Gyógyszerészet, farmakogenomika, gyógyszerkutatás és tervezés, gyógyszeres kezelés
Introduction Intestinal ischemia/reperfusion (I/R) injury is associated with high
mortality and there is an unmet need for novel therapies. The intestinal expression
of cyclooxygenase-2 (COX-2) increases rapidly after mesenteric I/R, but it is still
a question of debate whether selective COX-2 inhibitors can mitigate I/R-induced gut
injury. Here we aimed to compare the effect of celecoxib and rofecoxib, two selective
COX-2 inhibitors, on intestinal I/R-induced injury in rats.Methods Wistar rats were
treated with celecoxib (10 and 100 mg/kg), rofecoxib (5 and 50 mg/kg), or vehicle
for 8 days via gavage and then were subjected to sham operation or mesenteric I/R.
Small intestinal inflammation and tissue damage were assessed by histology and quantification
of inflammatory and tight junction proteins. The intestinal activity of COX enzymes
was determined by a COX activity assay.Results The higher dose of celecoxib reduced
the I/R-associated increase in inflammatory mediators (myeloperoxidase, pentraxin
3, COX-2, interleukin-1 beta) and loss of tight junction proteins (claudin-1, occludin),
whereas the lower dose of celecoxib was only marginally effective. However, even high-dose
celecoxib failed to prevent the histological injury of the mucosa. In contrast to
celecoxib, rofecoxib did not affect intestinal inflammation and injury at any of the
tested doses. Neither celecoxib nor rofecoxib affected the I/R-induced changes of
HO-1 and PPAR-gamma, known off-targets of COX-inhibitors, but celecoxib increased
the I/R-induced elevation of Bax/Bcl-2, a marker of apoptosis, whereas rofecoxib reduced
the elevation of phospho-Akt. Importantly, high-dose celecoxib, but not rofecoxib,
has already reduced intestinal COX-1 activity.Conclusion Our study provides evidence
for the higher anti-inflammatory efficacy of celecoxib compared to rofecoxib in mesenteric
I/R injury, which is likely due to its lower selectivity for COX-2. However, even
high-dose celecoxib was unable to reduce the mucosal damage. Our results suggest that
selective COX-2 inhibitors have only limited therapeutic value in intestinal I/R injury.
