Cepharanthine alleviated chronic prostatitis/chronic pelvic pain syndrome by activating Nrf2 and inhibiting the NF-κB pathway.

BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common disorder impacting the genitourinary system of adult males, primarily driven by pathogenic mechanisms involving immune and inflammatory mediators, immune cells and molecules, oxidative stress, and apoptosis. Cepharanthine (CEP), a bisbenzylisoquinoline alkaloid, exhibits properties such as immunomodulatory, antioxidant, anti-inflammatory, and antitumor activities. Nevertheless, the effects of CEP on CP/CPPS and its underlying mechanisms remain insufficiently characterized. METHODS: Two experimental models were developed, one utilizing experimental autoimmune prostatitis (EAP) mouse models and the other employing LPS-induced RWPE-1 cells. The pivotal role of Nrf2 was investigated using Nrf2 knockout mice and the Nrf2 inhibitor ML385. RESULTS: Treatment with CEP reduced prostate inflammation scores, alleviated tactile sensitization of the pelvic region in EAP mice, improved pathological damage in prostate tissues, and inhibited the upregulation of systemic and localized pain and pro-inflammatory mediators in the prostate. Furthermore, CEP treatment was shown to inhibit oxidative stress, ameliorate mitochondrial dysfunction, and suppress apoptosis. In vitro studies indicate that CEP treatment stabilizes Nrf2 protein levels by binding to the Nrf2 protein and inhibiting its ubiquitination-mediated degradation. Consequently, CEP treatment activates the Nrf2 signaling pathway, facilitates its nuclear translocation, and upregulates the expression of downstream target proteins, such as HO-1 and NQO1. Concurrently, CEP suppresses the activation of the NF-κB pathway. Notably, the blockade of Nrf2 signaling negates the protective effects mediated by CEP. CONCLUSIONS: CEP inhibits the ubiquitination-mediated degradation of Nrf2 and exhibits potential to activate the Nrf2 pathway while concurrently inhibiting the NF-κB pathway, thereby alleviating CP/CPPS.