Evidence for the anxiolytic- and antidepressant-like effects of three semi-synthetic derivatives of xylopic acid in mice

Purpose: Major depressive disorder is one of the most common and burdensome psychiatric disorders worldwide. This study evaluated the anxiolytic- and antidepressant-like activity of three semi-synthetic derivatives of xylopic acid (XA) to identify the most promising derivative based on mechanism(s) of action, in vivo pharmacokinetics and in vitro cytotoxicity. Methods: The anxiolytic potential and the involvement of GABAergic mechanisms were assessed in the elevated plus-maze and open field tests in mice. The antidepressant-like effects were also investigated in the tail suspension test (TST) and forced swim test (FST). Possible mechanism(s) of antidepressant-effect was assessed by selective depletion of monoamines, using either reserpine, alpha-methyl-para-tyrosine or para-chlorophenylalanine (pCPA) prior to repeating the TST and FST. A single oral (100 mg kg ⁻¹) and intravenous bolus dose (100 mg kg ⁻¹) of XA or deacetylated XA (dXA) was administered separately to mice and the plasma concentration of each compound subjected to non-compartmental analyses. The potential cytotoxic effect of XA and dXA was also assessed with the MTT assay using HepG2 and Caco-2 cells. Results: XA and all the derivatives (10–100 mg kg ⁻¹) reduced anxiety- and depression-related behaviours. The anxiolytic-like effect of dXA was attenuated by pentylenetetrazole while its antidepressant-like properties were reversed in reserpine and pCPA pre-treated mice. In comparison to XA, dXA had lower oral clearance, longer half-life, shorter time to reach peak plasma concentration and was less toxic to hepG2 cells. Conclusion: All the semi-synthetic derivatives of XA exert varying degrees of anxiolytic- and antidepressant-like effects in mice. The anxiolytic- and antidepressant-like effects of dXA and XA are mediated, at least partly, through GABAergic and serotoninergic systems, respectively. In comparison with XA, dXA has a much lower clearance, longer half-life, shorter time to reach peak plasma concentration and was less toxic to HepG2 cells.