Acrolein is a urinary metabolite of
cyclophosphamide and
ifosfamide, which has been reported to be the causative agent of
hemorrhagic cystitis induced by these compounds. A direct cytotoxic effect of
acrolein, however, has not yet been demonstrated. In the present study, the effects of
intravesical injection of
acrolein and
mesna, the classical
acrolein chemical inhibitor, were evaluated. Male Swiss mice weighing 25 to 35 g (N = 6 per group) received saline or
acrolein (25, 75, 225 microg) intravesically 3, 6, 12, and 24 h before sacrifice for evaluation of bladder wet weight, macroscopic and histopathological changes by Gray's criteria, and 3 and 24 h for assessment of increase in vascular permeability. In other animals,
mesna was administered intravesically (2 mg) or systemically (80 mg/kg) 1 h before
acrolein.
Intravesical administration of
acrolein induced a dose- and time-dependent increase in vascular permeability and bladder wet weight (within 3 h: 2.2- and 21-fold increases in bladder wet weight and
Evans blue dye exuded, respectively, at doses of 75 microg/bladder), as confirmed by Gray's criteria. Pretreatment with
mesna (2-mercaptoethanesulfonic acid), which interacts with
acrolein resulting in an inactive compound, inhibited all changes induced by
acrolein. Our results are the first demonstration that
intravesical administration of
acrolein induces
hemorrhagic cystitis. This model of
acrolein-induced
hemorrhagic cystitis in mice may be an important tool for the evaluation of the mechanism by which
acrolein induces bladder lesion, as well as for investigation of new uroprotective drugs.