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

Sung Eun Kim, Ming Zhe Yin, Jae Won Roh, Hyun Jong Kim, Seong Woo Choi, Brian J. Wainger, Woo Kyung Kim, Sung Joon Kim, Joo Hyun Nam

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Background: α-Mangostin is a xanthone isolated from the pericarps of mangosteen fruit with, and has analgesic properties. Although the effects suggest an interaction of α-mangostin with ion channels in the nociceptive neurons, electrophysiological investigation of the underlying mechanism has not been performed. Hypothesis: We hypothesized that α-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 α-mangostin (1–3 µM) 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, α-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 α-mangostin (0.43 ± 0.27 µM), and partly suppressed tetrodotoxin-sensitive voltage-gated Na+ channel (NaV) currents. MD simulation revealed that multiple oxygen atoms in α-mangostin may form stable hydrogen bonds with TREKs, TRAAK, TRPV1, and NaV channels. In silico ADME tests suggested that α-mangostin may satisfy the drug-likeness properties without penetrating the blood–brain barrier. Conclusion: The analgesic properties of α-mangostin might be mediated by the multi-target modulation of ion channels, including TREK/TRAAK activation, TRPV1 inhibition, and reduction of the tetrodotoxin-sensitive NaV current. The findings suggest that the phytochemical can be a multi-ion channel-targeting drug and an alternative drug for effective pain management.

Original languageEnglish
Article number154791
JournalPhytomedicine
Volume115
DOIs
StatePublished - Jul 2023

Keywords

  • Analgesic mechanism
  • Dorsal root ganglion
  • Nociceptor
  • TREK/TRAAK
  • TRPV1
  • Voltage-operated Na channel
  • α-Mangostin

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