Chemical Composition, Antioxidant Activities, Antidepressant Effect, and Lipid Peroxidation of Peruvian Blueberry: Molecular Docking Studies on Targets Involved in Oxidative Stress and Depression.

Blueberries (Vaccinium corymbosum L.) are cultivated worldwide and are among the best dietary sources of bioactive compounds with beneficial health effects. This study aimed to investigate the components of Peruvian blueberry using high-performance liquid chromatography coupled to electrospray ionization and quadrupole time-of-flight mass spectrometry (HPLC-ESI-QTOF-MS/MS), identifying 11 compounds. Furthermore, we assessed in vitro the antioxidant activity and in vivo the antidepressant effect using a rat model and protective effect on lipid peroxidation (in the serum, brain, liver, and stomach). We also conducted molecular docking simulations with proteins involved in oxidative stress and depression for the identified compounds. Antioxidant activity was assessed by measuring total phenolic and flavonoid contents, as well as using 1,1-diphenyl-2-picrylhydrazin (DPPH), 2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulfonic) acid (ABTS•+), and ferric-reducing antioxidant power (FRAP) assays. Peruvian blueberries demonstrated higher antioxidant activity than Vaccinium corymbosum fruits from Chile, Brazil, the United States, Turkey, Portugal, and China. The results showed that oral administration of Peruvian blueberries (10 and 20 mg/kg) for 28 days significantly (p < 0.001) increased swimming and reduced immobility in the forced swimming test (FST). Additionally, at doses of 40 and 80 mg/kg, oxidative stress was reduced in vivo (p < 0.001) by decreasing lipid peroxidation in brain, liver, stomach, and serum. Molecular docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions were performed. In the molecular docking studies, quercitrin and 3,5-di-O-caffeoylquinic acid showed the best docking scores for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, superoxide dismutase, and xanthine oxidase; while 3,5-dicaffeoylquinic acid methyl ester and caffeoyl coumaroylquinic acid had the best docking scores for monoamine oxidase and serotonin receptor 5-HT2. In summary, our results suggest that the antidepressant and protective effects against lipid peroxidation might be related to the antioxidant activity of Peruvian Vaccinium corymbosum L.

Targeting 2-arachidonoylglycerol signalling in the neurobiology and treatment of depression.

The endocannabinoid 2-arachidonoylglycerol (2-AG) is an atypical neurotransmitter synthesized on demand in response to a wide range of stimuli, including exposure to stress. Through the activation of cannabinoid receptors, 2-AG can interfere with excitatory and inhibitory neurotransmission in different brain regions and modulate behavioural, endocrine and emotional components of the stress response. Exposure to chronic or intense unpredictable stress predisposes to maladaptive behaviour and is one of the main risk factors involved in developing mood disorders, such as major depressive disorder (MDD). In this review, we describe the molecular mechanisms involved in 2-AG signalling in the brain of healthy and stressed animals and discuss how such mechanisms could modulate stress adaptation and susceptibility to depression. Furthermore, we review preclinical evidence indicating that the pharmacological modulation of 2-AG signalling stands as a potential new therapeutic target in treating MDD. Particular emphasis is given to the pharmacological augmentation of 2-AG levels by monoacylglycerol lipase (MAGL) inhibitors and the modulation of CB2 receptors.

Environmental Enrichment and Physical Exercise Attenuate the Depressive-Like Effects Induced by Social Isolation Stress in Rats.

We assessed the antidepressant-like effects of environmental enrichment (EE) and physical exercise (PE) compared with the selective serotonin reuptake inhibitor fluoxetine against the depression-related neurobehavioral alterations induced by postweaning social isolation (SI) in rats. After 1 month of SI, rats were submitted to PE (treadmill), EE, or fluoxetine (10 mg/kg), which were compared with naïve SI and group-housed rats. After 1 month, behavior was analyzed in the open field (OFT), the sucrose preference (SPT), and the forced swimming (FST) tests. Afterward, the hippocampal serotonin contents, its metabolite, and turnover were measured. SI induced a depression-related phenotype characterized by a marginal bodyweight gain, anxiety, anhedonia, behavioral despair, and alterations of serotonin metabolism. EE produced the widest and largest antidepressive-like effect, followed by PE and fluoxetine, which were almost equivalent. The treatments, however, affected differentially the neurobehavioral domains investigated. EE exerted its largest effect on anhedonia and was the only treatment inducing anxiolytic-like effects. Fluoxetine, in contrast, produced its largest effect on serotonin metabolism, followed by its anti-behavioral despair action. PE was a middle-ground treatment with broader behavioral outcomes than fluoxetine, but ineffective to reverse the serotonergic alterations induced by SI. The most responsive test to the treatments was the FST, followed closely by the SPT. Although OFT locomotion and body weight varied considerably between groups, they were barely responsive to PE and fluoxetine. From a translational standpoint, our data suggest that exercise and recreational activities may have broader health benefits than antidepressants to overcome confinement and the consequences of chronic stress.

