Ondansetron alleviates testosterone-induced BPH in rats through cross regulation of the 5-HT/AR/P-STAT3 and the non-canonical NF-κB pathways

Benign prostatic hyperplasia (BPH) is a widespread age-related health issue. Every year, new pathological cues are revealed in the pathogenesis of BPH, however, the role of serotonin, Janus tyrosine kinase (JAK)-2/signal transducer and activator of the transcription (STAT)-3 and non-canonical nuclear factor-kappa B (NF-κB p52) pathways and their interaction with the androgen receptor (AR) in BPH are still not fully investigated. Accordingly, the aim of the current study was to unveil the possible modulatory effect of ondansetron alone and in combination with tamsulosin on these pathways and their utilization as therapeutic targets. Five groups of rats were utilized; group 1 received corn oil to serve as normal control, while the other groups administered testosterone (3 mg/kg, subcutaneously) dissolved in corn oil for 2 weeks followed by the co-administration of either tamsulosin (0.2 mg/kg, orally), ondansetron (2 mg/kg, intraperitoneally) or their combination for another 15 days along with testosterone injections. All treatments improved kidney function (creatinine and blood urea nitrogen), decreased oxidative stress (reduced glutathione and malondialdehyde), attenuated inflammation (NF-κB, cyclooxygenase-2), decreased AR expression, NF-κB p52, P-STAT3, transforming growth factor beta-1 in addition to markers of epithelial-mesenchymal transition (alpha smooth muscle actin and vimentin) this was associated with an increase in the prostatic content of serotonin, improvement in the histopathological picture and overall shrinkage in relative prostate weight. These results show that ondansetron is a very promising treatment for BPH especially in combination with tamsulosin and unveiled NF-κB p52 and serotonin as novel therapeutic targets in the management of BPH.