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

doi:10.1016/j.phymed.2023.154791

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

Phytomedicine. 2023 Jul:115:154791. doi: 10.1016/j.phymed.2023.154791. Epub 2023 Mar 31.

Authors

Sung Eun Kim¹, Ming Zhe Yin², Jae Won Roh³, Hyun Jong Kim⁴, Seong Woo Choi⁵, Brian J Wainger⁶, Woo Kyung Kim⁷, Sung Joon Kim⁸, Joo Hyun Nam⁹

Affiliations

¹ Department of Physiology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
² Department of Anesthesiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.
³ Department of Pharmacology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
⁴ Department of Physiology, Dongguk University College of Medicine, Gyeongju 38066, Republic of Korea; Channelopathy Research Center (CRC), Dongguk University College of Medicine, Gyeonggi-do 10326, Republic of Korea.
⁵ Department of Physiology, Dongguk University College of Medicine, Gyeongju 38066, Republic of Korea.
⁶ Departments Anesthesia, Critical Care & Pain Medicine and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston 02114, ts, USA.
⁷ Channelopathy Research Center (CRC), Dongguk University College of Medicine, Gyeonggi-do 10326, Republic of Korea; Department of Internal Medicine Graduate School of Medicine, Dongguk University, Gyeonggi-do 10326, Republic of Korea. Electronic address: wk2kim@naver.com.
⁸ Department of Physiology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. Electronic address: sjoonkim@snu.ac.kr.
⁹ Department of Physiology, Dongguk University College of Medicine, Gyeongju 38066, Republic of Korea; Departments Anesthesia, Critical Care & Pain Medicine and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston 02114, ts, USA; Channelopathy Research Center (CRC), Dongguk University College of Medicine, Gyeonggi-do 10326, Republic of Korea. Electronic address: jhnam@dongguk.ac.kr.

PMID: 37094425
DOI: 10.1016/j.phymed.2023.154791

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 (Na_V) currents. MD simulation revealed that multiple oxygen atoms in α-mangostin may form stable hydrogen bonds with TREKs, TRAAK, TRPV1, and Na_V 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 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.

Keywords: Analgesic mechanism; Dorsal root ganglion; Nociceptor; TREK/TRAAK; TRPV1; Voltage-operated Na(+) channel; α-Mangostin.

MeSH terms

Animals
Ganglia, Spinal*
HEK293 Cells
Humans
Mice
Molecular Docking Simulation
Neurons*
Tetrodotoxin / metabolism
Tetrodotoxin / pharmacology

Substances

mangostin
Tetrodotoxin