Emerging Mechanisms of Omega-3 Fatty Acids in Depression---The Effects of EPA and DHA on Chronic Stress, Neurogenesis and Neuroinflammation(3/3)

Background: Chronic stress has been widely considered as predisposing factors for the vulnerability of depressive episodes. In both pre-clinical and clinical evidences suggest these established factors are in strong association of depression with alterations of immune/inflammatory system, neuroplasticity changes including reduced neurogenesis, and diseases characterized by elevations of immune mediators in pathophysiology of depression. Omega-3 fatty acids in particular represent an exciting area of research, with eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) emerging as potential agent in the treatment of depression. However, the profound knowledge in their molecular and cellular effect that may help mitigate psychosis deleterious effect on brain tissue is still unclear. Several questions need to be addressed like 1) What would be the possible contributing factors like genetic vulnerability, dietary factors involved in depressive-like behaviour in chronic mild stress? 2) Are they any neuro-modulation link between inflammation and CMS-induced depression, especially, inflammatory and fatty acid genes modification in response to stress 3) Whether and how stress/inflammation changes the function of fatty acids sensitive receptors, proliferator-activated proteins? 4) How fatty acids in brain attenuate the effect of inflammation and whether there is any differential effect of EPA or DHA targeted mechanisms? 5) What are the possible cellular effects of EPA and DHA in specific for brain cells? On these bases, the purpose of our study was to analyse the expression of several markers of the immune/inflammatory system in an chronic stress induced animal model of depression in order to establish its relationship with the depressive phenotype as well as the involvement in the antidepressant response of omega-3 fatty acids in targeting inflammatory/neuroplasticity mechanism in depression. This 3 year project involving both in vivo and in vitro studies on drug effect in stress–induced depression/inflammation could provide promising evidence of mechanistic treatment effect of omega-3 fatty acids supplementation associated with improved outcomes in depression. Methods: To this aim, we will use the most validated unpredictable chronic mild stress paradigm for 6 weeks to induce core symptoms of depressive-like behaviour in rats; during the last 4 weeks of UCMS protocol, animals will be administered with EPA or DHA or celecoxib or fluoxetine. Depressive-like behaviour will be measured. Assessments will be made in order to evaluate lipid profile, inflammatory marker, biomarker genes; morphometric analysis of neurons will be examined. In in vitro studies, we will use C6 glioma cell line induced with lipopolysaccharides and drugs, and determine the cellular effect of EPA or DHA against inflammatory mechanism in order to evaluate the ability of the antidepressant treatment to interfere with potential inflammatory alterations. Outcome of this project will create new avenue of research targeting the omega-3 fatty acids as effective treatment in psychiatric disorder and also provides a novel antidepressant mechanisms of DHA and EPA including their role in protecting neurons can be explained scientifically. In a translational prospective, this concepts will lead to new explanations for a range of biological phenomena in major depression in human for potential nutritional-based drug discoveries provide realistic and alternative strategies for the antidepressant therapy.