Antidepressant-like effect of dehydrozingerone from Zingiber officinale by elevating monoamines in brain: in silico and in vivo studies

Abstract

Background: Dehydrozingerone (DHZ) is an active ingredient of Zingiber officinale and structural half analogue of curcumin. In the present study, DHZ was evaluated for monoamine oxidase (MAO) inhibitory activity in silico and antidepressant activity in vivo.

Method: The binding affinity of DHZ with MAO-A (PDB ID: 2Z5Y) was assessed using Schrodinger's Maestro followed by free energy calculation, pharmacokinetic property prediction using Qikprop and Molecular dynamics simulation using Desmond. In vivo antidepressant activity of DHZ was evaluated on C57 BL/6 male mice using Escilatopram as the standard antidepressant. Open field test (OFT), forced swimming test (FST) and tail suspension test (TST) were used to evaluate the antidepressant effect of the drugs on days 1 and 7. Following the behavioural study, neurotransmitters (noradrenaline, dopamine and serotonin) were estimated using liquid chromatography-mass spectrometry.

Results: DHZ demonstrated a greater binding affinity for the MAO-A enzyme compared to moclobemide in silico. Immobility in TST and FST were significantly (p < 0.05) reduced in vivo with 100mg/kg DHZ as compared to respective controls. DHZ treatment was more effective 1 h post treatment compared to vehicle control. A significant increase in levels of neurotransmitters was observed in mice brain homogenate in response to DHZ treatment, reassuring its antidepressant-like potential.

Conclusion: DHZ demonstrated MAO-A inhibition in silico, and the increased neurotransmitter levels in the brain in vivo were associated with an antidepressant-like effect.

Keywords: Dehydrozingerone; Depression; LCMS; Molecular dynamics; Monoamine oxidase-A; Neurotransmitter.

Fig. 1

Superposition of the inbound and redocked molecule

Fig. 2

Molecular dynamics simulation of MAO-A with DHZ. a 2D interaction diagram of DHZ during MD simulation. b Plot showing the interaction of MAO-A and DHZ molecule throughout the simulation. c RMSD plot of DHZ and MAO-A protein complex

Fig. 3

IR data of DHZ

Fig. 4

Mass data of DHZ

Fig. 5

Open Field Test of 1st Day and 7th Day. The results of open field test (OFT) performed on 1st and 7th day of treatment represented as bar diagrams. One-way ANOVA followed by Tukey’s multiple comparison test was used for statistical analysis. The data are presented as mean ± SEM of six animals where ^ap < 0.05 as compared to normal control, ^bp < 0.05 as compared to escitalopram, ^bp < 0.05 as compared to DHZ (1 h), ^cp < 0.05 as compared to DHZ (3 h), ^bp < 0.05 as compared to DHZ (6 h)

Fig. 6

Forced swim test and tail suspension test of 1st day and 7th day. The results of tail suspension test (TST) and forced swim test (FST) performed on 1st and 7th day of treatment represented as bar diagrams. One-way ANOVA followed by Tukey’s multiple comparison test was used for statistical analysis. The data are presented as mean ± SEM of six animals where ^ap < 0.05 as compared to normal control, ^bp < 0.05 as compared to escitalopram, ^bp < 0.05 as compared to DHZ (1 h), ^cp < 0.05 as compared to DHZ (3 h), ^bp < 0.05 as compared to DHZ (6 h)

Fig. 7

Extracted-ion chromatogram of neurotransmitters. Legend: MS2 extracted ion chromatogram of dopamine (5.71 min), noradrenaline (6.01 min), serotonin (5.51 min) and isoprenaline (Internal standard) (5.65 min)

Fig. 8

Neurotransmitter levels in whole brain. Legend: Two-way ANOVA followed by Tukey’s multiple comparison test was used for statistical analysis. The data are presented as mean ± SEM of six animals where ^ap < 0.05 compared to normal control, ^bp < 0.05 compared to escitalopram, ^bp < 0.05 compared to DHZ (1 h), ^cp < 0.05 compared to DHZ (3 h), ^bp < 0.05 compared to DHZ (6 h)