Protective effect of ketamine against hemorrhagic cystitis in rats receiving ifosfamide

Indian J Pharmacol. 2014 Mar-Apr;46(2):147-51. doi: 10.4103/0253-7613.129301.


Objective: To investigate the possible protective effect of a single dose of ketamine and the synergistic effect between ketamine and 2-mercaptoethane sulfonate (mesna) against ifosfamide-induced hemorrhagic cystitis.

Materials and methods: 35 adult female wistar rats were divided into five groups and pretreated with ketamine at 10 mg/kg and/or mesna 400 mg/kg 30 minutes before intraperitoneal injection of IFS (400 mg/kg) or with saline (control group). Hemorrhagic cystitis was evaluated 24 hours after IFS injection according to bladder wet weight (BWW), and microscopic changes, i.e. edema, hemorrhage, cellular infiltration, and urothelial desquamation. The markers of oxidative damage including nitric oxide (NO) and malondialdehyde (MDA) levels and the expressions of tumor necrosis factor alpha (TNF-α), interleukin 1-beta (IL-1β), inducible nitric oxide synthase (i-NOS) and endothelial nitric oxide synthase (e-NOS) were also assayed in the bladder tissues.

Results: Pretreatment with ketamine alone or ketamine in combination with mesna reduced the IFS-induced increase of BWW (58,47% and 63,33%, respectively, P < 0.05). IFS- induced microscopic alterations were also prevented by ketamine with or without mesna (P < 0.05). In addition, also statistically insignificant, the bladder tissue expressions of IL-1β were lower in ketamine and/or mesna-receiving groups (P > 0,05). The parameters of oxidative stress, the NO and the MDA contents of the bladder tissues of the study groups were not different.

Conclusion: The results of the present study suggest that a single dose of ketamine pretreatment attenuates experimental IFS-induced bladder damage. It is therefore necessary to investigate ketamine locally and systematically with various dosing schedules in order to reduce the bladder damage secondary to oxazaphosphorine-alkylating agents and these results may widen the spectrum of ketamine.

Keywords: Hemorrhagic cystitis; Ifosfamide; ketamine; mesna; protective.

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating / toxicity*
  • Biomarkers / analysis
  • Cystitis / chemically induced
  • Cystitis / prevention & control*
  • Drug Therapy, Combination
  • Female
  • Hemorrhage / chemically induced
  • Hemorrhage / prevention & control*
  • Ifosfamide / toxicity*
  • Immunohistochemistry
  • Ketamine / administration & dosage
  • Ketamine / therapeutic use*
  • Mesna / administration & dosage
  • Mesna / therapeutic use*
  • Organ Size / drug effects
  • Oxidative Stress / drug effects
  • Rats, Wistar
  • Urinary Bladder / drug effects
  • Urinary Bladder / metabolism
  • Urinary Bladder / pathology


  • Antineoplastic Agents, Alkylating
  • Biomarkers
  • Ketamine
  • Mesna
  • Ifosfamide