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.

Autor: Zhou Y; Department of Clinical Laboratory, the First Hospital of Jilin University, Changchun, 130021, China.; Department of Pharmacology, College of Medicine, University of Arizona, 1501 North Campbell Drive, P.O. Box 245050, Tucson, AZ, 85724, USA., Cai S; Department of Pharmacology, College of Medicine, University of Arizona, 1501 North Campbell Drive, P.O. Box 245050, Tucson, AZ, 85724, USA., Gomez K; Department of Pharmacology, College of Medicine, University of Arizona, 1501 North Campbell Drive, P.O. Box 245050, Tucson, AZ, 85724, USA., Wijeratne EMK; Southwest Center for Natural Products Research, School of Natural Resources & the Environment, College of Agriculture & Life Sciences, The University of Arizona, Tucson, AZ, 85724, USA., Ji Y; Department of Pharmacology, College of Medicine, University of Arizona, 1501 North Campbell Drive, P.O. Box 245050, Tucson, AZ, 85724, USA., Bellampalli SS; Department of Pharmacology, College of Medicine, University of Arizona, 1501 North Campbell Drive, P.O. Box 245050, Tucson, AZ, 85724, USA., Luo S; Department of Pharmacology, College of Medicine, University of Arizona, 1501 North Campbell Drive, P.O. Box 245050, Tucson, AZ, 85724, USA., Moutal A; Department of Pharmacology, College of Medicine, University of Arizona, 1501 North Campbell Drive, P.O. Box 245050, Tucson, AZ, 85724, USA., Gunatilaka AAL; Southwest Center for Natural Products Research, School of Natural Resources & the Environment, College of Agriculture & Life Sciences, The University of Arizona, Tucson, AZ, 85724, USA., Khanna R; Department of Pharmacology, College of Medicine, University of Arizona, 1501 North Campbell Drive, P.O. Box 245050, Tucson, AZ, 85724, USA. rkhanna@email.arizona.edu.; Neuroscience Graduate Interdisciplinary Program, College of Medicine, Tucson, AZ, 85724, USA. rkhanna@email.arizona.edu.; The Center for Innovation in Brain Sciences, The University of Arizona Health Sciences, Tucson, AZ, 85724, USA. rkhanna@email.arizona.edu.
Jazyk: angličtina
Zdroj: Molecular brain [Mol Brain] 2020 May 11; Vol. 13 (1), pp. 73. Date of Electronic Publication: 2020 May 11.
DOI: 10.1186/s13041-020-00616-2
Abstrakt: 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.
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje