1-O-Acetylgeopyxin A, a derivative of a fungal metabolite, blocks tetrodotoxin-sensitive voltage-gated sodium, calcium channels and neuronal excitability which correlates with inhibition of neuropathic pain
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Author
Zhou, YuanCai, Song
Gomez, Kimberly
Wijeratne, E M Kithsiri
Ji, Yingshi
Bellampalli, Shreya S
Luo, Shizhen
Moutal, Aubin
Gunatilaka, A A Leslie
Khanna, Rajesh
Affiliation
Univ Arizona, Coll Med, Dept PharmacolUniv Arizona, Coll Agr & Life Sci, Southwest Ctr Nat Prod Res, Sch Nat Resources & Environm
Univ Arizona, Coll Med, Neurosci Grad Interdisciplinary Program
Univ Arizona Hlth Sci, Ctr Innovat Brain Sci
Issue Date
2020-05-11Keywords
1-O-acetylgeopyxin aVoltage-gated sodium channels
Tetrodotoxin-sensitive voltage-gated sodium channels
Excitability
Non-opioid pain-relieving therapeutics
HIV-induced sensory neuropathy
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Zhou, Y., Cai, S., Gomez, K., Wijeratne, E. K., Ji, Y., Bellampalli, S. S., ... & Khanna, R. (2020). 1-O-Acetylgeopyxin A, a derivative of a fungal metabolite, blocks tetrodotoxin-sensitive voltage-gated sodium, calcium channels and neuronal excitability which correlates with inhibition of neuropathic pain. Molecular Brain, 13, 1-12.Journal
MOLECULAR BRAINRights
© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.Abstract
Chronic pain can be the result of an underlying disease or condition, medical treatment, inflammation, or injury. The number of persons experiencing this type of pain is substantial, affecting upwards of 50 million adults in the United States. Pharmacotherapy of most of the severe chronic pain patients includes drugs such as gabapentinoids, re-uptake blockers and opioids. Unfortunately, gabapentinoids are not effective in up to two-thirds of this population and although opioids can be initially effective, their long-term use is associated with multiple side effects. Therefore, there is a great need to develop novel non-opioid alternative therapies to relieve chronic pain. For this purpose, we screened a small library of natural products and their derivatives in the search for pharmacological inhibitors of voltage-gated calcium and sodium channels, which are outstanding molecular targets due to their important roles in nociceptive pathways. We discovered that the acetylated derivative of the ent-kaurane diterpenoid, geopyxin A, 1-O-acetylgeopyxin A, blocks voltage-gated calcium and tetrodotoxin-sensitive voltage-gated sodium channels but not tetrodotoxin-resistant sodium channels in dorsal root ganglion (DRG) neurons. Consistent with inhibition of voltage-gated sodium and calcium channels, 1-O-acetylgeopyxin A reduced reduce action potential firing frequency and increased firing threshold (rheobase) in DRG neurons. Finally, we identified the potential of 1-O-acetylgeopyxin A to reverse mechanical allodynia in a preclinical rat model of HIV-induced sensory neuropathy. Dual targeting of both sodium and calcium channels may permit block of nociceptor excitability and of release of pro-nociceptive transmitters. Future studies will harness the core structure of geopyxins for the generation of antinociceptive drugs.Note
Open access journalISSN
1756-6606EISSN
1756-6606PubMed ID
32393368Version
Final published versionae974a485f413a2113503eed53cd6c53
10.1186/s13041-020-00616-2
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Except where otherwise noted, this item's license is described as © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
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