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

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. 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. 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. 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.