Deacetyl xylopic acid exhibits synergistic antidepressant-like effects and augments fluoxetine activity in a chronic restraint-induced depression model in mice.

Xylopic acid (XA) and the deacetyl derivative (dXA) have been shown to exhibit antidepressant activity in acute models of depression in mice. This study evaluated and compared the effect of the deacetyl derivative in a chronic restrain model of depression. In the first phase of the study, the synergistic potential of dXA was evaluated using the mouse tail suspension test (TST) and forced swim test (FST). In the second phase, mice were subjected to chronic restraint stress for 42 days, starting from day 0, in ventilated tubes (0800-1400 h). On day 42, stress-naïve and stressed mice were assessed using both the FST and TST to identify the more sensitive behavioural assay for subsequent evaluation of treatment effects. Stressed mice were then administered fluoxetine, XA, dXA, vehicle for 72 h or single acute dosing of combinations of fluoxetine with XA or dXA, followed by repeat behavioural testing 90 min after the last dose of either a single acute or a chronic dosing regimen. The interaction index (γ), together with the significantly lower ED50mix compared to the ED50add, for the dXA combinations, with fluoxetine, sertraline, imipramine and ketamine is indicative of synergistic effect. An 8-hourly dosing, for 72 h of XA (100 mg kg-1) and dXA (100 mg kg-1) in the acute models did not reverse the behavioural traits of chronic restrain. However, fluoxetine (30 mg kg-1), given 12 hourly for 72 h, and the acute administration of combinations of fluoxetine (100 mg kg-1) and dXA (100 mg kg-1) significantly reversed the duration of immobility. The present study demonstrates that deacetyl xylopic acid (dXA) exerts synergistic antidepressant-like effects with selective antidepressants and augments the antidepressant effects of fluoxetine in a mouse model of chronic restraint stress-induced depression. These findings suggest that dXA may represent a promising adjunctive agent for improving antidepressant efficacy, particularly in stress-related depressive disorders.