Translocation of NF-κB and Expression of Cyclooxygenase-2 Are Enhanced by Ketamine-Induced Ulcerative Cystitis in Rat Bladder

Yung Shun Juan, Yi Lun Lee, Cheng Yu Long, Jhen Hong Wong, Mei Yu Jang, Jian He Lu, Wen Jeng Wu, Yen Shun Huang, Wei Chiao Chang, Shu Mien Chuang

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Abstract

The number of ketamine abusers has increased significantly recently. Ketamine abusers exhibit urinary frequency, urgency, and at times urinary incontinence. Our aim was to investigate the role of transcription factor NF-κB and cyclooxygenase (COX)-2 in ketamine-induced cystitis. Sprague-Dawley rats were distributed into three groups, which received saline or treatment with ketamine or ketamine combined with a Cox-2 inhibitor (parecoxib). In addition, the toxic effect of ketamine and its metabolites were examined by primary urothelial cell culture. The ketamine-treated group displayed bladder hyperactivity and decreased bladder capacity. Treatment with ketamine + COX-2 inhibitor prevented these bladder dysfunctions. These bladder dysfunctions were accompanied by increases in the expression of NF-κB and COX-2 at the protein and mRNA levels. Ketamine treatment also enhanced bladder interstitial fibrosis, whereas ketamine + Cox-2 inhibitor decreased the intensity of fibrosis. Treatment of primary urothelial cells in vitro with ketamine or urine obtained from ketamine-treated rats stimulated the expression of NF-κB p65 and COX-2. Ketamine also initiated NF-κB translocation from cell cytoplasm to nucleus. Treatment with NF-κB inhibitor suppressed Cox-2 mRNA expression. Promoter-deletion analysis revealed that NF-κB was a necessary transcription factor for COX-2 gene (Ptgs2) activation. These results demonstrate that the regulation of COX-2 via the NF-κB pathway is involved in the inflammatory signaling of ketamine-induced cystitis in rat urinary bladder.

Original languageEnglish
Pages (from-to)2269-2285
Number of pages17
JournalAmerican Journal of Pathology
Volume185
Issue number8
DOIs
Publication statusPublished - Aug 1 2015

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Juan, Y. S., Lee, Y. L., Long, C. Y., Wong, J. H., Jang, M. Y., Lu, J. H., Wu, W. J., Huang, Y. S., Chang, W. C., & Chuang, S. M. (2015). Translocation of NF-κB and Expression of Cyclooxygenase-2 Are Enhanced by Ketamine-Induced Ulcerative Cystitis in Rat Bladder. American Journal of Pathology, 185(8), 2269-2285. https://doi.org/10.1016/j.ajpath.2015.04.020