The Isopropyl Gallate Counteracts Cyclophosphamide-Induced Hemorrhagic Cystitis in Mice

SIMPLE SUMMARY: Ifosfamide (IFOS) is an antineoplastic drug used to treat various cancers. Hemorrhagic cystitis (HC) is the main adverse effect related to the use of IFOS. Acrolein, a metabolite of IFOS, is the main molecule responsible for this side-effect, resulting in increased oxidative stress and production of inflammatory mediators, which culminate in the degradation of bladder tissue. In clinical practice, mesna is used to reduce the incidence of HC. However, this drug presents some dose-dependent side effects. Isopropyl gallate (IPG), a gallic acid-derived compound, is promising for the development of new anti-inflammatory agents. In the present study, the effects of oral administration of IPG against IFOS-induced hemorrhagic cystitis in mice were investigated. Interestingly pretreatment of IPG was able to reduce IFOS-induced bladder damage evidenced by a decrease of inflammatory parameters and improvement in histology and antioxidants of the urinary bladder. Furthermore, IPG significantly decreased the expression levels of inflammatory biomarkers in the bladder tissue. These preliminary findings suggest that IPG represents a promising adjuvant therapy for protecting against IFOS-induced urotoxicity. ABSTRACT: Hemorrhagic cystitis is the main adverse effect associated with the clinical use of oxazaphosphorine, resulting in increased oxidative stress and proinflammatory cytokines, which culminate in injury of the bladder tissue. The aim of this study was to evaluate the protective effect of isopropyl gallate (IPG) against ifosfamide (IFOS)-induced hemorrhagic cystitis in mice. The induction of the hemorrhagic cystitis model was carried out using a single dose of IFOS (400 mg/kg, i.p.) four hours after oral pretreatment with IPG (6.25, 12.5, 25, and 50 mg/kg) or saline (vehicle). Mesna (positive control; 80 mg/kg, i.p.) was administered four hours before and eight hours after induction of cystitis. In the present study, IPG 25 mg/kg significantly decreased edema and hemorrhage, with a reduction of the bladder wet weight (36.86%), hemoglobin content (54.55%), and peritoneal vascular permeability (42.94%) in urinary bladders of mice. Interestingly, IPG increased SOD activity (89.27%) and reduced MDA levels (35.53%), as well as displayed anti-inflammatory activity by decreasing TNF-α (88.77%), IL-1β (62.87%), and C-reactive protein (56.41%) levels. Our findings demonstrate that IPG has a substantial protective role against IFOS-induced hemorrhagic cystitis in mice by enhancing antioxidant activity and proinflammatory mechanisms. Thus, IPG represents a promising co-adjuvant agent in oxazaphosphorine-based chemotherapy treatments.