Protocatechuic acid counteracts cisplatin-induced oxidative testicular injury in rats through modulation of redox homeostasis

This investigation sought to ascertain the protective effects of protocatechuic acid (PCA) against cisplatin (CIS)-induced testicular toxicity in adult rats by exploring various underlying mechanisms, including oxidative stress (OS), the nuclear factor kappa (NF-κB)/interleukin-6 (IL-6) inflammatory axis, endoplasmic reticulum stress (ERS) and the sirtuin 1 (SIRT1)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. Thirty rats were split into five groups: sham control, 100 mg/kg of PCA alone, CIS (7.5 mg/kg), CIS + PCA (50 or 100 mg/kg). CIS was administered intraperitoneally on day 2 of the experiment, whilst PCA was administered orally for seven days. CIS administration caused a dramatic inhibition of the antioxidant system and severe lipid peroxidation by decreasing the levels of SIRT1 and Nrf2 in testicular tissue. In addition, the CIS administration triggered the NF-κB/IL-6 axis in testicular tissue, consequently resulting in a substantial inflammatory response, elevated ERS and apoptosis, as substantiated by histopathological and TUNEL observations. Conversely, PCA treatments exhibited a marked enhancement in testicular tissue, with significant improvements observed in OS, inflammation, ERS, and apoptosis levels. Additionally, PCA treatments resulted in a significant improvement in testicular tissue, at least in part by relieving the suppression of the SIRT1 and Nrf2 levels originating from the CIS. The present study is the first to demonstrate that PCA can offer a protective effect against CIS-induced testicular toxicity, by modulating the key pathways associated with antioxidant, anti-inflammatory, and anti-apoptotic responses. It is hypothesised that PCA may represent a promising chemopreventive molecule for the amelioration of testicular toxicity in male patients undergoing clinical CIS treatment.