Dimethyl Fumarate Attenuates Cyclophosphamide-Induced Bladder Damage and Enhances Cytotoxic Activity Against SH-SY5Y Cells

Abstract

Cylophosphamide (CP)-induced acute cystitis is a debilitating bladder dysfunction commonly observed in cancer patients, primarily resulting from oxidative damage and inflammation in the bladder tissue. Dimethyl fumarate (DMF) is a fumaric acid ester approved for the treatment of multiple sclerosis due to its antioxidant and anti-inflammatory properties. Thus, we aimed to investigate the multiple effects of DMF, involving both its potential synergistic effect with CP on the SH-SY5Y cells and its uroprotective effect on CP-induced acute cystitis. Female Balb/c mice were orally administrated DMF (100 or 300 mg/kg/day) for five consecutive days before a single intraperitoneal (i.p) dose of CP. Mesna was administered 20 min before and at 4 h, 8 h after CP application. Following 24 h of CP injection, bladders were removed for functional, biochemical analysis and evaluation of vesical vascular permeability. SH-SY5Y cell viability was assayed by MTT test. CP markedly decreased carbachol-induced contraction of detrusor strips (p < 0.01), which was prevented by the high-dose DMF treatment (p < 0.05). Evans blue dye extravasation was greatly increased in the bladders of cystitis group (p < 0.001), which was significantly decreased in DMF-treated mice with cystitis (p < 0.01). Total GSH content was decreased (p < 0.01) whereas TNF-α level was increased (p < 0.05) in the bladders of cystitis group. High-dose DMF-treated mice showed an increment in total GSH content (p < 0.05) without any alterations on TNF-α levels of the bladders with cystitis. Additionally, combination of different concentrations of CP and DMF exhibited a potent synergistic cytotoxic effect in SH-SY5Y cells. DMF improved CP-induced acute cystitis by partially suppressing oxidative stress and inflammation, while also enhancing the cytotoxic effects of CP.