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

Yuan Zhou, Song Cai, Kimberly Gomez, E. M.Kithsiri Wijeratne, Yingshi Ji, Shreya S. Bellampalli, Shizhen Luo, Aubin Moutal, A. A.Leslie Gunatilaka, Rajesh Khanna

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number73
JournalMolecular Brain
Volume13
Issue number1
DOIs
StatePublished - May 11 2020

Keywords

  • 1-O-acetylgeopyxin a
  • Excitability
  • HIV-induced sensory neuropathy
  • Non-opioid pain-relieving therapeutics
  • Tetrodotoxin-sensitive voltage-gated sodium channels
  • Voltage-gated calcium channels
  • Voltage-gated sodium channels

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

  • Cite this