Metabolic Brain Disease

, Volume 31, Issue 6, pp 1445–1453 | Cite as

Agomelatine reduces brain, kidney and liver oxidative stress but increases plasma cytokine production in the rats with chronic mild stress-induced depression

  • Arif Demirdaş
  • Mustafa Nazıroğlu
  • Gülin Özdamar Ünal
Original Article


Agomelatine (AGOM) as an antidepressant acts both as a melatonin-receptor agonist and a selective serotonin-receptor antagonist. As a potent melatonin derived antioxidant, AGOM might modulate depression-induced lipid peroxidation and pro-inflammatory cytokines in brain, kidney and liver. The present study explores whether AGOM protects against experimental depression-induced brain, kidney and liver oxidative stress, and plasma cytokine production in rats with chronic mild stress (CMS)-induced depression. Thirty-six rats were divided into four groups. The first group was used as an untreated control. The second group received AGOM for 4 weeks. The third group was exposed to chronic mild stress (CMS) of 4 weeks for induction depression. The fourth group received 40 mg/kg AGOM and CMS for 4 weeks. Liver and kidney lipid peroxidation levels were high in the CMS group although they were low in AGOM treatments. AGOM and AGOM + CMS treatments increased the lowered glutathione peroxidase activity and reduced glutathione levels in brain, kidney and liver of CMS group. β-carotene, vitamin A and vitamin E concentrations in the brain, kidney and liver of the four groups were not changed by CMS and AGOM treatments. However, plasma TNF-α, interleukin (IL)-1β, and IL-4 levels were high in the CMS and AGOM group and their levels were further increased by the AGOM + CMS treatment. In conclusions, AGOM induced protective effects against experimental depression-induced brain, kidney, and liver oxidative injuries through regulation of the glutathione concentrations and glutathione peroxidase activity. However, plasma cytokine productions were increased by the AGOM treatment.


Depression Brain Liver Oxidative stress Cytokine Glutathione 





chronic mild stress


reduced glutathione


glutathione peroxidase


reactive oxygen species



The abstract of the study was submitted to the 6th World Congress of Oxidative Stress, Calcium Signaling and TRP Channels, held 24 and 27 May 2016 in Isparta, Turkey ( The authors wish to thank researcher Bilal Çiğ and technician Muhammet Şahin (Neuroscience Research Center, SDU, Isparta, Turkey) for helping with the cytokine, lipid peroxidation and antioxidant analyses.

Author’s contributions

AD and MN formulated the hypothesis and was responsible for writing the report. GÖÜ was responsible for the animal experiments.

Compliance with ethical standards

Financial disclosure

There is no financial disclosure for the current study.

Conflict of interest

None of the authors have any conflicts to disclose. All authors approved the final manuscript.


