Antidepressant-Like Activity and Molecular Docking Analysis of a Sesquiterpene Lactone Isolated from the Root Bark of Ximenia americana (L.)

Abstract

Depression, a global cause of disability and premature death, is often treated by traditional healers in Africa using medicinal herbs such as Ximenia americana (L.). With recent pharmacological studies showing the potential antidepressant properties of X. americana extract, this study aimed to evaluate the antidepressant-like effects of the compound(s) isolated from X. americana extract using the forced swim test (FST) and tail suspension test (TST) models predictive of depression. The extracts, administered orally within a dose range of 100-400 mg/kg, notably decreased the immobility time in both the FST and the TST. The most significant reduction occurred at the highest dose of 400 mg/kg, with a decrease of 117.66 s in FST and 53.5 s in TST. However, this reduction in immobility was not linked to changes in movements, as observed in an open-field test (OFT), suggesting that the effect of the extracts was not due to activation of locomotion. Subsequently, a sesquiterpene lactone, dehydrocostus lactone (1) was isolated through solubility-based fractionation and column chromatography of the active root bark extract of X. americana. Dehydrocostus lactone (400 mg/kg) demonstrated a 46.50 s reduction in immobility time in the FST, which was comparable to the positive control, imipramine (30 mg/kg). With a highly favorable docking score of -8.365 kcal/mol on an antidepressant target, monoamine oxidase A (MAO-A; pdb ID: 2BXS), dehydrocostus lactone (1) potentially outperforms the standard MAO-A inhibitor drug, isocarboxazid (-5.847 kcal/mol). Dehydrocostus lactone (1) displayed strong interactions involving hydrogen bond and hydrophobic and electrostatic interactions with specific MAO-A binding site residues. These findings highlight that the antidepressant-like activity of X. americana is partly attributed to the presence of dehydrocostus lactone. Additionally, it also supports the traditional medicinal use of the plant for treating depression.

Figure 1

Structure of compound 1.

Figure 2

Effect of treatment with Ximenia americana root bark extract or standard drug (imipramine), given orally, on the immobility of mice in the FST. Values are presented as mean ± SEM; n = 6; vehicle: received 2% Tween-80 in distilled water; different letters indicate statistical significance by one-way ANOVA test followed by Tukey post hoc test (p<0.05).

Figure 3

Effect of treatment with Ximenia americana root bark extract or standard drug (imipramine), given orally, on the immobility of mice in the TST. Values are presented as mean ± SEM; n = 6; vehicle: received 2% Tween-80 in distilled water; different letters indicate statistical significance by one-way ANOVA test followed by Tukey post hoc test (p<0.05).

Figure 4

Effect of treatment with dehydrocostus lactone (1) or standard drug (imipramine), given orally, on the immobility of mice in the FST. Values are presented as mean ± SEM; n = 6; vehicle: received 2% Tween-80 in distilled water; different letters indicate statistical significance by one-way ANOVA test followed by Tukey post hoc test (p<0.05).

Figure 5

(a) 3D representation of dehydrocostus lactone (1) docked within the active site of MAO-A; (b) the 3D zoomed view of the dehydrocostus lactone (1) interaction (c) 2D model of dehydrocostus lactone (1) showing interactions with residues at the MAO-A enzyme.