Ferulic acid is a polyphenol that has antioxidant, anti-inflammatory and anticancer properties. The present study analyzed the antidepressant-like potential of ferulic acid using two well-validated mouse models of despair test, tail suspension and forced swim tests. The results suggested that ferulic acid treatment at doses of 10, 20, 40 and 80 mg/kg (p.o.) significantly reduced the immobility time in both of these two tests. These doses that affected the depressive-like behaviors did now show any effect on locomotion counts. The further neurochemical assays suggested that ferulic acid increased monoamine neurotransmitter levels in the brain regions that are relative to mood disorders: the hippocampus and frontal cortex. The increased tend to serotonin and norepinephrine was also found in the hypothalamus after higher dose of ferulic acid treatment. The subsequent study suggested that monoamine oxidase A (MAO-A) activity was inhibited in the frontal cortex and hippocampus when treatment with 40 and 80 mg/kg ferulic acid; while MAO-B activity did not change significantly. The current study provides the first lines of evidence that serotonin and norepinephrine, but not dopamine levels were elevated in mouse hippocampus and frontal cortex after ferulic acid treatment. These changes may be attributable to the inhibition of MAO-A activities in the same brain regions.

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Major depression is characterized by dysfunction of neuroendocrine and immune networks. Trans-resveratrol, a phenolic compound presented in polygonum cuspidatum, was demonstrated previously to exert antidepressant-like effects through regulating monoaminergic system, oxidative/antioxidant defense and inflammatory response. The present study investigated the synergistic antidepressant-like effect of trans-resveratrol and piperine, a bioavailability enhancer, in mice and explored the possible mechanism. Trans-resveratrol was shown to reduce the immobility time both in the tail suspension and forced swimming tests (TST and FST). But the maximal inhibition was nearly 60% even if the doses were increased by 160 mg/kg; while piperine produced weak antidepressant-like effects in these two models. The interaction between trans-resveratrol and piperine was shown a clear-cut synergistic effect as evidenced by an isobolographic analysis. The further study suggested that the anti-immobility response from the subthreshold dose of piperine (2.5 mg/kg) and low doses of trans-resveratrol (10 and 20 mg/kg) was abolished by pretreatment with para-chlorophenylalanine (PCPA, 300 mg/kg, i.p.) in TST and FST, indicating the involvement of serotonergic system. Moreover, treatment with the subthreshold dose of piperine and low doses of trans-resveratrol attenuated reserpine-induced hypothermia and ptosis arguing for the relevance of noradrenaline. Additional evidence from neurochemical (monoamines in the frontal cortex, hippocampus, and hypothalamus) and biochemical (monoamine oxidase, MAO activity) assays corroborated the synergistically elevated monoaminergic system after co-treatment with trans-resveratrol and piperine. The present results indicate the effect of trans-resveratrol combined with piperine on depressive-like behaviors may be partly due to the potentiated activation of monoaminergic system in the brain. Further studies are necessary to elucidate the involvement of the oxidative/nitrosative stress, inflammatory and neuroprotective pathway in the antidepressant-like effect of this combination. The synergistic effect obtained from the combination may provide innovative clues for designing novel antidepressants with high efficacy and low side effects.

The lifetime prevalence rate for major depressive disorder (MDD) is approximately 17 % for most developed countries around the world. Dietary polyphenols are currently used as an adjuvant therapy to accelerate the therapeutic efficacy on depression. Ferulic acid (FA) or 4-hydroxy-3-methoxy-cinnamic acid (Fig. 1a) is a main polyphenolic component of Chinese herb Radix Angelicae Sinensis, which is found to have antidepressant-like effects through regulating serotonergic and noradrenergic function. The present study examined the synergistic effect of low doses of FA combined with subthreshold dose of piperine, a bioavailability enhancer, on depression-like behaviors in mice, and investigated the possible mechanism. The administration of FA, even in the highest dose tested, reduced immobility time by 60 % in the tail suspension and forced swimming tests (TST and FST) in mice when compared to control. The maximal antidepressant-like effect of FA was obtained with 200 mg/kg. In addition, piperine only produced a weak antidepressant-like effect in the TST and FST. However, the evidence from the interaction analysis suggested a synergistic effect when low doses of FA were combined with a subthreshold dose of piperine. Further neurochemical evidence such as monoamine levels in the frontal cortex, hippocampus, and hypothalamus and measurements of monoamine oxidase activity also supported a synergistic effect of FA and piperine in the enhancement of monoaminergic function. This finding supports the concept that the combination strategy might be an alternative therapy in the treatment of psychiatric disorders with high efficacy and low side effects.

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