Effects of the compounds MV8608 and MV8612 obtained from Mandevilla velutina in the model of hemorrhagic cystitis induced by cyclophosphamide in rats

Abstract

Hemorrhagic cystitis (HC) is a common side effect observed in patients under chemotherapy with cyclophosphamide (CYP). The urotoxic side effects of CYP are attributed to the metabolic compound acrolein, and can be partially prevented by the uroprotector agent 2-mercaptoethene sulfate (Mesna). The present study analyzed the anti-inflammatory and the antinociceptive effects of compounds MV8608 and MV8612 obtained from Mandevilla velutina in the rat model of CYP-induced HC. Male Wistar rats were used (6 to 8 per group, 220-250g). Hemorrhagic cystitis was induced by a single administration of CYP (100 mg/kg, ip). Three behavioral parameters, breathing rate, closing of the eyes, and specific posture were used as nociception indexes, and scored at different time intervals (15-180 min) after cystitis induction. As inflammatory parameters, hemorrhage presence, edema formation, and bladder weight were determined at 24 h after CYP administration. The neutrophil migration was assessed by means of myeloperoxidase (MPO activity), 4 h after cystitis induction. As expected, Mesna treatment was able to reduce in a significant manner the all the inflammatory and the nociceptive parameters induced by CYP. Of note, the administration of MV8608 significantly inhibited the hemorrhage formation and the neutrophil recruitment, while the MV8612 treatment markedly reduced the bladder weight, without interfering with neutrophil influx. Interestingly, the treatment with either MV8608 or MV8612 markedly reduced the nociceptive responses. The present results clearly indicate that MV8608 and MV8612 might represent important alternatives to prevent side effects, especially the nociception, following chemotherapy with CYP.