  1. Akpinar A, Uğuz AC, Nazıroğlu M (2014) Agomelatine and duloxetine synergistically modulates apoptotic pathway by inhibiting oxidative stress triggered intracellular calcium entry in neuronal PC12 cells: role of TRPM2 and voltage-gated calcium channels. J Membr Biol 247:451–459CrossRefPubMedGoogle Scholar
  2. Andreasson A, Arborelius L, Erlanson-Albertsson C, Lekander M (2007) A putative role for cytokines in the impaired appetite in depression. Brain Behav Immun 21:147–152CrossRefPubMedGoogle Scholar
  3. Aygün H, Aydın D, İnanır S, Ekici F, Ayyıldız M, Ağar E (2015) The effects of agomelatine and melatonin on ECoG activity of absence epilepsy model in WAG/Rij rats. Turk J Biol 39:904–910CrossRefGoogle Scholar
  4. Bakunina N, Pariante CM, Zunszain PA (2015) Immune mechanisms linked to depression via oxidative stress and neuroprogression. Immunology 144:365–373PubMedCentralGoogle Scholar
  5. Balaban H, Nazıroğlu M, Demirci K (2016) The protective role of selenium on scopolamine-induced memory impairment, oxidative stress, and apoptosis in aged rats: The involvement of TRPM2 and TRPV1 channels. doi:10.1007/s12035-016-9835-0Google Scholar
  6. Cyranowski JM, Marsland AL, Bromberger JT, Whiteside TL, Chang Y, Matthews KA (2007) Depressive symptoms and production of proinflammatory cytokines by peripheral blood mononuclear cells stimulated in vitro. Brain Behav Immun 21:229–237CrossRefPubMedGoogle Scholar
  7. Dagyte D, Crescente I, Postema F, Seguin L, Gabriel C, Mocaer E, Den Boer JA, Jaap Koolhaas JM (2011) Agomelatine reverses the decrease in hippocampal cell survival induced by chronic mild stress. Behav Brain Res 218:121–128CrossRefPubMedGoogle Scholar
  8. de Mello AH, da Rosa SL, Moreira Cereja AC, de Bona SR, Florentino D, Modolon Martins M, Petronilho F, Quevedo J, Tezza Rezin G (2015) Effect of subchronic administration of agomelatine on brain energy metabolism and oxidative stress parameters in rats. Psychiatry Clin Neurosci. doi: 10.1111/pcn.12371 PubMedGoogle Scholar
  9. Demyttenaere K (2011) Agomelatine: a narrative review. Eur Neuropsychopharmacol 21: S703–S709.Google Scholar
  10. Desai ID (1984) Vitamin E analysis methods for animal tissues. Methods Enzymol 105:138–147CrossRefPubMedGoogle Scholar
  11. Ekmekcioglu C. (2006) Melatonin receptors in humans: biological role and clinical relevance. Biomed Pharmacother 60:97–108.Google Scholar
  12. Eren I, Nazıroğlu M, Demirdaş A (2007a) Protective effects of lamotrigine, aripiprazole and escitalopram on depression-induced oxidative stress in rat brain. Neurochem Res 32:1188–1195CrossRefPubMedGoogle Scholar
  13. Eren I, Naziroğlu M, Demirdaş A, Celik O, Uğuz AC, Altunbaşak A, Ozmen I, Uz E (2007b) Venlafaxine modulates depression-induced oxidative stress in brain and medulla of rat. Neurochem Res 32:497–505CrossRefPubMedGoogle Scholar
  14. Espino J, Bejarano I, Paredes SD, Barriga C, Rodríguez AB, Pariente JA (2011) Protective effect of melatonin against human leukocyte apoptosis induced by intracellular calcium overload: relation with its antioxidant actions. J Pineal Res 51:195–206CrossRefPubMedGoogle Scholar
  15. Freiesleben SD, Furczyk K (2015) A systematic review of agomelatine-induced liver injury. J Mol Psych 3:4CrossRefGoogle Scholar
  16. Gupta S, Sharma B (2014) Pharmacological benefits of agomelatine and vanillin in experimental model of Huntington’s disease. Pharmacol Biochem Behav 122:122–135CrossRefPubMedGoogle Scholar
  17. Halliwell B (2006) Oxidative stress and neurodegeneration: where are we now? J Neurochem 97:1634–1658CrossRefPubMedGoogle Scholar
  18. Inanir S, Copoglu US, Kokacya H, Dokuyucu R, Erbas O, Inanır A (2015) Agomelatine protection in an LPS-induced psychosis-relevant behavior model. Med Sci Monit 21:3834–3839CrossRefPubMedPubMedCentralGoogle Scholar
  19. Kahya MC, Naziroğlu M, Çiğ B. (2015) Melatonin and selenium reduce plasma cytokine and brain oxidative stress levels in diabetic rats. Brain Inj 29:1490–1406.Google Scholar
  20. Karakus E, Halici Z, Albayrak A, Polat B, Bayir Y, Kiki I, Cadirci E, Topcu A, Aksak S (2013) Agomelatine: An antidepressant with new potent hepatoprotective effects on paracetamol-induced liver damage in rats. Hum Exp Toxicol 32:846–857CrossRefPubMedGoogle Scholar