Antidepressant-Like Effect of Lippia sidoides CHAM (Verbenaceae) Essential Oil and Its Major Compound Thymol in Mice.

Depression is a common disease affecting more than 300 million people worldwide. Since Lippia sidoides has shown central nervous system effects in previous works, we aimed to investigate the effect of L. sidoides essential oil and its major compound, thymol on a corticosterone-induced depression model in mice. Male mice (20⁻25 g) received corticosterone (20 mg/kg, subcutaneously), once a day for 22 days. From the 16th day on, mice were grouped to receive either corticosterone or L. sidoides essential oil (100 and 200 mg/kg), or thymol (25 and 50 mg/kg) or fluoxetine (35 mg/kg) by gavage. The forced swimming test, tail suspension, open field, elevated plus maze and sucrose preference tests were performed from the 19th to 22nd day. Data were analyzed by ANOVA followed by the Student-Newman-Keuls as a post hoc test and the results were considered significant when p < 0.05. It was shown that L. sidoides essential oil, thymol and fluoxetine decreased the immobility time in the tail suspension and forced swimming tests and none of these altered locomotor activity in the open field test. However, the drugs increased the amount of grooming. In the elevated plus maze, all drugs increased the number of entries and the time of permanence in the open arms. In the sucrose preference test, the L. sidoides essential oil, thymol and fluoxetine reversed anhedonia. These results suggest that the thymol and L. sidoides essential oil have an antidepressant-like effect, similar to fluoxetine. However, future studies should be encouraged to enhance understanding of the effects of essential oil and thymol for the treatment of depression.

Evidence for the involvement of opioid system in the antidepressant-like effect of ascorbic acid.

Considering the involvement of the opioid system in major depressive disorder (MDD), mainly concerning refractory MDD, and the evidence that ascorbic acid may exert a beneficial effect for the treatment of this disorder, this study investigated the involvement of the opioid system in the antidepressant-like effect of ascorbic acid in the tail suspension test (TST). Treatment of Swiss mice with the non-selective opioid receptor antagonist naloxone (1 mg/kg, i.p.) prevented the reduced immobility time caused by ascorbic acid (1 mg/kg, p.o.) in the TST. Additionally, administration of the selective µ1-opioid receptor antagonist, naloxonazine (10 mg/kg, i.p.), also abolished the antidepressant-like action of the same dose of ascorbic acid in the TST. We also investigated the possible relationship between the opioid system and NMDA receptors in the mechanism of action of ascorbic acid or ketamine (0.1 mg/kg, i.p.) in the TST. Treatment of mice with naloxone (1 mg/kg, i.p.) blocked the synergistic antidepressant-like effect of ascorbic acid (0.1 mg/kg. p.o.) and MK-801 (0.001 mg/kg, p.o., a non-competitive NMDA receptor antagonist) in the TST. Combined administration of ketamine and MK-801 induced a synergistic antidepressant-like action, and naloxone partially abolished this effect. Our results indicate that the antidepressant-like effect of ascorbic acid in the TST appears to be dependent on the activation of the opioid system, especially µ1-opioid receptors, which might be an indirect consequence of NMDA receptor inhibition elicited by ascorbic acid administration.

Biological activities of Zn(II)-S-methyl-cysteine complex as antiradical, inhibitor of acid phosphatase enzyme and in vivo antidepressant effects.

The antidepressant effect of simple Zn(II) salts has been proved in several animal models of depression. In this study, a coordination metal complex of Zn(II) having a sulfur containing ligand is tested as antidepressant for the first time. Forced swimming test method on male Wistar rats shows a decrease in the immobility and an increase in the swimming behavior after treatment with [Zn(S-Met)2] (S-Met=S-methyl-l-cysteine) being more effective and remarkable than ZnCl2. The thiobarbituric acid and the pyranine consumption (hydroxyl and peroxyl radicals, respectively) methods were applied to evaluate the antioxidant activity of S-Met and [Zn(S-Met)2] showing evidence of attenuation of hydroxyl but not peroxyl radicals activities. UV-vis studies on the inhibition of acid phosphatase enzyme (AcP) demonstrated that S-methyl-l-cysteine did not produce any effect but, in contrast, [Zn(S-Met)2] complex behaved as a moderate inhibitor. Finally, bioavailability studies were performed by fluorescence spectroscopy denoting the ability of the albumin to transport the complex.