• Experimental neurology · Oct 2019

    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, and M Imad Damaj.
    • Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States of America. Electronic address: tomawb@vcu.edu.
    • Exp. Neurol. 2019 Oct 1; 320: 113010.

    AbstractVarious 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.Copyright © 2019 Elsevier Inc. All rights reserved.

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