Evidence of an antidepressant-like effect of xylopic acid mediated by serotonergic mechanisms

Background Depression causes significant debilitating symptoms and economic burden. Current management is challenged by
slow onset of action and modest efficacies of antidepressants; thus, the search for newer antidepressants remains relevant. We
evaluated the antidepressant effects of a kaurene diterpene, xylopic acid (XA), in zebrafish and mouse models.
Methods The chronic unpredictable stress (CUS) protocol in zebrafish and the tail suspension test (TST), forced swim test (FST),
lipopolysaccharide-induced depression-like behaviour test (LID) and repeated open space swimming test (OSST) in mice were
used. We further examined the impact of depleting monoamines on XA’s antidepressant effects. The contribution of glutamatergic and nitrergic pathways on the antidepressant effect of XA in mice and XA’s effects on 5-HT receptors and monoamine
oxidase (MAO) enzymes were also evaluated. Finally, XA’s influence on neuroprotection was evaluated by measuring BDNF
and oxidative stress enzymes in whole brain. XA doses (1–10 μM) in zebrafish and (10, 30, 100 mg kg−1
) in mice exerted potent
antidepressant-like potential in FST, TST, LID and showed fast-onset antidepressant-like property in the OSST.
Results The antidepressant-like properties in mice were reversed by blocking synthesis/release of serotonin but not noradrenaline
using p-chlorophenylalanine and α-methyl-p-tyrosine, respectively. This antidepressant-like effect was potentiated by D-cycloserine and Nω-Nitro-L-arginine methyl ester (L-NAME) but not by D-serine and L-arginine. XA also evoked partial agonist-like
effects on 5-hydroxytrptamine receptors on the rat fundus but it did not have MAO inhibition effect. It also increased BDNF,
glutathione and antioxidant enzymes.
Conclusion Therefore, xylopic acid possesses antidepressant-like effects largely mediated by serotonergic and neuroprotective
mechanisms.