The role of xanthones in the antidepressant activity of Hypericum perforatum involving dopaminergic and serotonergic systems

Xanthones isolated from Hypericum perforatum (St. John's wort, SJW) were su bjected to antidepressant and receptor binding studies. Contribution of xan thones to the antidepressant activity of H. perforatum has hitherto not bee n considered due to the apprehension that this class of compounds occurs in traces in SJW and in commercial Hypericum extracts. However, in the presen t study, we observed that Indian H. perforatum contains appreciable quantit ies of xanthones (2-4%) comprising 1,3,5-trioxygenated xanthones and xantha nolignoids, keilkorin and cadensin, as major entities. Commercial extracts also contain xanthones to the extent of 1-3%. Xanthone- enriched fraction ( XEF) (5 mg/kg) of SJW exhibited significant antidepressant activity in the forced swim test. Pure trioxygenated xanthones, viz. 1,3,5-(OH)(3)-, 1-(OH) -3,5-(OMe)(2)-, 1,3,5-(OMe)(3)-, 1,3,5-(OAc)(3) xanthone, isolated from SJW and derivatized, were also screened for antidepressant activity. All these xanthones (5 mg/kg) produced significant antidepressant activity in mice. The ranking of the antidepressant activity of the xanthones was found to be in the order of 1-(OH)-3,5-(OMe)(2)- >1,3,5-(OMe)(3)- >1,3,5-(OH)(3) - >1, 3,5-(OAc)(3) xanthone. An attempt was made to elucidate the neurochemical m echanism of the antidepressant activity exhibited by the xanthones. Recepto r binding studies indicated that 1,3,5-(OMe)-xanthone (5 mg/kg) and xanthon e enriched fraction (5 mg/kg) of SJW caused significant decrease in the bin ding of [H-3] spiroperone (DA-D-2 R) to striatum and increase in the bindin g of [H-3] ketanserin (5-HT2A R) and [H-3] flunitrazepam (BDZ R) to frontal cortex in rats. These findings suggest the downregulation of dopamine D-2 receptors and upregulation of 5-HT2A and BDZ receptors. Thus, xanthones of SJW seem to contribute significantly to its antidepressant activity.