Prophylaxis with mesna prevents oxidative stress induced by ischemia reperfusion in the intestine via inhibition of nuclear factor-kappaB activation.
OBJECTIVE
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 administration 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-kappaB (NF-kappaB) 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-kappaB 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-kappaB activation in the intestinal mucosa which was inhibited by mesna pretreatment. In the absence of oxidative damage, mesna led to downregulation of activated NF-kappaB.


CONCLUSIONS
Prophylaxis with mesna prevents oxidative stress induced by I/R in the intestine via inhibition of NF-kappaB activation.
Ypsilantis
Petros
P
Laboratory of Experimental Surgery and Surgical Research, School of Medicine, Democritus University of Thrace, Alexandroupolis, Greece. pipsil@med.duth.gr
Tentes
Ioannis
I
Lambropoulou
Maria
M
Anagnostopoulos
Konstantinos
K
Papadopoulos
Nikolaos
N
Kortsaris
Alexandros
A
Simopoulos
Constantinos
C
D000284:Administration, Oral; D000818:Animals; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019803:Glutathione Disulfide / Q000378:metabolism; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000098:blood supply*; D008315:Malondialdehyde / Q000378:metabolism; D015080:Mesna / Q000008:administration & dosage / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D018384:Oxidative Stress / Q000187:drug effects*; D020011:Protective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors
D016328:NF-kappa B; D020011:Protective Agents; D008315:Malondialdehyde; D013482:Superoxide Dismutase; D015080:Mesna; D019803:Glutathione Disulfide