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

Abstract

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 + , IA and IK currents. Key results: Extracellularly applied hypericin dose-dependently increased AP duration but barely affected its amplitude. Further analysis revealed that hypericin inhibited both transient IA and delayed rectifier IK 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 IA and IK 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.

Effects of St John's wort and its active constituents, hypericin and hyperforin, on isolated rat urinary bladder

“…Our results are supported by previous studies in which micromolar hypericin has been demonstrated to increase L‐type calcium channel conductance in cardiac myocytes as a consequence of a decreased cGMP level via inhibition of soluble guanylate cyclase [24] . Additionally, hypericin acts on voltage‐dependent K + channels in neurons, enhancing presynaptic efficiency [25] . Moreover, when the hypericin concentration is raised to a much higher range, a relaxant effect was observed.…”

“…[24] Additionally, hypericin acts on voltage-dependent K + channels in neurons, enhancing presynaptic efficiency. [25] Moreover, when the hypericin concentration is raised to a much higher range, a relaxant effect was observed. This could be due to a negative feedback mechanism by which Ca 2+ concentration is decreased.…”

The antidepressant citalopram inhibits delayed rectifier outward K+current in mouse cortical neurons

“…Although in our experiments AP firing frequency of the neuron evoked by the suprathreshold current injection was significantly reduced by applying citalopram, AP duration was increased. This effect is similar to that observed with the antidepressant hypericin in rat hippocampal neurons, in which AP duration as well as I A and I K currents were affected (Wang et al,2010); this might be ascribed to the citalopram‐induced inhibitory effect on I K channels, because citalopram did not modify the I A and Na + current of cortical neurons (data not shown). In addition, Gong et al (2008) demonstrated that the membrane potential affected AP duration through regulation of I A and the I K in cultured hippocampal neurons and in pyramidal neurons in ferret prefrontal cortical slices (Shu et al,2006); citalopram‐induced depolarization of resting membrane potential might have resulted in increased AP duration in our study.…”

“…In addition, Gong et al (2008) demonstrated that the membrane potential affected AP duration through regulation of I A and the I K in cultured hippocampal neurons and in pyramidal neurons in ferret prefrontal cortical slices (Shu et al,2006); citalopram‐induced depolarization of resting membrane potential might have resulted in increased AP duration in our study. A small increase in AP duration could lead to a dramatic increase in synaptic efficiency (Wang et al,2010), so our results imply that I K might exert its antidepressant effects by enhancing presynaptic efficiency. However, our data are preliminary, so further studies will be required to address this hypothesis.…”

Semi-Synthesis of α-Mangostin Derivatives and Evaluation of their Cholinesterase Inhibitory Activity

“…It has been shown that lipid soluble molecules can regulate many K + channels, such as Ca 2+-dependent BKCa channels [38] and voltage-dependent K + channels [39]. Wang et al [40] study found that extracellularly applied hypericin increased action potential duration in hippocampal neurons and that effect of hypericin might be explained by its modulation of voltage-gated K + currents. Sauviat et al [41] work showed that hypericin prolonged action potential duration in cardiac myocytes.…”