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

• Published in: Brain, behavior, and immunity Vol. 68; pp. 158 - 168
• Main Authors: Nie, Bilin, Liu, Cuicui, Bai, Xiaohui, Chen, Xiaodi, Wu, Shaoyong, Zhang, Subo, Huang, Zhuxi, Xie, Manxiu, Xu, Ting, Xin, Wenjun, Zeng, Weian, Ouyang, Handong
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.02.2018
• Subjects: A Kinase Anchor Proteins - metabolism; A Kinase Anchor Proteins - physiology; AKAP150; Animals; Calcineurin; Calcineurin - drug effects; Calcineurin - metabolism; Cytokines - metabolism; Dorsal root ganglion; Down-Regulation; Ganglia, Spinal - metabolism; Hyperalgesia - metabolism; IL-4; Injections, Spinal; Interleukin-4 - metabolism; Male; Neuralgia - metabolism; Neuralgia - physiopathology; Neuropathic pain; NFAT2; NFATC Transcription Factors - drug effects; NFATC Transcription Factors - metabolism; Paclitaxel; Paclitaxel - adverse effects; Rats; Rats, Sprague-Dawley; Spinal Cord - metabolism; Up-Regulation; Calcineurin; Paclitaxel; IL-4; AKAP150; Dorsal root ganglion; NFAT2; Neuropathic pain
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2017.10.015

•AKAP150 was significantly upregulated in DRG after paclitaxel injection.•Increased AKAP150 affected CN enzyme activity after paclitaxel treatment.•Paclitaxel injection inhibited CN enzyme activity and reduced NFAT2 translocation.•IL-4 expression mediated by NFAT2 inhibited paclitaxel-induced neuropathic pain.•AKAP150 mediated CN/NFAT2 pathway might be a novel target for pain management. 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.