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.

References

Benarroch, E.E., 2015. Ion channels in nociceptors: recent developments. Neurology 84,
1153–1164. https://doi.org/10.1212/WNL.0000000000001382.
Chen, G., Li, Y., Wang, W., Deng, L., 2018. Bioactivity and pharmacological properties of
alpha-mangostin from the mangosteen fruit: a review. Expert Opin. Ther. Pat. 28,
415–427. https://doi.org/10.1080/13543776.2018.1455829.
Cui, J., Hu, W., Cai, Z., Liu, Y., Li, S., Tao, W., Xiang, H., 2010. New medicinal properties
of mangostins: analgesic activity and pharmacological characterization of active
ingredients from the fruit hull of Garcinia mangostana L. Pharmacol. Biochem. Behav.
95, 166–172. https://doi.org/10.1016/j.pbb.2009.12.021.
Daina, A., Michielin, O., Zoete, V., 2017. SwissADME: a free web tool to evaluate
pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small
molecules. Sci. Rep. 7, 42717. https://doi.org/10.1038/srep42717.
Dib-Hajj, S., 2017. Sodium channels in pain disorders: pathophysiology and prospects for
treatment. Pain 158, S97–S107. https://doi.org/10.1097/j.
pain.0000000000000854.
Dubin, A.E., Patapoutian, A., 2010. Nociceptors: the sensors of the pain pathway. J. Clin.
Invest. 120, 3760–3772. https://doi.org/10.1172/JCI42843.
Fink, M., Lesage, F., Duprat, F., Heurteaux, C., Reyes, R., Fosset, M., Lazdunski, M., 1998.
A neuronal two P domain K+ channel stimulated by arachidonic acid and
polyunsaturated fatty acids. EMBO J 17, 3297–3308. https://doi.org/10.1093/
emboj/17.12.3297.
Garami, A., Pakai, E., McDonald, H.A., Reilly, R.M., Gomtsyan, A., Corrigan, J.J., et al.,
2018. TRPV1 antagonists that cause hypothermia, instead of hyperthermia, in
rodents: compounds’ pharmacological profiles, in vivo targets, thermoeffectors
recruited and implications for drug development. Acta Physiol. (Oxf.). 223, e13038.
https://doi.org/10.1111/apha.13038.
Garami, A., Shimansky, Y.P., Pakai, E., Oliveira, D.L., Gavva, N.R., Romanovsky, A.A.,
2010. Contributions of different modes of TRPV1 activation to TRPV1 antagonistinduced
hyperthermia. J. Neurosci. 30, 1435–1440. https://doi.org/10.1523/
JNEUROSCI.5150-09.2010
Goodwin, G., McMahon, S.B., 2021. The physiological function of different voltage-gated
sodium channels in pain. Nat. Rev. Neurosci. 22, 263–274. https://doi.org/10.1038/
s41583-021-00444-w.
Kim, H.J., Park, S., Shin, H.Y., Nam, Y.R., Lam Hong, P.T., Chin, Y.W., Nam, J.H.,
Kim, W.K., 2021. Inhibitory effects of alpha-mangostin on T cell cytokine secretion
via ORAI1 calcium channel and K+ channels inhibition. PeerJ 9, e10973. https://
doi.org/10.7717/peerj.10973.
Kittipaspallop, W., Taepavarapruk, P., Chanchao, C., Pimtong, W., 2018. Acute toxicity
and teratogenicity of alpha-mangostin in zebrafish embryos. Exp. Biol. Med.
(Maywood) 243, 1212–1219. https://doi.org/10.1177/1535370218819743.
Lee, J., Kim, S., Kim, H.M., Kim, H.J., Yu, F.H., 2019. NaV1.6 and NaV1.7 channels are
major endogenous voltage-gated sodium channels in ND7/23 cells. PLoS One 14,
e0221156. https://doi.org/10.1371/journal.pone.0221156.
Lin, Y.T., Chen, J.C., 2018. Dorsal Root Ganglia Isolation and Primary Culture to Study
Neurotransmitter Release. J. Vis. Exp. 140, 57569. https://doi.org/10.3791/57569.
Mathie, A., Veale, E.L., 2015. Two-pore domain potassium channels: potential
therapeutic targets for the treatment of pain. Pflugers Arch 467, 931–943. https://
doi.org/10.1007/s00424-014-1655-3.
Moore, C., Gupta, R., Jordt, S.E., Chen, Y., Liedtke, W.B., 2018. Regulation of pain and
itch by TRP channels. Neurosci. Bull. 34, 120–142. https://doi.org/10.1007/s12264-
017-0200-8.
Muegge, I., Heald, S.L., Brittelli, D., 2001. Simple selection criteria for drug-like chemical
matter. J. Med. Chem. 44, 1841–1846. https://doi.org/10.1021/jm015507e.
Plant, L.D., 2012. A role for K2P channels in the operation of somatosensory nociceptors.
Front. Mol. Neurosci. 5, 21. https://doi.org/10.3389/fnmol.2012.00021.
Ramsay, R.R., Popovic-Nikolic, M.R., Nikolic, K., Uliassi, E., Bolognesi, M.L., 2018.
A perspective on multi-target drug discovery and design for complex diseases. Clin.
Transl. Med. 7, 3. https://doi.org/10.1186/s40169-017-0181-2.
Romanovsky, A.A., Almeida, M.C., Garami, A., Steiner, A.A., Norman, M.H., Morrison, S.
F., et al., 2009. The transient receptor potential vanilloid-1 channel in
thermoregulation: a thermosensor it is not. Pharmacol. Rev. 61, 228–261. https://
doi.org/10.1124/pr.109.001263.
Ruankham, W., Suwanjang, W., Phopin, K., Songtawee, N., Prachayasittikul, V.,
Prachayasittikul, S., 2021. Modulatory effects of alpha-mangostin mediated by
SIRT1/3-FOXO3a pathway in oxidative stress-induced neuronal cells. Front. Nutr. 8,
714463 https://doi.org/10.3389/fnut.2021.714463.
Sani, M.H., Taher, M., Susanti, D., Kek, T.L., Salleh, M.Z., Zakaria, Z.A., 2015.
Mechanisms of alpha-mangostin-induced antinociception in a rodent model. Biol.
Res. Nurs. 17, 68–77. https://doi.org/10.1177/1099800414529648.
Tiwari, A., Khera, R., Rahi, S., Mehan, S., Makeen, H.A., Khormi, Y.H., et al., 2021.
Neuroprotective effect of alpha-mangostin in the ameliorating propionic acidinduced
experimental model of autism in Wistar rats. Brain. Sci. 11, 288. https://doi.
org/10.3390/brainsci11030288.
Trott, O., Olson, A.J., 2010. AutoDock Vina: improving the speed and accuracy of
docking with a new scoring function, efficient optimization, and multithreading.
J. Comput. Chem. 31, 455–461. https://doi.org/10.1002/jcc.21334.
Tulleuda, A., Cokic, B., Callejo, G., Saiani, B., Serra, J., Gasull, X., 2011. TRESK channel
contribution to nociceptive sensory neurons excitability: modulation by nerve injury.
Mol. Pain. 7, 30. https://doi.org/10.1186/1744-8069-7-30.
Wang, M.H., Zhang, K.J., Gu, Q.L., Bi, X.L., Wang, J.X., 2017. Pharmacology of
mangostins and their derivatives: a comprehensive review. Chin. J. Nat. Med. 15,
81–93. https://doi.org/10.1016/S1875-5364(17)30024-9.

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