Nuclear factor-κB inhibition by pyrrolidinedithiocarbamate attenuates gastric ischemia-reperfusion injury in rats
- 1 June 2005
- journal article
- Published by Canadian Science Publishing in Canadian Journal of Physiology and Pharmacology
- Vol. 83 (6), 483-492
- https://doi.org/10.1139/y05-034
Abstract
Pyrrolidinedithiocarbamate (PDTC) is a potent antioxidant and an inhibitor of nuclear factor-κB (NF-κB). 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-α (TNF-α). 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-κB 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-α levels, and thiobarbituric acid reactive substances content, and increased gastric glutathione content. Moreover, PDTC pretreatment abolished p53 expression and inhibited NF-κB translocation. Finally, histopathological changes were nearly restored by PDTC pretreatment. These results clearly demonstrate that NF-κB 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-κB inhibition, and by reduction of pro-apoptotic protein p53 expression, which seems to be downstream to NF-κB, thus promoting cell survival. Key words: pyrrolidinedithiocarbamate, ischemia–reperfusion injury, gastric mucosa, nuclear factor-κB, inflammatory cytokines, oxidative stress.Keywords
This publication has 57 references indexed in Scilit:
- Nuclear Factor-κB Contributes to Infarction After Permanent Focal IschemiaStroke, 2004
- Pyrrolidine Dithiocarbamate Inhibits TNF-α-Dependent Activation of NF-κB by Increasing Intracellular Copper Level in Human Aortic Smooth Muscle CellsBiochemical and Biophysical Research Communications, 2000
- NF-κB activationCritical Care Medicine, 2000
- NF-κB Inhibition Ameliorates Angiotensin II–Induced Inflammatory Damage in RatsHypertension, 2000
- Upregulation of P53 Protein in Rat Heart Subjected to a Transient Occlusion of the Coronary Artery Followed by Reperfusion.The Japanese Journal of Physiology, 2000
- Possible role of NF-κB and p53 in the glutamate-induced pro-apoptotic neuronal pathwayCell Death & Differentiation, 1999
- NF-κB AND REL PROTEINS: Evolutionarily Conserved Mediators of Immune ResponsesAnnual Review of Immunology, 1998
- Rel/NF-κB and IκB proteins: an overviewSeminars in Cancer Biology, 1997
- Protection against gastric ischemia-reperfusion injury by nitric oxide generatorsDigestive Diseases and Sciences, 1994
- Sequence of gastric mucosal injury following ischemia and reperfusionDigestive Diseases and Sciences, 1992