Effects of celecoxib on acid-challenged gastric mucosa of rats: comparison with metamizol and piroxicam.

Selective COX-2 inhibitors have been shown to produce fewer gastrointestinal adverse reactions than classical NSAIDs. Nevertheless, these new agents may worsen and delay the healing of experimentally induced gastric ulcers in animals. In this study, we compared the effects of a selective COX-2 inhibitor (celecoxib), a preferential COX-1 inhibitor (piroxicam), and a nonnarcotic analgesic (metamizol) on normal gastric mucosa of rats and, on the other hand, in a setting of preexisting acute gastric lesions induced by 0.6 N hydrochloric acid. Under normal conditions, only piroxicam produced appreciable gastric lesions. However, after acid challenge the three assayed drugs induced significant macroscopic and microscopic damage. Myeloperoxidase activity as an index of neutrophil infiltration was elevated with celecoxib and piroxicam on normal gastric mucosa. On inflamed mucosa, celecoxib augmented enzymatic activity at the lower dose, which was parallelled by an increase in the interleukin 1beta level. Acid instillaton produced a significant rise in PGE2 content at 7 hr. Drug treatment after acid challenge decreased prostaglandin values in all cases, although to a lesser extent than after single drug dose administration. COX-2 mRNA expression was visible 1 hr after acid application, whereas COX-2 protein could only be detected at 7 hr. Piroxicam increased both expression levels. All NSAIDs enhanced transforming growth factor alpha and epidermal growth factor receptor immunoreactivity around the acid-induced lesions. It is concluded that selective COX-2 inhibitors, like conventional NSAIDs, impair the healing of gastric damage, and therefore special attention should be paid in patients with gastric pathologies.

Resveratrol, a polyphenol found in grapes, suppresses oxidative damage and stimulates apoptosis during early colonic inflammation in rats.

Oxidative stress, neutrophil infiltration, proinflammatory cytokines and eicosanoid generation are clearly involved in the pathogenesis of intestinal bowel disease. Resveratrol, a polyphenolic compound found in grapes and wine, has been shown to have anti-inflammatory, antioxidant, antitumour and immunomodulatory activities, however, its effects on experimental colitis remain unknown. We have investigated the effects of resveratrol on the colon injury caused by intracolonic instillation of trinitrobenzenesulphonic acid (TNBS) in rats. We determined the production of prostaglandin (PG)E(2) and PGD(2) in colon mucosa and the expression of cyclo-oxygenases (COX)-1 and -2 immunohistochemically. The inflammatory response was assessed by histology and myeloperoxidase activity, as an index of neutrophil infiltration. Interleukin-1 beta production, histological and histochemical analysis of the lesions were also carried out. Finally, since resveratrol has been found to modulate apoptosis we intended to elucidate its effects on colonic mucosa under early acute inflammatory conditions. Resveratrol (5-10mg/kg/day) significantly reduced the degree of colonic injury, the index of neutrophil infiltration and the levels of the cytokine. Resveratrol did not revert the increased PGE(2) levels but produced a significant fall in the PGD(2) concentration. Compared with inflamed colon, no changes in staining for COX-1 were observed in colon of resveratrol and TNBS-treated rats. In contrast, COX-2 expression was decreased. Furthermore, resveratrol enhanced apoptosis compared with already high level induced by TNBS. In conclusion, resveratrol reduces the damage in experimentally induced colitis, alleviates the oxidative events and stimulates apoptosis.

Mucosal damage induced by preferential COX-1 and COX-2 inhibitors: role of prostaglandins and inflammatory response.

Nonsteroidal anti-inflammatory drugs (NSAID) are well known to induce gastric mucosal damage including bleeding, ulceration and perforation in humans and animals too. These effects are related with the inhibition of the enzyme cyclooxygenase, which is the main established mechanism of action for these drugs. Fasted rats were given piroxicam, preferential COX-1 inhibitor (10-20 mg/kg) or meloxicam, preferential COX-2 inhibitor (7.5-15 mg/kg) orally. Six or nine hours (h) later, respectively, the stomach was excised, the severity of the damage assessed and myeloperoxidase (MPO) activity measured, as well as prostaglandin PGE(2) content. Furthermore, in order to assess the effects of these oxicams over previously damaged gastric mucosa, 1 ml of 0.6 N HCl was administered p.o. followed, 1 h after, of the correspondent dose of each NSAID, and the same parameters were determined. Oral administration of both drugs dose-dependently caused acute gastric haemorrhage erosions. Myeloperoxidase activity was significantly increased by piroxicam administration. In addition, PGE(2) content was significantly reduced. The association between the administration of the acid and NSAID caused a worsening of the damage and, while myeloperoxidase activity did not modify by both piroxicam and meloxicam, PGE(2) levels were reduced. These results suggest that the PG derived from both COX-1 and COX-2 pathway plays a beneficial role in the gastroprotection, and thus caution should be exercise in the clinical use of preferential COX-2 inhibitors.

