김성준 (서울대학교 의과대학)

한빛사논문

조회334

김성준Sung Joon Kim

서울대학교 의과대학

Phytomedicine, Jul 2023, 115 S0944-7113(23)00152-6 | https://doi.org/10.1016/j.phymed.2023.154791 Multi-target modulation of ion channels underlying the analgesic effects of α-mangostin in dorsal root ganglion neurons

Sung Eun Kim ^a,1, Ming Zhe Yin ^b,1, Jae Won Roh ^d,1, Hyun Jong Kim ^c,f, Seong Woo Choi ^c, Brian J. Wainger ^e, Woo Kyung Kim ^f,g, Sung Joon Kim ^a, Joo Hyun Nam ^c,e,f

^aDepartment of Physiology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea

^bDepartment of Anesthesiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China

^cDepartment of Physiology, Dongguk University College of Medicine, Gyeongju 38066, Republic of Korea

^dDepartment of Pharmacology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of Korea

^eDepartments Anesthesia, Critical Care & Pain Medicine and Neurology, Massachusetts General Hospital, Harvard Medical School, Boston 02114, ts, USA

^fChannelopathy Research Center (CRC), Dongguk University College of Medicine, Gyeonggi-do 10326, Republic of Korea

^gDepartment of Internal Medicine Graduate School of Medicine, Dongguk University, Gyeonggi-do 10326, Republic of Korea

¹These authors contributed equally to this work.

Corresponding authors : Woo Kyung Kim, Sung Joon Kim, Joo Hyun Nam

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.

논문정보

형식Research article
게재일2023년 07월 (BRIC 등록일 2023-12-28)
연구진국내(교신)+국외 연구진
분야 의약학 > 의약학 기타

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