RESUMEN
The transcription factor, nuclear factor-κB (NF-κB) is a key inducer of inducible nitric oxide synthase (iNOS) gene expression. The aim of the present study was to investigate the potential protective effect of l-arginine (Arg; nitric oxide precursor) and aminoguanidine (inducible nitric oxide synthase inhibitor) against acetic acid (AA)-induced colitis in rats, and the potential role of NF-κB. Colitis was induced by intrarectal inoculation of rats with 4% acetic acid for three consecutive days. The effect of Arg and aminoguanidine on nitric oxide levels was assessed by Greiss assay and protein expression of NF-κB/p65, and inducible nitric oxide synthase was also investigated by immunohistochemistry. Slides were examined using ImageJ, and results reported as the percent area positive for each marker. Intrarectal AA caused a significant increase in bodyweight loss and colon weights. Arg at 100 mg/day for 7 days before induction of colitis diminished the changes in both bodyweight loss and colon weights. Furthermore, Arg attenuated the colonic tissues macroscopic and microscopic damage induced by acetic acid. In addition, i.p. AG 100 mg/kg given during and after induction of colitis recovered the colonic ulcerative lesion induced by AA. Arg can protect against colonic inflammation; an effect that probably be attributed to its nitric oxide-donating property, resulting in modulatory effects on the expression of NF-κB/p65 in the colon tissues. The results suggested that Arg might reduce the inflammation associated with colitis as confirmed by histopathological investigations. Arg might inhibit AA-induced colitis through the NF-κB/nitric oxide pathway.
Asunto(s)
Ácido Acético/farmacología , Arginina/farmacología , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colon/efectos de los fármacos , Guanidinas/farmacología , FN-kappa B/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Colitis/metabolismo , Colon/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacosRESUMEN
The effect of medical use of NO donors on the pathogenesis of arthritis is still yet unclear. We investigated the effects of the NO donor, sodium nitroprusside (SNP), on the pathogenesis of adjuvant-induced arthritis in rats. Rats were given SNP intraperitoneally either from day 5 to day 14 (as a prophylactic protocol) or from day 16 to day 25 (as a therapeutic protocol) after inoculation of adjuvant. SNP administration, whether prophylactic or therapeutic, in doses of 0.1 and 1 mg/kg/d significantly aggravated pathogenesis of adjuvant arthritis in rats. SNP-treated rats showed significant (P<0.05) increase in arthritis index, hind paw volume, ankle joint diameter and hyperalgesia compared with control adjuvant arthritic rats. However, in adjuvant rats given the smallest dose of SNP (0.01 mg/kg/d), arthritis index, volume of hind paws, ankle joint diameter, body weight loss, and hyperalgesia were significantly lower than that of control adjuvant rats. After 30 d of the induction of adjuvant arthritis, TNF alpha levels exhibited insignificant changes either in control adjuvant rats or in rats given SNP compared with control non adjuvant rats. IL-10 levels in adjuvant control rats and adjuvant rats given 1 mg or 0.1 mg/kg/d from day 15 to day 25 were significantly lower than that of control non adjuvant rats. Histopathology examination of ankle joint showed that large doses of SNP (1 mg or 0.1 mg/kg/d) increased the mononuclear cells infiltration and erosion of cartilage induced by adjuvant while the infiltration of the inflammatory cells in the synovium of adjuvant rats treated with 0.01 mg/kg/d was minimal and the pannus was inhibited with alleviation of erosion of articular cartilage. Prophylactic small dose of SNP improved the histological status more than the therapeutic small dose. The present work reveals that SNP administration, either prophylactic or therapeutic, was deleterious in higher doses. However, the smallest dose used 0.01 mg/kg/d attenuates joint inflammation, hyperalgesia and body weight loss in adjuvant arthritic rats. These results suggest that small dose of NO donor may exert partial protective effects while the safety of the clinical use of NO donors, in higher doses, in patients with rheumatoid arthritis is questioned.