The cyclo-oxygenase-2 inhibitor, rofecoxib, attenuates mucosal damage due to colitis induced by trinitrobenzene sulphonic acid in rats.

Cyclo-oxygenase-2 overexpression has been described in experimental colitis. However, there are controversial findings suggesting that its inhibition by selective cyclo-oxygenase-2 inhibitors not only may have a beneficial effect on experimental colitis, but also exacerbate the inflammation-associated colonic injury. Thus, the role of cyclo-oxygenase-2 inhibitors in the possible modulation of colon inflammation is controversial and remains uncertain. In this study, we evaluated the effects of the selective cyclo-oxygenase-2 inhibitor, rofecoxib, on the extent and severity of ulcerative colitis caused by intracolonic administration of 2,4,6-trinitrobenzene sulphonic acid (TNBS) in rats. The lesions and the inflammatory response were assessed by histology and measurement of myeloperoxidase activity. Interleukin-1 beta, prostaglandin E(2) and D(2) levels in colon mucosa and the immunohistochemical expression of the cyclo-oxygenases-1 and -2 were also studied. Finally, we investigated the effects of rofecoxib on apoptosis of colonocytes by the appearance of DNA fragmentation. Inflammation following TNBS was characterized by increased colonic wall thickness, oedema, diffuse inflammatory cell infiltration in the mucosa, and necrosis. Increased myeloperoxidase activity, as an index of neutrophil infiltration in the mucosa, and interleukin-1 beta levels were also measured in the colon. Administration of rofecoxib significantly (P<0.05) reduced the colonic damage, the degree of neutrophil infiltration, and interleukin-1 beta levels. In addition, apoptosis was significantly increased in TNBS-treated rats, but not in rofecoxib plus TNBS-treated rats. We concluded that rofecoxib seems to have beneficial effects in TNBS-induced colitis by diminishing the initial stage of inflammation, probably by a mechanism related to inhibition of prostaglandin E(2) by the cyclo-oxygenase-2 pathway. The data suggest that cyclo-oxygenase-2-selective inhibitors may have a therapeutic role in ulcerative colitis.

A new flavonoid derivative, dosmalfate, attenuates the development of dextran sulphate sodium-induced colitis in mice.

In this study, we have evaluated the efficacy of dosmalfate, a new flavonoid derivative compound, for the prevention and treatment of experimental colitis. To induce colitis, BALB/c mice received 5% dextran sulphate sodium (DSS) in their drinking water continuously for 7 days. Colitis was quantified by a clinical damage score, colon length, weight loss, stool consistency and rectal bleeding. Inflammatory response was assessed by neutrophil infiltration, determined by histology and myeloperoxidase (MPO) activity. Interleukin (IL)-1 beta, prostaglandins (PG)E(2) and (PG)D(2) concentrations in colonic tissue, histological and histochemical analysis of the lesions were also measured. Dosmalfate (400-800 mg/kg body weight, p.o.) ameliorated severe colitis reduced the degree of inflammation through reduction of neutrophil infiltration and IL-1 beta levels. (PG)E(2) and (PG)D(2) synthesis were significantly reduced in colitis control group and treatment with dosmalfate abolished the decrease in PG synthesis in colon mucosa. We conclude that dosmalfate is protective in acute DSS-induced colitis. The beneficial effects seem to be related to a decrease of neutrophil infiltration, absence of up-regulation of IL-1 beta and increase of PG production in colon mucosa.

Effects of dosmalfate, a new cytoprotective agent, on acute and chronic trinitrobenzene sulphonic acid-induced colitis in rats.

Activated neutrophils and proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) are clearly involved in the pathogenesis of bowel disease. Increased expression of epidermal growth factor-receptor (EGF receptor) has been reported for the colon mucosa surrounding areas of ulceration, suggesting a pivotal role in mucosal defence and repair. In this study, we examined the effects of dosmalfate, a new flavonoid derivative compound (diosmin heptakis) with antioxidant and cytoprotective properties, on acute and chronic experimental trinitrobenzene sulphonic acid (TNBS)-induced colitis in rats. The inflammation response was assessed by neutrophil infiltration as evaluated by histology and myeloperoxidase activity. Mucosal TNF-alpha production and histological analysis of the lesions was also carried out. In addition, we studied the expression of the EGF receptor inmunohistochemically during the healing of TNBS-induced chronic colitis. A 2-day treatment with 400 or 800 mg/kg of dosmalfate ameliorated the colon damage score and the incidence of adhesions. It also significantly (P<0.05) decreased myeloperoxidase activity and colonic mucosal production of TNF-alpha. Chronic treatment (14 days) with 800 mg/kg/day of dosmalfate also had significant protective effects on TNBS-induced colitis which were reflected by significant attenuation (P<0.05) of the damage score while the inflammatory indicators were not improved. The chronic beneficial effect of dosmalfate was apparently related to the enhancement of EGF receptor expression. These findings confirm the protective effects of dosmalfate in acute and chronic experimental colitis.