  21. Kharwar RK, Haldar C (2012) Daily variation in antioxidant enzymes and lipid peroxidation in lungs of a tropical bird Perdicula asiatica: role of melatonin and nuclear receptor RORα. Comp Biochem Physiol A Mol Integr Physiol 162:296–302CrossRefPubMedGoogle Scholar
  22. Kumar H, Sharma BM, Sharma B (2015) Benefits of agomelatine in behavioral, neurochemical and blood brain barrier alterations in prenatal valproic acid induced autism spectrum disorder. Neurochem Int 91:34–45CrossRefPubMedGoogle Scholar
  23. Lawrence RA, Burk RF (1976) Glutathione peroxidase activity in selenium-deficient rat liver. Biochem Biophys Res Commun 71:952–958CrossRefPubMedGoogle Scholar
  24. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin- Phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  25. Millan MJ, Gobert A, Lejeune F, Dekeyne A, Newman-Tancredi A, Pasteau V, Rivet JM, Cussac D (2003) The novel melatonin agonist Agomelatine (S20098) Is anantagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways. J Pharmacol Exp Ther 306:954–964CrossRefPubMedGoogle Scholar
  26. Nazıroğlu M (2007) New molecular mechanisms on the activation of TRPM2 channels by oxidative stress and ADP-ribose. Neurochem Res 32:1990–2001CrossRefPubMedGoogle Scholar
  27. Nazıroğlu M (2009) Role of selenium on calcium signaling and oxidative stress-induced molecular pathways in epilepsy. Neurochem Res 34:2181–2191CrossRefPubMedGoogle Scholar
  28. Nazıroğlu M, Demirdaş A (2015) Psychiatric disorders and TRP channels: Focus on psychotropic drugs. Curr Neuropharmacol 13:248–257CrossRefPubMedPubMedCentralGoogle Scholar
  29. Nestler EJ, Gould E, Manji H, Buncan M, Duman RS, Greshenfeld HK, et al. (2002) Preclinical models: status of basic research in depression. Biol Psychiatry 52:503–528CrossRefPubMedGoogle Scholar
  30. Nicholson TE, Renton KW (2001) Role of cytokines in the lipopolysaccharide-evoked depression of cytochrome P450 in the brain and liver. Biochem Pharmacol 62:1709–1717CrossRefPubMedGoogle Scholar
  31. Placer ZA, Cushman L, Johnson BC (1966) Estimation of products of lipid peroxidation (malonyl dialdehyde) in biological fluids. Anal Biochem 16:359–364CrossRefPubMedGoogle Scholar
  32. Sedlak J, Lindsay RHC (1968) Estimation of total, protein bound and non-protein sulfhydryl groups in tissue with Ellmann’ s reagent. Anal Biochem 25:192–205CrossRefPubMedGoogle Scholar
  33. Senol N, Nazıroğlu M, Yürüker V (2014) N-acetylcysteine and selenium modulate oxidative stress, antioxidant vitamin and cytokine values in traumatic brain injury-induced rats. Neurochem Res 39:685–692CrossRefPubMedGoogle Scholar
  34. Shirazi A, Mihandoost E, Ghobadi G, Mohseni M, Ghazi-Khansari M (2013) Evaluation of radioprotective effect of melatonin onwhole body irradiation induced liver tissue damage. Cell J 14:292–297PubMedPubMedCentralGoogle Scholar
  35. Sierra-Honigmann MR, Murphy PA (1992) Suppression of interleukin–1 action by phospholipase-A2 inhibitors in helper T lymphocytes. Pept Res 5:258–261PubMedGoogle Scholar
  36. Suzuki J, Katoh N (1990) A simple and cheap method for measuring vitamin A in cattle using only a spectrophotometer. Jpn J Vet Sci 52:1282–1284Google Scholar
  37. Tardito D, Molteni R, Popoli M, Racagni G (2012) Synergisticmechanisms involved in the antidepressant effects of agomelatine. Eur Neuropsychopharmacol 22:S482–S486CrossRefPubMedGoogle Scholar
  38. Vaváková M, Ďuračková Z, Trebatická J (2015) Markers of oxidative stress and neuroprogression in depression disorder. Oxidative Med Cell Longev 12:898393Google Scholar
  39. Voican CS, Corruble E, Naveau S, Perlemuter G (2014) Antidepressant-induced liver injury: a review for clinicians. Am J Psychiatry 171:404–415CrossRefPubMedGoogle Scholar
  40. Willner P (1997) Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation. Psychopharmacology 134:319–329.Google Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Arif Demirdaş
    • 1
  • Mustafa Nazıroğlu
    • 2
  • Gülin Özdamar Ünal
    • 1
  1. 1.Department of Psychiatry, Faculty of MedicineSuleyman Demirel UniversityIspartaTurkey
  2. 2.Neuroscience Research CenterSuleyman Demirel UniversityIspartaTurkey

Personalised recommendations