar]
  37. JeonS.W. KimY.K. Neuroinflammation and cytokine abnormality in major depression: Cause or consequence in that illness?World J. Psychiatry20166328329310.5498/wjp.v6.i3.283 27679767
     [Google Scholar]
  38. AliT. HaoQ. UllahN. RahmanS.U. ShahF.A. HeK. ZhengC. LiW. MurtazaI. LiY. JiangY. TanZ. LiS. Melatonin act as an antidepressant via attenuation of neuroinflammation by targeting Sirt1/Nrf2/HO-1 signaling.Front. Mol. Neurosci.2020139610.3389/fnmol.2020.00096 32595452
     [Google Scholar]
  39. AlcendorR.R. GaoS. ZhaiP. ZablockiD. HolleE. YuX. TianB. WagnerT. VatnerS.F. SadoshimaJ. Sirt1 regulates aging and resistance to oxidative stress in the heart.Circ. Res.2007100101512152110.1161/01.RES.0000267723.65696.4a 17446436
     [Google Scholar]
  40. SalminenA. KauppinenA. SuuronenT. KaarnirantaK. SIRT1 longevity factor suppresses NF‐κB ‐driven immune responses: Regulation of aging via NF‐κB acetylation?BioEssays2008301093994210.1002/bies.20799 18800364
     [Google Scholar]
  41. MohseniG. OstadhadiS. Imran-KhanM. Norouzi-JavidanA. ZolfaghariS. HaddadiN.S. Agmatine enhances the antidepressant-like effect of lithium in mouse forced swimming test through NMDA pathway.Biomed. pharmaco.88, 931-938.2017,10.1016/j.biopha.2017.01.119
     [Google Scholar]
  42. SkolnickP. Antidepressants for the new millennium.Eur. J. Pharmacol.19993751-3314010.1016/S0014‑2999(99)00330‑1 10443562
     [Google Scholar]
  43. Dias Elpo ZomkowskiA. Oscar RosaA. LinJ. SantosA.R.S. Batista CalixtoJ. Lúcia Severo RodriguesA. Evidence for serotonin receptor subtypes involvement in agmatine antidepressant like-effect in the mouse forced swimming test.Brain Res.20041023225326310.1016/j.brainres.2004.07.041 15374751
     [Google Scholar]
  44. NeisV.B. MorettiM. ManossoL.M. LopesM.W. LealR.B. RodriguesA.L.S. Agmatine enhances antidepressant potency of MK-801 and conventional antidepressants in mice.Pharmacol. Biochem. Behav.201513091410.1016/j.pbb.2014.12.009 25553821
     [Google Scholar]
  45. TaksandeB.G. KotagaleN.R. TripathiS.J. UgaleR.R. ChopdeC.T. Antidepressant like effect of selective serotonin reuptake inhibitors involve modulation of imidazoline receptors by agmatine.Neuropharmacology200957441542410.1016/j.neuropharm.2009.06.035 19589348
     [Google Scholar]
  46. BhagwagarZ. WylezinskaM. JezzardP. EvansJ. BoormanE. M MatthewsP. J CowenP. Low GABA concentrations in occipital cortex and anterior cingulate cortex in medication-free, recovered depressed patients.Int. J. Neuropsychopharmacol.200811225526010.1017/S1461145707007924 17625025
     [Google Scholar]
  47. NeisV.B. RosadoA.F. OlescowiczG. MorettiM. RosaP.B. PlattN. RodriguesA.L.S. The involvement of GABAergic system in the antidepressant-like effect of agmatine.Naunyn Schmiedebergs Arch. Pharmacol.2020393101931193910.1007/s00210‑020‑01910‑5 32447465
     [Google Scholar]
  48. FreitasA.E. EgeaJ. BuendiaI. Gómez-RangelV. ParadaE. NavarroE. CasasA.I. WojniczA. OrtizJ.A. CuadradoA. Ruiz-NuñoA. RodriguesA.L.S. LopezM.G. Agmatine, by improving neuroplasticity markers and inducing Nrf2, prevents corticosterone-induced depressive-like behavior in mice.Mol. Neurobiol.20165353030304510.1007/s12035‑015‑9182‑6 25966970
     [Google Scholar]
/content/journals/cnsamc/10.2174/0118715249347833250307041355
Loading
Study of the Antidepressant Effects of the Combination of Agmatine and Melatonin Following Restraint Stress in Mice: the Role of Oxidative Factors
Central Nervous System Agents in Medicinal Chemistry 26, 95 (2026); https://doi.org/10.2174/0118715249347833250307041355
/content/journals/cnsamc/10.2174/0118715249347833250307041355
/content/journals/cnsamc/10.2174/0118715249347833250307041355
Loading

Data & Media loading...


  • Article Type:     Research Article
Keyword(s): agmatine; depression; hippocampus antioxidant activity; hippocampus catalase activity; melatonin; oxidative stress; Pharmacology

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test