TY - JOUR
T1 - (-)-Hardwickiic Acid and Hautriwaic Acid Induce Antinociception via Blockade of Tetrodotoxin-Sensitive Voltage-Dependent Sodium Channels
AU - Cai, Song
AU - Bellampalli, Shreya S.
AU - Yu, Jie
AU - Li, Wennan
AU - Ji, Yingshi
AU - Wijeratne, E. M.Kithsiri
AU - Dorame, Angie
AU - Luo, Shizhen
AU - Shan, Zhiming
AU - Khanna, May
AU - Moutal, Aubin
AU - Streicher, John M.
AU - Gunatilaka, A. A.Leslie
AU - Khanna, Rajesh
N1 - Funding Information:
*Mailing address; Department of Pharmacology, College of Medicine, University of Arizona, 1501 North Campbell Drive, P.O. Box 245050, Tucson, AZ 85724, USA. Office phone: 520-626-4281. Fax: 520-626-2204. E-mail: rkhanna@email.arizona. edu. ORCID May Khanna: 0000-0002-9989-6374 John M. Streicher: 0000-0002-4173-7362 Rajesh Khanna: 0000-0002-9066-2969 Author Contributions S.C. and S.S.B. are co-first authors. S.C., J.Y., W.L., and Z.S. conducted whole-cell electrophysiology. E.M.K.W. synthesized the compounds. S.S.B., Y.J., A.D., A.M. performed calcium imaging experiments. S.L. performed the behavioral experiments. J.M.S. supervised the opioid receptor binding experiments. A.A.L.G. and R.K. conceived the study. A.A.L.G., M.K., and R.K. designed/supervised the overall project and wrote the manuscript. Funding This work is supported by a National Institutes of Health Award (1R01NS098772, 1R01DA042852, and 1R01NS098772) to R.K. A.M. was supported by a Young Investigator’s Award from the Children’s Tumor Foundation.
Publisher Copyright:
© 2018 American Chemical Society.
PY - 2019/3/20
Y1 - 2019/3/20
N2 - For an affliction that debilitates an estimated 50 million adults in the United States, the current chronic pain management approaches are inadequate. The Centers for Disease Control and Prevention have called for a minimization in opioid prescription and use for chronic pain conditions, and thus, it is imperative to discover alternative non-opioid based strategies. For the realization of this call, a library of natural products was screened in search of pharmacological inhibitors of both voltage-gated calcium channels and voltage-gated sodium channels, which are excellent targets due to their well-established roles in nociceptive pathways. We discovered (-)-hardwickiic acid ((-)-HDA) and hautriwaic acid (HTA) isolated from plants, Croton californicus and Eremocarpus setigerus, respectively, inhibited tetrodotoxin-sensitive sodium, but not calcium or potassium, channels in small diameter, presumptively nociceptive, dorsal root ganglion (DRG) neurons. Failure to inhibit spontaneous postsynaptic excitatory currents indicated a preferential targeting of voltage-gated sodium channels over voltage-gated calcium channels by these extracts. Neither compound was a ligand at opioid receptors. Finally, we identified the potential of both (-)-HDA and HTA to reverse chronic pain behavior in preclinical rat models of HIV-sensory neuropathy, and for (-)-HDA specifically, in chemotherapy-induced peripheral neuropathy. Our results illustrate the therapeutic potential for (-)-HDA and HTA for chronic pain management and could represent a scaffold, that, if optimized by structure-activity relationship studies, may yield novel specific sodium channel antagonists for pain relief.
AB - For an affliction that debilitates an estimated 50 million adults in the United States, the current chronic pain management approaches are inadequate. The Centers for Disease Control and Prevention have called for a minimization in opioid prescription and use for chronic pain conditions, and thus, it is imperative to discover alternative non-opioid based strategies. For the realization of this call, a library of natural products was screened in search of pharmacological inhibitors of both voltage-gated calcium channels and voltage-gated sodium channels, which are excellent targets due to their well-established roles in nociceptive pathways. We discovered (-)-hardwickiic acid ((-)-HDA) and hautriwaic acid (HTA) isolated from plants, Croton californicus and Eremocarpus setigerus, respectively, inhibited tetrodotoxin-sensitive sodium, but not calcium or potassium, channels in small diameter, presumptively nociceptive, dorsal root ganglion (DRG) neurons. Failure to inhibit spontaneous postsynaptic excitatory currents indicated a preferential targeting of voltage-gated sodium channels over voltage-gated calcium channels by these extracts. Neither compound was a ligand at opioid receptors. Finally, we identified the potential of both (-)-HDA and HTA to reverse chronic pain behavior in preclinical rat models of HIV-sensory neuropathy, and for (-)-HDA specifically, in chemotherapy-induced peripheral neuropathy. Our results illustrate the therapeutic potential for (-)-HDA and HTA for chronic pain management and could represent a scaffold, that, if optimized by structure-activity relationship studies, may yield novel specific sodium channel antagonists for pain relief.
KW - (-)-hardwickiic acid
KW - HIV-associated sensory neuropathy
KW - Natural products
KW - chemotherapy-induced peripheral neuropathy
KW - hautriwaic acid
KW - non-opioid
KW - voltage-gated sodium channels
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UR - http://www.scopus.com/inward/citedby.url?scp=85063202765&partnerID=8YFLogxK
U2 - 10.1021/acschemneuro.8b00617
DO - 10.1021/acschemneuro.8b00617
M3 - Article
C2 - 30525440
AN - SCOPUS:85063202765
VL - 10
SP - 1716
EP - 1728
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
SN - 1948-7193
IS - 3
ER -