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

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 AKAP150 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.