Indomethacin induces a chronic model of
inflammatory bowel disease (IBD) characterized by spontaneous relapses of
inflammation, bacterial translocation, and long-lasting motor disturbances derived from cyclical up-regulated
inducible nitric-oxide synthase (iNOS) and sustained down-regulated neuronal NOS (nNOS). The aims of this study were to evaluate whether
LA-419 [
S-(6-nitro-oxi-hexahydro-furo[3,2-b]
furan-3-1-il)thioacetate], a NO-donor
drug, could re-establish the normal expression of NOS and, hence, prevent the development of intestinal dysmotility, bacterial translocation, and relapses of
inflammation associated to this model.
Enteritis was induced in rats by administration of
indomethacin with and without treatment with a novel NO-donor:
LA-419 (0.5 mg/ml in the
drinking water). Inflammatory reaction was evaluated by measuring blood leukocytes, serum
tumor necrosis factor, and tissue
myeloperoxidase. Intestinal motor activity was evaluated using strain-gauges. Ileal expression of iNOS and nNOS
mRNA was determined by reverse transcription-polymerase chain reaction. Bacterial translocation was evaluated in cultures from mesenteric lymph nodes. The
indomethacin-induced acute inflammatory reaction was associated with a rise in blood leukocytes and
tumor necrosis factor. In the chronic stage, blood leukocyte monitoring allowed the selection of animals in active and inactive phases. Active phase was associated with iNOS up-regulation, high
myeloperoxidase levels, hypomotility, and bacterial translocation. In contrast, inactive phase was associated with hypermotility and absence of bacterial translocation.
LA-419 treatment restored
nitric-oxide synthase isoenzyme expression and prevented the oscillation of both inflammatory and motor parameters that could be cyclically observed in inflamed rats.
LA-419 also prevented intestinal dysmotility, bacterial translocation, and relapses of intestinal
inflammation.
LA-419 might be a novel therapeutic approach to prevent acute inflammatory relapses in patients with IBD.