Synergistic antidepressant-like effect of ferulic acid in combination with piperine: involvement of monoaminergic system

Abstract

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.

Keywords: Depression; Ferulic acid; MAO; Monoamines; Piperine.

Fig. 1

Structures of Ferulic Acid (a) and piperine (b)

Fig. 2

An isobologram for the combination of Ferulic Acid with piperine which generates a synergistic effect. a Isobologram illustration for maximal anti-immobility response which achieved in the forced swim and b in the tail suspension tests. The dose at which 50 % of treated mice achieved a maximal anti-immobility response (ID₅₀) for each drug is indicated on their respective axes. The two points below “the line of additivity” connecting the ID₅₀s of the individual drug represent the ID₅₀s of the combination, which are 10 mg/kg piperine and FA, and 3 mg/kg FA and piperine, respectively. The ID₅₀s of the combination as shown do not cross the line of additivity (a position above the line indicates antagonism)

Fig. 3

Locomotor activity in mice after subthreshold dose of piperine (10 mg/kg) combined with FA. The locomotor activity was recorded for 10 min. Values are expressed as mean ± S.E.M. with 10 mice in each group