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

Josiane Budni, Andréa Dias Zomkowski, Daiane Engel, Danúbia Bonfanti Santos, Alessandra Antunes dos Santos, Morgana Moretti, Samira Valvassori, Felipe Ornell, João Quevedo, Marcelo Farina e Ana Lúcia S. Rodrigues

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 (50mg/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.

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