Folic acid prevents depressive-like behavior and hippocampal antioxidant imbalance induced by restraint stress in mice.

Experimental and epidemiological studies have shown the close relationship between stressful events, depression, and cognitive impairment. Folic acid has been reported to present antidepressant-like effects in both experimental and clinical approaches. However, the mechanisms mediating such effects are not understood. In the present study, we evaluated if folic acid administration to mice could protect against restraint stress-induced depressive-like behavior and cognitive deficit. Considering that oxidative stress has been pointed as a key event involved with depressive disorders, cerebrocortical and hippocampal oxidative stress-related parameters, such as the activities of antioxidant enzymes (mainly those related to the hydroperoxide-detoxifying system) and markers of lipid peroxidation, were also investigated. Restraint stress induced depressive-like behavior in the forced swimming test and memory impairment in the object recognition test, without altering locomotor activity of mice. Folic acid (50 mg/kg, p.o.) was able to prevent the stress-induced increase on immobility time in the forced swimming test, but did not prevent memory impairment. Moreover, restraint stress increased thiobarbituric acid reactive substance levels, and catalase, glutathione peroxidase and glutathione reductase activities in the cerebral cortex and hippocampus, and superoxide dismutase activity in the hippocampus. Folic acid treatment restored the activity of the antioxidant enzymes and reduced lipid peroxidation in the hippocampus. Glutathione, a non-enzymatic antioxidant, was not altered by stress and/or folic acid administration. Together, the results of the present work reinforce the notion that folic acid displays a specific antidepressant profile in the restraint stress paradigm that may be at least partly due to its antioxidant role.

Involvement of PKA, CaMKII, PKC, MAPK/ERK and PI3K in the acute antidepressant-like effect of ferulic acid in the tail suspension test.

Ferulic acid (FA, 4-hydroxy-3-methoxycinnamic acid) is a phytochemical compound naturally present in several plants and foods that is approved as an antioxidant additive and food preservative. It exerts a beneficial action in chronic mild stress-induced depressive-like behavior and produces an acute antidepressant-like effect in the tail suspension test (TST) through the activation of the serotonergic system. This study was aimed at investigating the possible involvement of signaling pathways in the antidepressant-like effect of acute and oral administration of FA, in the TST in mice. The anti-immobility effect of orally administered FA (0.01mg/kg, p.o.) was prevented by pretreatment of mice with H-89 (1µg/site, i.c.v., an inhibitor of PKA), KN-62 (1µg/site, i.c.v., an inhibitor of CaMKII), GF109203X (5ng/site, i.c.v., an inhibitor of PKC), U0126 (5µg/site, i.c.v., an inhibitor of MAPK/ERK) or LY294002 (10nmol/site, i.c.v., an inhibitor of PI3K), all involved with neurotrophic signaling pathways. The results demonstrated that FA exerts antidepressant-like effect in the TST in mice, through the activation of signaling pathways related to neuroplasticity, neurogenesis and cell survival.

Ferulic acid exerts antidepressant-like effect in the tail suspension test in mice: evidence for the involvement of the serotonergic system.

Ferulic acid (4-hydroxy-3-methoxycinnamic acid) is a phenolic compound present in several plants with claimed beneficial effects in prevention and treatment of disorders linked to oxidative stress and inflammation. In this study, we aimed to verify the possible antidepressant-like effect of acute oral administration of ferulic acid in the forced swimming test (FST) and tail suspension test (TST) in mice. Additionally, the mechanisms involved in the antidepressant-like action and the effects of the association of ferulic acid with the antidepressants fluoxetine, paroxetine, and sertraline in the TST were investigated. Ferulic acid produced an antidepressant-like effect in the FST and TST (0.01-10 mg/kg, p.o.), without accompanying changes in ambulation. The pretreatment of mice with WAY100635 (0.1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist) or ketanserin (5 mg/kg, i.p., a 5-HT(2A) receptor antagonist) was able to reverse the anti-immobility effect of ferulic acid (0.01 mg/kg, p.o.) in the TST. The combination of fluoxetine (5 mg/kg, p.o.), paroxetine (0.1 mg/kg, p.o.) or sertraline (1 mg/kg, p.o.) with a sub-effective dose of ferulic acid (0.001 mg/kg, p.o.) produced a synergistic antidepressant-like effect in the TST, without causing hyperlocomotion in the open-field test. Taken together, these results demonstrate that ferulic acid exerts antidepressant-like effect in the FST and TST in mice through modulation of the serotonergic system.

Antidepressant-like and neuroprotective effects of Aloysia gratissima: investigation of involvement of L-arginine-nitric oxide-cyclic guanosine monophosphate pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Aloysia gratissima (Gill. et Hook) Tronc. (Verbenaceae) is used traditionally for the treatment of headache, bronchitis, and nervous systems disorders including depression. AIM OF THE STUDY: To investigate the antidepressant-like and neuroprotective effects of Aloysia gratissima aqueous extract (AE) and the involvement of l-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway. MATERIALS AND METHODS: The antidepressant-like effect of AE was evaluated through behavioral despair in forced swimming test (FST) and tail suspension test (TST). Swiss albino mice were treated by oral route and after 1h were analyzed the time of immobility in the FST and TST. In addition, the neuroprotective effect of AE against glutamate excitotoxicity was evaluate through cell viability of hippocampal slices, phosphorylation of Akt, and the immunocontent of inducible oxide nitric synthase (iNOS) were investigated by western blotting. RESULTS: The immobility time in the FST and TST were reduced by AE (100-1000 and 10-300 mg/kg, respectively). The antidepressant-like effect of AE in the TST was prevented by the pretreatment with N-methyl-d-aspartate (NMDA), l-arginine or sildenafil. The subeffective dose of AE produced a synergistic antidepressant-like effect with MK-801 (an antagonist of NMDA receptor), methylene blue, l-NNA (an inhibitor of NO synthase) or ODQ (an inhibitor of soluble guanylate cyclase). In ex vivo experiments, pretreatment with AE prevented the loss of cell viability induced by glutamate, thus affording neuroprotection. Glutamate toxicity caused a decreased Akt phosphorylation and an increased iNOS expression. CONCLUSIONS: The present study provides convincing evidence of neuroprotection and the involvement of the l-arginine-NO-cGMP pathway in the antidepressant-like effect of AE. Therefore, AE could be of potential interest for the treatment of depressive disorders and neurological conditions associated with glutamate excitotoxicity.