AKAP150 involved in paclitaxel-induced neuropathic pain via inhibiting CN/NFAT2 pathway and downregulating IL-4.

Abstract

Antitubulin chemotherapeutics agents, such as paclitaxel, are effective chemotherapy drugs for cancer treatment. However, painful neuropathy is a major adverse effect limiting the wider application of chemotherapeutics. In this study, we found that A-kinase anchor protein 150 (AKAP150) was significantly upregulated after paclitaxel injection. Inhibition of AKAP150 via siRNA or AKAP150flox/flox in rodents alleviated the pain behavior induced by paclitaxel, and partly restored the decreased calcineurin (CN) phosphatase activity after paclitaxel treatment. Paclitaxel decreased the expression of anti-inflammatory cytokine interleukin-4 (IL-4), and intrathecal injections of IL-4 effectively alleviated paclitaxel-induced hypersensitivity and the frequency of dorsal root ganglion (DRG) neurons action potential. The decreased CN enzyme activity, resulted in reduced protein expression of nuclear factor of activated T cells 2 (NFAT2) in cell nuclei. Chromatin immunoprecipitation showed that, NFAT2 binds to the IL-4 gene promoter regulating the protein expression of IL-4. Overexpression of NFAT2 by intrathecal injection of the AAV5-NFAT2-GFP virus alleviated the pain behavior induced by paclitaxel via increasing the expression of IL-4. Knocked down AKAP150 by siRNA or AAV5-Cre-GFP partly restored the expression of IL-4 in DRG. Our results indicated that regulation of IL-4 via the CN/NFAT2 pathway mediated by AKAP150 could be a pivotal treatment target for paclitaxel-induced neuropathic pain and or other neuropsychiatric disorders.

• Authors: Bilin Nie, Cuicui Liu, Xiaohui Bai, Xiaodi Chen, Shaoyong Wu, Subo Zhang, Zhuxi Huang, Manxiu Xie, Ting Xu, Wenjun Xin, Weian Zeng, Handong Ouyang
• Journal: Brain, behavior, and immunity (Brain Behav Immun) Vol. 68 Pg. 158-168 (02 2018) ISSN: 1090-2139 [Electronic] Netherlands
• PMID: 29056557 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• A Kinase Anchor Proteins
• Akap5 protein, rat
• Cytokines
• NFATC Transcription Factors
• Interleukin-4
• Calcineurin
• Paclitaxel

Topics

• A Kinase Anchor Proteins (metabolism, physiology)
• Animals
• Calcineurin (drug effects, metabolism)
• Cytokines (metabolism)
• Down-Regulation
• Ganglia, Spinal (metabolism)
• Hyperalgesia (metabolism)
• Injections, Spinal
• Interleukin-4 (metabolism)
• Male
• NFATC Transcription Factors (drug effects, metabolism)
• Neuralgia (metabolism, physiopathology)
• Paclitaxel (adverse effects)
• Rats
• Rats, Sprague-Dawley
• Spinal Cord (metabolism)
• Up-Regulation