The restore normal endogenous rhythmic patterns, to

The World Health Organization ranks major depressive disorder (MDD) among top public health concerns worldwide, causing significant disability and disease burden 1.

MDD has profound negative impacts on patients’ quality of life, work productivity, and physical health 2-4. Current antidepressant treatments fail to meet clinical needs, as the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) reported approximately one-third of patients did not remit after one-year of vigorous treatment with combination of psychotherapy and pharmacotherapy 5. In fact, treatment resistance among patients with depression is common and might be as high as 50 % to 60 % 6. Circadian rhythms are endogenously generated oscillations in behavior and physiology that are closely synchronized within a diurnal change. Recent studies have demonstrated the association among circadian rhythm dysregulation, immune dysfunction, neurodegeneration, oxidative stress and depression 7-13.

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Several antidepressants have been shown to restore normal endogenous rhythmic patterns, to reduce levels of oxidative stress markers and to resolve depressed states 8,14-16. Recently, melatonin receptor agonist ramelteon (RMT) is widely used as a treatment for sleep disorders 17 and depression associated sleep disorders 18,19. In addition, RMT has shown the effects of neuroprotection by involving receptor-mediated transcriptional signaling via the induction of antioxidant genes, such as superoxide dismutase (SOD) and catalase (CAT) 20,21.

The chronobiotic and neuroprotective properties of RMT provide the explanation of its wide-range therapeutic effects on psychopathology of sleep and depressive disorders 12,18,19,22-24.  Several lines of evidences suggest omega-3 polyunsaturated fatty acids (omega-3 or n-3 PUFAs) to be one promising treatment for MDD 25,26. The n-3 PUFAs, mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are essential nutritional compounds with high safety profiles and have been commonly recommended as a preventive and therapeutic nutrient for several neuropsychiatric disorders 25,27-30. The beneficial effects of n-3 PUFAs in depression are further supported in several pre-clinical studies of animal and cellular models 31-36. We proposed several biological mechanisms of the antidepressant effect of n-3 PUFAs in previous reviews, including: (i) neurotransmitter regulations, (ii) anti-inflammation and anti-oxidation, (iii) neuroplasticity effects, and (iv) arachidonic acid cascade 37,38,29,39.

Thus these important nutritional essentials possess antioxidant properties 40,41 as they decrease the production of reactive oxygen species 42. The relationship between n-3 PUFAs and sleep disorders is still rarely evaluated and described in the literature 43. Recent studies shows that treatments including omega-3 and omega-6 PUFAs with other nutrients improved sleep quality 44 and reduced sleep disorders 45 among children with behavioral problems. Our previous study elucidated the anti-oxidative and anti-inflammatory effects of n-3 PUFAs and the manner in which the regulatory molecular mechanisms of DHA-induced HO-1 expression operate through the PI-3 kinase/AKT and ERK signaling pathways by increasing IKK?/? phosphorylation, p65 Ser536 phosphorylation, NF-?B activation, and HO-1 protein expression in BV-2 microglia 46.

However, this theory has not been proven and been generalized with clinical studies due to the heterogeneity of depression. Oxidative stress remains an important etiological factor for depressive disorders and associated conditions, and also remains a potential pharmaceutical treatment target needing special attention. Despite evidences revealing the distinct mode of action of both RMT and n-3 PUFAs in treating comorbid depressive conditions, to date there are no studies inspecting their mechanisms in preventing neurodegeneration from oxidative stress. Thus, the goal of this study was to investigate synergistic anti-oxidative, anti-inflammatory and neuroprotective mechanisms of RMT in combination with n-3 PUFAs EPA and DHA in a H2O2-induced oxidative model using SH-SY5Y neuronal cells. Alongside, a novel antidepressant fluoxetine (FLX) with proven neuroprotective effects and a leading role with enzymes of the antioxidant defense system was scrutinized as an antidepressant control.


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