NSAID-Induced Enteropathy: Are the Currently Available Selective COX-2 Inhibitors All the Same?

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) can induce intestinal mucosal damage, but the underlying mechanisms remain poorly understood. The present study investigated the effects of celecoxib, etoricoxib, indomethacin, and diclofenac on small bowel integrity in rats. Male rats were treated orally with test drugs for 14 days. Animals were processed for assessment of blood hemoglobin levels and hepatic mitochondrial functions, microscopic evaluation of small intestinal damage, Western blot analysis of cyclooxygenase-1 and -2 (COX-1, COX-2) expression, and assay of malondialdehyde (MDA), myeloperoxidase (MPO), and prostaglandin E 2 (PGE 2 ) levels in small intestine. Indomethacin and diclofenac decreased blood hemoglobin levels, whereas etoricoxib and celecoxib were without effects. Celecoxib caused a lower degree of intestinal damage in comparison with the other test drugs. Indomethacin and diclofenac, but not etoricoxib or celecoxib, reduced intestinal PGE 2 levels. Test drugs did not modify intestinal COX-1 expression, although they enhanced COX-2, with the exception of celecoxib, which downregulated COX-2. Indomethacin, diclofenac, and etoricoxib altered mitochondrial respiratory parameters, although celecoxib was without effects. Indomethacin or diclofenac increased MDA and MPO levels in both jejunum and ileum. In the jejunum, etoricoxib or celecoxib did not modify such parameters, whereas in the ileum, etoricoxib, but not celecoxib, increased both MDA and MPO levels. These findings suggest that nonselective NSAIDs and etoricoxib can induce enteropathy through a topic action, whereas celecoxib lacks relevant detrimental actions. The selectivity profile of COX-1/COX-2 inhibition by test drugs and the related effects on prostaglandin production do not appear to play a major role in the pathogenesis of enteropathy.

Uric acid ameliorates indomethacin‐induced enteropathy in mice through its antioxidant activity

“…However, recent reports using capsule endoscopy have shown that small intestinal damage, including ulcerations, can be found in up to 68% of subjects taking NSAIDs. The prevalence of NSAID‐induced small intestinal damage could even exceed the prevalence of NSAID‐induced damage in the upper gastrointestinal tract . NSAID‐induced small intestinal injury (NSAID‐induced enteropathy) is caused by inhibition of mitochondrial oxidative phosphorylation, which triggers ROS production, lipid peroxidation, and subsequent cell death, further exaggerating the injuries …”

Anti-Ulcer Efficacy of Soluble Epoxide Hydrolase Inhibitor TPPU on Diclofenac-Induced Intestinal Ulcers

“…However, the role of acid in the generation and aggravation of intestinal ulcers is negligible, because the pH of intestine is alkaline. However, the decrease in the level of PGE 2 is still a risk factor (Fornai et al, 2014). Unlike NSAIDs, which exhibit their anti-inflammatory effect because of COX inhibition, anti-inflammatory properties of sEH inhibitors in this experiment result from mechanisms other than COX inhibition, because TPPU does not significantly inhibit COX at up to 100 mM in vitro.…”

“…4, B and C). Fornai et al (2014) reported an increase in MPO level in the intestine of Wistar rats orally fed with DCF (8 mg/kg per day, 14 days) 1 OME (0.7 mg/kg per day, 14 days) in comparison with control rats. This 2-fold increase in the level of MPO by OME could be attributable to the difference in dose of OME and duration of treatment.…”

Perforated diverticulitis sigmoidei after laparoscopic cholecystectomy

“…Recent studies on rats have shown that the selective COX-2 inhibitor Celecoxib has a less detrimental effect on the mucosa of the intestines [10]. This might be an alternative to be used in patients susceptible to gut ulceration.…”