Flavonoids, which are polyphenolic compounds, have been reported to possess remarkable antioxidant and anti-inflammatory activities. Among the dietary flavonoids, fisetin (3,3',4',7-tetrahydroxyflavone) possesses a significant spectrum of biochemical and pharmacological actions. The present study aimed to investigate the antidepressant potential of fisetin and its possible mechanism. Two mouse models of despair tests were used to evaluate the antidepressant-like effect of fisetin. The results suggested that fisetin (10 and 20mg/kg, p.o.) dose dependently inhibited the immobility time in both behavioral tests, while the doses that affected the immobile response did not affect locomotor activity. Two behavioral models, reserpine-induced hypothermia and ptosis, and p-chlorophenylalanine (PCPA)-induced depletion of serotonin, were used to explore the possible involvement of fisetin in the noradrenergic and serotonergic system. The higher dose of fisetin was found to effectively antagonize the hypothermia, but not ptosis, induced by reserpine. Pre-treatment with PCPA abolished the anti-immobility effect of fisetin in the forced swimming and tail suspension tests. Moreover, neurochemical assays showed that fisetin produced an increase in serotonin and noradrenaline levels in the frontal cortex and hippocampus. Monoamine oxidase (MAO) activity in the mouse brain was inhibited by 14.7% after treatment with fisetin, while MAO-B activity was not affected. These findings indicate that the antidepressant-like effect of fisetin involves the regulation of the central serotonin and noradrenaline levels.
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