Molecular Neurobiology

, Volume 55, Issue 9, pp 7271–7284 | Cite as

Anti-Oxidative Effects of Melatonin Receptor Agonist and Omega-3 Polyunsaturated Fatty Acids in Neuronal SH-SY5Y Cells: Deciphering Synergic Effects on Anti-Depressant Mechanisms

  • Senthil Kumaran Satyanarayanan
  • Yin-Hwa Shih
  • Yu-Chuan Chien
  • Shih-Yi Huang
  • Piotr Gałecki
  • Siegfried Kasper
  • Jane Pei-Chen Chang
  • Kuan-Pin Su


Omega-3 polyunsaturated fatty acids (n-3 or omega-3 PUFAs) and melatonin receptor agonist ramelteon (RMT) both display antidepressant effects, while their cellular effects on anti-oxidative and neuroprotective mechanisms might be different. In this study, we aimed to decipher the individual and synergistic actions of n-3 PUFAs and RMT, as compared with the conventional antidepressant fluoxetine (FLX), in a cellular model of oxidative stress, which might play an important role in the pathophysiology of depression and associated disorders. We investigated the rescue and prevention effects of FLX, RMT, and n-3 PUFAs, e.g., eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by using cell viability in SH-SY5Y cells under oxidative stress along with measurements of key cellular markers of oxidative stress, inflammatory, and neuroprotection. The results revealed that the RMT and EPA combination significantly increased the cell viability in a dose-dependent manner. RMT showed preventive effects, FLX and DHA possessed rescue effects, while EPA showed both rescue and preventive effects. We observed the dose-dependent activation and translocation of nuclear factor-κB to the nucleus augmented by the expressions of peroxisome proliferator activator receptor-gamma, tyrosine hydroxylase, c-Fos expression, and reactive oxygen species, implying that RMT and EPA combination reversed oxidative and neuroinflammatory pathophysiology and protected the neuronal cells from further damage. The results demonstrated that RMT and EPA synergistically provide effective neuroprotective, anti-oxidative/inflammatory effect against oxidative stress. Our study provides pre-clinical evidence to conduct future clinical trials of using n-3 PUFAs/RMT combination in depressive disorders.


Oxidative stress Depression Circadian rhythm Ramelteon Omega-3 fatty acids EPA DHA 


Funding Information

The work was supported by the China Medical University under the Aim for Top University Plan of the Ministry of Education, Taiwan, and by the following Grants: MOST 106-2314-B-038-049; MOST 106-2314-B-039-027-MY3; 106-2314-B-038-049; 106-2314-B-039-031; 106-2314-B-039-035; 104-2314-B-039-022-MY2, and 104-2314-B-039-050-MY3 from the Ministry of Science and Technology, Taiwan; NHRI-EX105-10528NI from the National Health Research Institutes, Taiwan; and CMU104-S-1603 and CMU104-S44 from the China Medical University, Taiwan.

Compliance with Ethical Standards

Conflict of Interest

Dr. Siegfried Kasper received grants/research support, consulting fees, and/or honoraria within the last 3 years from Angelini, AOP Orphan Pharmaceuticals AG, AstraZeneca, Eli Lilly, Janssen, KRKA-Pharma, Lundbeck, Neuraxpharm, Pfizer, Pierre Fabre, Schwabe, and Servier. The other authors declare no potential conflict of interest.

Supplementary material

12035_2018_899_MOESM1_ESM.jpg (113 kb)
Supplementary Fig. 1 Cell viability as detected by the MTT assay in SH-SY5Y neuronal cells with increasing H2O2, ramelteon (RMT), fluoxetine (FLX) and n-3 PUFAs (EPA & DHA) doses for 24h. Data were normalized to control values that were taken as 100% of cell viability. The arrow indicates the optimal concentration chosen for further experiments. Error bars indicate the standard error. (JPEG 113kb)
12035_2018_899_MOESM2_ESM.jpg (604 kb)
Supplementary Fig. 2 (a-l): Quantitative analysis of the effects of ramelteon (RMT), fluoxetine (FLX), n-3 PUFAs (EPA & DHA) and their combination under oxidative stress (H2O2) on c-Fos, tyrosine hydroxylase (TH), proliferators-activator receptor-gamma (PPAR-γ), catalase, superoxide dismutase (SOD1 and SOD2) protein markers. Protein band intensities, normalized to GAPDH. Histogram of densitometry data showing the individual and synergistic effects of RMT, FLX, EPA and DHA treatment; rescue effect (a, c, e, g, i, k) and prevention effect (b, d, f, h, j, l). The values presented are the means ± SEM of three independent experiments, *p<0.05 or **p<0.01 or ***p<0.001, versus H2O2 treatment group, ##p<0.01 or ### p<0.001 versus control group. (JPEG 604kb)
12035_2018_899_MOESM3_ESM.jpg (677 kb)
ESM 1 (JPEG 677kb)


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Authors and Affiliations

  1. 1.Department of Psychiatry & Mind-Body Interface Laboratory (MBI-Lab)China Medical UniversityHospitalTaichungTaiwan
  2. 2.School of Nutrition and Health SciencesTaipei Medical UniversityTaipeiTaiwan
  3. 3.Department of Oral Hygiene, College of Dental MedicineKaohsiung Medical UniversityKaohsiungTaiwan
  4. 4.College of MedicineChina Medical UniversityTaichungTaiwan
  5. 5.Medical University of ŁódźŁódźPoland
  6. 6.Department of Psychiatry and PsychotherapyMedical University of ViennaViennaAustria
  7. 7.Institute of PsychiatryKing’s College LondonLondonUK

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