Protective effect of ketamine against hemorrhagic cystitis in rats receiving ifosfamide

Abstract

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 schedulesin order to reduce the bladder damage secondary to oxazaphosphorine-alkylating agents and these results may widen the spectrum of ketamine.

Clinical significance of interleukin‑6 and inducible nitric oxide synthase in ketamine‑induced cystitis

“…This result suggested that IFS (or CTX) and ketamine have opposing effects on the urinary bladder, probably due to their different effects on iNOS activities. In the present study, the results observed in the ketamine-treated SMCs are consistent with the results of previous studies, which suggested that the production of proinflammatory mediators, such as IL-6 and free oxygen radicals (nitric oxide), are reduced in SMCs following ketamine treatment ( 60 , 62 ).…”

“…Following administration of CTX, iNOS bladder activity increases, which is associated with histopathological alterations ( 61 ). Ozguven et al reported that appropriate ketamine pretreatment attenuated experimental IFS-induced hemorrhagic cystitis in a rat model ( 62 ). This result suggested that IFS (or CTX) and ketamine have opposing effects on the urinary bladder, probably due to their different effects on iNOS activities.…”

Does ketamine ameliorate the social stress‐related bladder dysfunction in mice?

“…However, we did not observe any change of detrusor relaxation or bladder compliance in stressed mice (Figure 5), which was in line with the results by Mingin et al, 3 Short‐term (28 days) ketamine (25 mg/kg/day) treatment could induce bladder overactivity and ketamine‐induced cystitis in female rats 10,11 . But single low dose of ketamine pretreatment attenuates experimental ifosfamide‐induced bladder damage 12 . In our current study, single dose of ketamine treatment did not induce bladder overactivity (Figure 3), and short‐term (5 days) ketamine (25 mg/kg/day) is not associated with more intensity of SS‐induced detrusor overactivity.…”

“…10,11 But single low dose of ketamine pretreatment attenuates experimental ifosfamideinduced bladder damage. 12 In our current study, single dose of ketamine treatment did not induce bladder overactivity (Figure 3), and short-term (5 days) ketamine (25 mg/kg/day) is not associated with more intensity of SS-induced detrusor overactivity. The results also showed that short-term (1 or 5 days) ketamine did not improve detrusor overactivity and impaired contractility as evidence by no altered urine BDNF level in ketaminetreated SS 1 mice when compared with SS 1 K 0 .…”

Osteopontin and fatty acid binding protein in ifosfamide-treated rats

“…According to literature data, IF administered in a larger single dose (400 – 500 mg/kg b.w.) exerts an intensified nephrotoxic effect, manifested with Fanconi syndrome [15,16]. Moreover, the choice of the applied IF dose was also consistent with the clinical data.…”