Background & Aims
Background: ?-Mangostin is a xanthone isolated from the pericarps of mangosteen fruit with, and has analgesic properties. Although the effects suggest an interaction of ?-mangostin with ion channels in the nociceptive neurons,electrophysiological investigation of the underlying mechanism has not been performed.
Hypothesis: We hypothesized that ?-Mangostin exerts its analgesic effects by modulating the activity of various ion channels in dorsal root ganglion (DRG) neurons.
Methods
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
Results: Application of ?-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, ?-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 ?-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 ?-mangostin may form stable hydrogen bonds with TREKs, TRAAK, TRPV1, and NaV channels. In silico ADME tests suggested that ?-mangostin may satisfy the drug-likeness properties without penetrating the blood–brain barrier.
Conclusions
Conclusion: The analgesic properties of ?-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.
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Presenting Author
Sung Eun Kim
Poster Authors
Sung Eun Kim
Ph.D.
Seoul National University
Lead Author
Topics
- Specific Pain Conditions/Pain in Specific Populations: Acute Pain and Nociceptive Pain