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dc.contributor.authorZhou, Yuan
dc.contributor.authorCai, Song
dc.contributor.authorGomez, Kimberly
dc.contributor.authorWijeratne, E M Kithsiri
dc.contributor.authorJi, Yingshi
dc.contributor.authorBellampalli, Shreya S
dc.contributor.authorLuo, Shizhen
dc.contributor.authorMoutal, Aubin
dc.contributor.authorGunatilaka, A A Leslie
dc.contributor.authorKhanna, Rajesh
dc.date.accessioned2020-11-19T00:30:14Z
dc.date.available2020-11-19T00:30:14Z
dc.date.issued2020-05-11
dc.identifier.citationZhou, 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.en_US
dc.identifier.issn1756-6606
dc.identifier.pmid32393368
dc.identifier.doi10.1186/s13041-020-00616-2
dc.identifier.urihttp://hdl.handle.net/10150/648555
dc.description.abstractChronic 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.en_US
dc.language.isoenen_US
dc.publisherBMCen_US
dc.rights© 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.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.subject1-O-acetylgeopyxin aen_US
dc.subjectVoltage-gated sodium channelsen_US
dc.subjectTetrodotoxin-sensitive voltage-gated sodium channelsen_US
dc.subjectExcitabilityen_US
dc.subjectNon-opioid pain-relieving therapeuticsen_US
dc.subjectHIV-induced sensory neuropathyen_US
dc.title1-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 painen_US
dc.typeArticleen_US
dc.identifier.eissn1756-6606
dc.contributor.departmentUniv Arizona, Coll Med, Dept Pharmacolen_US
dc.contributor.departmentUniv Arizona, Coll Agr & Life Sci, Southwest Ctr Nat Prod Res, Sch Nat Resources & Environmen_US
dc.contributor.departmentUniv Arizona, Coll Med, Neurosci Grad Interdisciplinary Programen_US
dc.contributor.departmentUniv Arizona Hlth Sci, Ctr Innovat Brain Scien_US
dc.identifier.journalMOLECULAR BRAINen_US
dc.description.noteOpen access journalen_US
dc.description.collectioninformationThis 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.en_US
dc.eprint.versionFinal published versionen_US
dc.source.journaltitleMolecular brain
dc.source.volume13
dc.source.issue1
dc.source.beginpage73
dc.source.endpage
refterms.dateFOA2020-11-19T00:30:15Z
dc.source.countryUnited States
dc.source.countryEngland


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© 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.
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.