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Brain Behav Immun. 2018 Feb;68:158-168. doi: 10.1016/j.bbi.2017.10.015. Epub 2017 Oct 19.

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

Author information

1
Department of Anesthesiology, Guangdong Women and Children Hospital, Guangzhou, China; Department of Anesthesiology, State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
2
Department of Rehabilitation Medicine and Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
3
Department of Anesthesiology, State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
4
Zhongshan Medicine School, Guangdong Province Key Laboratory of Brain Function and Disease, Sun Yat-sen University, Guangzhou, China. Electronic address: xuting35@mail2.sysu.edu.cn.
5
Zhongshan Medicine School, Guangdong Province Key Laboratory of Brain Function and Disease, Sun Yat-sen University, Guangzhou, China.
6
Department of Anesthesiology, State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. Electronic address: ouyhd@sysucc.org.cn.

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.

KEYWORDS:

AKAP150; Calcineurin; Dorsal root ganglion; IL-4; NFAT2; Neuropathic pain; Paclitaxel

PMID:
29056557
DOI:
10.1016/j.bbi.2017.10.015
[Indexed for MEDLINE]

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