Hypericin prolongs action potential duration in hippocampal neurons by acting on K+ channels.

BACKGROUND AND PURPOSE: Synaptic deficiency is generally accepted to be involved in major depression, and accordingly classic antidepressants exert their effects through enhancing synaptic efficiency. Hypericin is one of the major active constituents of extracts of St. John's Wort (Hypericum perforatum L.) with antidepressive actions, but little is known about its therapeutic mechanisms. Our aim was to explore whether hypericin has a modulatory effect on neuronal action potential (AP) duration by acting on voltage-gated ion channels.

EXPERIMENTAL APPROACH: We used voltage-clamp and current-clamp techniques in a whole-cell configuration to study primary cultures of neonatal rat hippocampal neurones. We measured the effects of extracellularly applied hypericin on AP duration as well as on voltage-gated Na(+), I(A) and I(K) currents.

KEY RESULTS: Extracellularly applied hypericin dose-dependently increased AP duration but barely affected its amplitude. Further analysis revealed that hypericin inhibited both transient I(A) and delayed rectifier I(K) potassium currents. In contrast, hypericin exerted no significant effect on both Na(+) peak current and its decay kinetics.

CONCLUSIONS AND IMPLICATIONS: Extracellularly applied hypericin increased AP duration, which might be ascribed to its effect on I(A) and I(K) currents. As a small increase in AP duration could lead to a dramatic increase in synaptic efficiency, our results imply that hypericin might exert its antidepressant effects by enhancing presynaptic efficiency.