Prophylaxis with mesna prevents oxidative stress induced by ischemia reperfusion in the intestine via inhibition of nuclear factor-κB activation

Abstract

Background and Aim: Mesna (2-mercaptoethane-sulfonate) has been shown to attenuate oxidative injury induced by ischemia reperfusion (I/R) in the kidneys, the liver, and the intestine; however, its mechanism of action has not been fully elucidated. We sought to determine a prophylactic admininstration schedule of mesna that would confer optimal antioxidant protection on the intestinal mucosa following I/R and to investigate whether mesna's action is mediated via inhibition of nuclear factor-κB (NF-κB) activity. Methods: Wistar rats were subjected to one of the following: (a) induction of 30 min ischemia followed by 60 min reperfusion (I30/R60) of the intestine, (b) pretreatment with intraperitoneal or oral mesna at various time- and dose- administration schedules plus I30/R60, (c) sham operation, (d) no operation (controls), or (e) oral mesna alone. At the end of the reperfusion period or at various time points after mesna alone administration, the oxidative state of the intestinal mucosa was assessed in terms of glutathione to glutathione disulfide ratio, malondialdehyde concentration, and superoxide dismutase activity. In addition, NF-κB activity in the intestinal mucosa was assessed immunohistochemically in the oral mesna plus I/R and in the oral mesna alone groups. Results: Sham operation caused mild stress, while I/R caused substantial oxidative stress in the intestinal mucosa. Mesna pretreatment had an antioxidant effect which varied from attenuation to prevention of oxidative stress. Over the two routes of administration, the oral proved to be more effective and had a time- and dose- dependent effect. The antioxidant action of mesna was not related to enhancement of the intestinal mucosa oxidative state. Furthermore, I/R induced NF-κB activation in the intestinal mucosa which was inhibited by mesna pretreatment. In the absence of oxidative damage, mesna led to downregulation of activated NF-κB. Conclusions: Prophylaxis with mesna prevents oxidative stress induced by I/R in the intestine via inhibition of NF-κB activation. © 2007 The Authors.