Biological effect of ketamine in urothelial cell lines and global gene expression analysis in the bladders of ketamineinjected mice

Abstract

Ketamine is used clinically for anesthesia but is also abused as a recreational drug. Previously, it has been established that ketamineinduced bladder interstitial cystitis is a common syndrome in ketamineabusing individuals. As the mechanisms underlying ketamineinduced cystitis have yet to be revealed, the present study investigated the effect of ketamine on human urothelial cell lines and utilized a ketamineinjected mouse model to identify ketamineinduced changes in gene expression in mice bladders. In the in vitro bladder cell line assay, ketamine induced cytotoxicity in a doseand timedependent manner. Ketamine arrested the cells in G1 phase and increased the subG1 population, and also increased the barrier permeability of these cell lines. In the ketamineinjected mouse model, ketamine did not change the body weight and bladder histology of the animals at the dose of 30 mg/kg/day for 60 days. Global gene expression analysis of the animals' bladders following data screening identified ten upregulated genes and 36 downregulated genes induced by ketamine. A total of 52% of keratin family genes were downregulated, particularly keratin 6a, 13 and 14, which was confirmed by polymerase chain reaction analysis. Keratin 14 protein, one of the 36 ketamineinduced downregulated genes, was also reduced in the ketaminetreated mouse bladder, as determined by immunohistochemical analysis. This suggested that cytotoxicity and keratin gene downregulation may have a critical role in ketamineinduced cystitis.