Bardoxolone Methyl Ameliorates Chemotherapy-Induced Neuropathic Pain by Activation of Phosphorylated Nuclear Factor Erythroid 2-Related Factor 2 in the Dorsal Root Ganglia

Authors

Hee Kee Kim
Qi Wang
Seon-Hee Hwang
Patrick M Dougherty
Jing Wang
Salahadin Abdi

Publication Date

3-1-2024

Journal

Anesthesia & Analgesia

DOI

10.1213/ANE.0000000000006736

PMID

38112490

PMCID

PMC10922949

PubMedCentral® Posted Date

9-1-2024

PubMedCentral® Full Text Version

Author MSS

Abstract

Background: Many chemotherapeutic drugs, including paclitaxel, produce neuropathic pain in patients with cancer, which is a dose-dependent adverse effect. Such chemotherapy-induced neuropathic pain (CINP) is difficult to treat with existing drugs. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a major regulator of antioxidative responses and activates phosphorylated Nrf2 (pNrf2). We determined the analgesic effects of bardoxolone methyl (BM), an Nrf2 activator, and the role of pNrf2 on CINP.

Methods: CINP was induced in rats by intraperitoneally injecting paclitaxel on 4 alternate days in rats. BM was injected systemically as single or repeated injections after pain fully developed. RNA transcriptome, mechanical hyperalgesia, levels of inflammatory mediators and pNrf2, and location of pNrf2 in the dorsal root ganglia (DRG) were measured by RNA sequencing, von Frey filaments, Western blotting, and immunohistochemistry in rats and human DRG samples. In addition, the mitochondrial functions in 50B11 DRG neuronal cells were measured by fluorescence assay.

Results: Our RNA transcriptome of CINP rats showed a downregulated Nrf2 pathway in the pain condition. Importantly, single and repeated systemic injections of BM ameliorated CINP. Paclitaxel increased inflammatory mediators, but BM decreased them and increased pNrf2 in the DRG. In addition, paclitaxel decreased mitochondrial membrane potential and increased mitochondrial volume in 50B11 cells, but BM restored them. Furthermore, pNrf2 was expressed in neurons and satellite cells in rat and human DRG.

Conclusions: Our results demonstrate the analgesic effects of BM by Nrf2 activation and the fundamental role of pNrf2 on CINP, suggesting a target for CINP and a therapeutic strategy for patients.

Keywords

Humans, Rats, Animals, Rats, Sprague-Dawley, Ganglia, Spinal, NF-E2-Related Factor 2, Neuralgia, Paclitaxel, Hyperalgesia, Antineoplastic Agents, Analgesics, RNA, Inflammation Mediators, Oleanolic Acid

Published Open-Access

yes

Recommended Citation

Kim, Hee Kee; Wang, Qi; Hwang, Seon-Hee; et al., "Bardoxolone Methyl Ameliorates Chemotherapy-Induced Neuropathic Pain by Activation of Phosphorylated Nuclear Factor Erythroid 2-Related Factor 2 in the Dorsal Root Ganglia" (2024). Faculty, Staff and Student Publications. 3030.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/3030