Defining the role of CFTR channel blocker and ClC-2 activator in DNBS induced gastrointestinal inflammation

Saudi Pharm J. 2021 Apr;29(4):291-304. doi: 10.1016/j.jsps.2021.02.005. Epub 2021 Mar 10.

Abstract

In the present study, we have investigated and/or compared the role of glibenclamide, G as cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor, and lubiprostone, L as chloride channel-2 (ClC-2) activator in the 2,4-dinitrobenzene sulfonic acid (DNBS)-induced gastrointestinal inflammation. GI inflammation was induced by intrarectal administration of DNBS. Rats were randomly allocated in 5 groups as sham control, distilled water + DNBS, sulfasalazine (S) + DNBS, G + DNBS, and L + DNBS. All the groups were pre-treated successively for five days before the induction of colitis. One day before and the first four days after DNBS administration various parameters were studied. Later, blood chemistry, colon's gross structure, histology, and the antioxidant load was examined. Pre-treatment with G significantly protected the change induced by DNBS concerning the change in body weight, food intake, diarrhea, occult blood in the feces, wet weight of the colon, and spleen. G because of its anti-inflammatory property down-regulated the neutrophil and WBC count and up-regulated the lymphocyte number. Moreover, G efficiently ameliorates the oxidative stress in the colon and declines the level of myeloperoxidase and malondialdehyde and up-regulated the level of superoxide dismutase and glutathione. Lubiprostone has not shown any promising effects, in fact, it causes an increase in diarrheal frequency. Our findings from this study represent that G has good potential to ameliorate GI inflammation induced by DNBS by its multiple actions including CFTR blockage and reducing the release of inflammatory markers from the MCs, anti-inflammatory and free radical scavenging property.

Keywords: CD, Crohn’s disease; CFTR; CFTR, Cystic fibrosis transmembrane conductance regulator; CLC, Chloride Channel; ClC-2; DAI, Disease Activity Index; DC, Disease Control; DM, Diabetes Mellitus; DNBS, 2,4-Dinitrobenzene sulfonic acid; EtOH, Ethanol; G, Glibenclamide; GI, Gastrointestinal; GSH, Reduced Glutathione; Glibenclamide; H & E, Hematoxylin and eosin; IAEC, Institutional Animal Ethical Committee; IBD; IBD, Inflammatory Bowel Disease; L, Lubiprostone; Lubiprostone; MC, Mast cell; MDA, Malonaldehyde; MPO, Myeloperoxidase; NCEB, National Committee of Bio Ethics; PMS, Post-Mitochondrial Supernatant; RBC, Red blood cells; S, Sulfasalazine; SOD, Superoxide dismutase levels.; UC, Ulcerative colitis; WBC, White blood cells; i.p., Intraperitoneal Injection; p.o., Per Orally; s.c., Subcutaneous.