Agomelatine effects on fat-enriched diet induced neuroinflammation and depression-like behavior in rats

Growing evidence suggests that a high fat diet (HFD) induces oxidative stress on the central nervous system (CNS), which predisposes to mood disorders and neuroinflammation. In this study we postulated that in addition to improving mood, antidepressant therapy would reverse inflammatory changes in the brain of rats exposed to a HFD. To test our hypothesis, we measured the effect of the antidepressant agomelatine (AGO) on anxiety- and depressive-like behaviors, as well as on CNS markers of inflammation in rats rendered obese. Agomelatine is an agonist of the melatonin receptors MT1 and MT2 and an antagonist of the serotonin receptors 5HT2B and 5HT2C. A subset of rats was also treated with lipopolysaccharides (LPS) to determine how additional neuroinflammation alters behavior and affects the response to the antidepressant. Specifically, rats were subjected to a 14-week HFD, during which time behavior was evaluated twice, first at the 10th week prior to LPS and/or agomelatine, and then at the 14th week after a bi-weekly exposure to LPS (250 μg/kg) and daily treatment with agomelatine (40 mg/kg). Immediately after the second behavioral testing we measured the proinflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and interleukin 1 beta (IL-1β), markers of oxidative stress thiobarbituric acid reactive substances (TABRS), catalase (CAT) and glutathione peroxidase (GPx), the growth factor BDNF, as well as the apoptosis marker caspase-3. Our results show that a HFD induced an anxiety-like behavior in the open field test (OFT) at the 10th week, followed by a depressive-like behavior in the forced swim test (FST) at the 14th week. In the prefrontal and hippocampal cortices of rats exposed to a HFD we noted an overproduction of TNF-α, IL-6, IL-1β, and TABRS, together with an increase in caspase-3 activity. We also observed a decrease in BDNF, as well as reduced CAT and GPx activity in the same brain areas. Treatment with agomelatine reversed the signs of anxiety and depression, and decreased the cytokines (TNF-α, IL-6 and IL-1β), TABRS, as well as caspase-3 activity. Agomelatine also restored BDNF levels and the activity of antioxidant enzymes CAT and GPx. Our findings suggest that the anxiolytic/antidepressant effect of agomelatine in obese rats could result from a reversal of the inflammatory and oxidative stress brought about by their diet.