The α7 nicotinic receptor silent agonist R-47 prevents and reverses paclitaxel-induced peripheral neuropathy in mice without tolerance or altering nicotine reward and withdrawal

Wisam Toma, S. Lauren Kyte, Deniz Bagdas, Asti Jackson, Julie A. Meade, Faria Rahman, Zhi Jian Chen, Egidio Del Fabbro, Lucas Cantwell, Abhijit Kulkarni, Ganesh A. Thakur, Roger L. Papke, John W. Bigbee, David A. Gewirtz, M. Imad Damaj

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Various antitumor drugs, including paclitaxel, frequently cause chemotherapy-induced peripheral neuropathy (CIPN) that can be sustained even after therapy has been completed. The current work was designed to evaluate R-47, an α7 nAChR silent agonist, in our mouse model of CIPN. R-47 was administered to male C57BL/6J mice prior to and during paclitaxel treatment. Additionally, we tested if R-47 would alter nicotine's reward and withdrawal effects. The H460 and A549 non-small cell lung cancer (NSCLC) cell lines were exposed to R-47 for 24–72 h, and tumor-bearing NSG mice received R-47 prior to and during paclitaxel treatment. R-47 prevents and reverses paclitaxel-induced mechanical hypersensitivity in mice in an α7 nAChR-dependent manner. No tolerance develops following repeated administration of R-47, and the drug lacks intrinsic rewarding effects. Additionally, R-47 neither changes the rewarding effect of nicotine in the Conditioned Place Preference test nor enhances mecamylamine-precipitated withdrawal. Furthermore, R-47 prevents paclitaxel-mediated loss of intraepidermal nerve fibers and morphological alterations of microglia in the spinal cord. Moreover, R-47 does not increase NSCLC cell viability, colony formation, or proliferation, and does not interfere with paclitaxel-induced growth arrest, DNA fragmentation, or apoptosis. Most importantly, R-47 does not increase the growth of A549 tumors or interfere with the antitumor activity of paclitaxel in tumor-bearing mice. These studies suggest that R-47 could be a viable and efficacious approach for the prevention and treatment of CIPN that would not interfere with the antitumor activity of paclitaxel or promote lung tumor growth.

Original languageEnglish (US)
Article number113010
JournalExperimental Neurology
Volume320
DOIs
StatePublished - Oct 2019
Externally publishedYes

Keywords

  • Cancer
  • Mice
  • Neuropathy
  • Paclitaxel
  • Withdrawal
  • α7 nAChR

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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