α-Phellandrene attenuates tissular damage, oxidative stress, and TNF-α levels on acute model ifosfamide-induced hemorrhagic cystitis in mice.

Hemorrhagic cystitis (HC) is the major dose-limiting adverse effect of the clinical use ifosfamide (IFOS). The incidence of this side effect can be as high as 75%. Mesna has been used to reduce the risk of HC, although 5% of patients who get IFOS treatment may still suffer from HC. In previous studies, our group demonstrated that α-phellandrene (α-PHE) possesses anti-inflammatory activity, which opens the door for its study in the attenuation of HC. The objective of this study was to investigate the potential uroprotective effect of the α-PHE in the mouse model of IFOS-induced HC. In order to analyze the reduction of the urothelial damage, the bladder wet weight, hemoglobin content, and the Evans blue dye extravasation from the bladder matrix were evaluated. To investigate the involvement of neutrophil migration and lipid peroxidation and involvement of enzymatic and endogenous non-enzymatic antioxidants, the tissue markers myeloperoxidase (MPO), malondialdehyde, nitrite/nitrate (NOx), superoxide dismutase (SOD), and reduced glutathione (GSH) were evaluated. TNF-α and IL-1β were measured by ELISA immunoassay technique. The results show that pretreatment with α-PHE significantly reduced urothelial damage that was accompanied by a decrease in the activity of MPO, MDA, and NOx levels and prevention of the depletion of SOD and GSH in bladder tissues. In the assessment of cytokines, α-PHE was able to significantly reduce TNF-α level. However, it does not affect the activities of IL-1β. These data confirm that α-PHE exerts potent anti-inflammatory properties and demonstrates that α-PHE represents a promising therapeutic option for this pathological condition.