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

Abstract

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.

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Funding

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.

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Correspondence to Kuan-Pin Su.

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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.

Electronic Supplementary Material

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)

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)

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Satyanarayanan, S.K., Shih, YH., Chien, YC. et al. 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. Mol Neurobiol 55, 7271–7284 (2018). https://doi.org/10.1007/s12035-018-0899-x

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Keywords

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