Multi-target modulation of ion channels underlying the analgesic effects of α-mangostin in dorsal root ganglion neurons

Abstract

Background: alpha-Mangostin is a xanthone isolated from the pericarps of mangosteen fruit with, and has analgesic properties. Although the effects suggest an interaction of alpha-mangostin with ion channels in the nociceptive neurons, electrophysiological investigation of the underlying mechanism has not been performed. Hypothesis: We hypothesized that alpha-Mangostin exerts its analgesic effects by modulating the activity of various ion channels in dorsal root ganglion (DRG) neurons. Methods: We performed a whole-cell patch clamp study using mouse DRG neurons, HEK293T cells overexpressing targeted ion channels, and ND7/23 cells. Molecular docking (MD) and in silico absorption, distribution, metabolism, and excretion (ADME) analyses were conducted to obtain further insights into the binding sites and pharmacokinetics, respectively. Results: Application of alpha-mangostin (1-3 mu M) hyperpolarized the resting membrane potential (RMP) of small-sized DRG neurons by increasing background K+ conductance and thereby inhibited action potential generation. At micromolar levels, alpha-mangostin activates TREK-1, TREK-2, or TRAAK, members of the two-pore domain K+ channel (K2P) family known to be involved in RMP formation in DRG neurons. Furthermore, capsaicin-induced TRPV1 currents were potently inhibited by alpha-mangostin (0.43 +/- 0.27 mu M), and partly suppressed tetrodotoxin-sensitive voltage-gated Na+ channel (Na-V) currents. MD simulation revealed that multiple oxygen atoms in alpha-mangostin may form stable hydrogen bonds with TREKs, TRAAK, TRPV1, and Na-V channels. In silico ADME tests suggested that alpha-mangostin may satisfy the drug-likeness properties without penetrating the blood-brain barrier. Conclusion: The analgesic properties of alpha-mangostin might be mediated by the multi-target modulation of ion channels, including TREK/TRAAK activation, TRPV1 inhibition, and reduction of the tetrodotoxin-sensitive Na-V current. The findings suggest that the phytochemical can be a multi-ion channel-targeting drug and an alternative drug for effective pain management.