title: Nuclear factor-kappaB inhibition by pyrrolidinedithiocarbamate attenuates gastric ischemia-reperfusion injury in rats.
abstract: Pyrrolidinedithiocarbamate (PDTC) is a potent antioxidant and an inhibitor of nuclear factor-kappaB (NF-kappaB). The present study examined the impact of PDTC preconditioning on gastric protection in response to ischemia-reperfusion (I/R) injury to the rat stomach. Male Wistar rats were recruited and divided into 3 groups (n = 7). One group was subjected to gastric ischemia for 30 min and reperfusion for 1 hour. The second group of rats was preconditioned with PDTC (200 mg/kg body mass i.v.) 15 min prior to ischemia and before reperfusion. The third group of rats was sham-operated and served as the control group. Gastric I/R injury increased serum lactate dehydrogenase level, vascular permeability of gastric mucosa (as indicated by Evans blue dye extravasation) and gastric content of inflammatory cytokine; tumor necrosis factor-alpha (TNF-alpha). Moreover, oxidative stress was increased as indicated by elevated lipid peroxides formation (measured as thiobarbituric acid reactive substances) and depleted reduced glutathione in gastric tissues. NF-kappaB translocation was also detected by electrophoretic mobility shift assay. Microscopically, gastric tissues subjected to I/R injury showed ulceration, hemorrhages, and neutrophil infiltration. Immunohistochemical studies of gastric sections revealed increased expression of p53 and Bcl-2 proteins. PDTC pretreatment reduced Evans blue extravasation, serum lactate dehydrogenase levels, gastric TNF-alpha levels, and thiobarbituric acid reactive substances content, and increased gastric glutathione content. Moreover, PDTC pretreatment abolished p53 expression and inhibited NF-kappaB translocation. Finally, histopathological changes were nearly restored by PDTC pretreatment. These results clearly demonstrate that NF-kappaB activation and pro-apoptotic protein p53 induction are involved in gastric I/R injury. PDTC protects against gastric I/R injury by an antioxidant, NF-kappaB inhibition, and by reduction of pro-apoptotic protein p53 expression, which seems to be downstream to NF-kappaB, thus promoting cell survival.
authors.affiliation: Physiology Department, Medical College & King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Eman
authors.initials: E
authors.lastname: El Eter
authors.forename: Hanan H
authors.initials: HH
authors.lastname: Hagar
authors.forename: Ali
authors.initials: A
authors.lastname: Al-Tuwaijiri
authors.forename: Maha
authors.initials: M
authors.lastname: Arafa
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D005753:Gastric Mucosa / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005978:Glutathione / Q000378:metabolism; D007150:Immunohistochemistry; D008054:Lipid Peroxides / Q000096:biosynthesis; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D018384:Oxidative Stress / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011759:Pyrrolidines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013270:Stomach / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology; D013859:Thiocarbamates / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: D000975:Antioxidants; D008054:Lipid Peroxides; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D011759:Pyrrolidines; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; C020972:pyrrolidine dithiocarbamic acid; D005978:Glutathione