Nuclear factor-κB 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.

Potential Contribution of Nuclear Factor-κB to Cerebral Vasospasm after Experimental Subarachnoid Hemorrhage in Rabbits

“…These results suggest that the activation of NF-kB was involved in the development of cerebral vasospasm and the therapy effects of PDTC were possibly mediated via inhibition of NF-kB activation. However, because PDTC has a variety of other biochemical activities such as heavy metal chelation, thiol modification, and oxygen radical scavenging properties (El Eter et al, 2005;Iseki et al, 2000;Li et al, 1999;Mihm et al, 1991), The possibility that PDTC attenuates cerebral vasospasm in part through these actions directly was not excluded by the present study. Furthermore, one previous study even showed that PDTC at high concentrations could induce glutathione oxidation and apoptotic cell death in cultured endothelial cells (Moellering et al, 1999).…”

Protective effects of pyrrolidine dithiocarbamate on myocardium apoptosis induced by adriamycin in rats

“…Recent studies showed that PDTC regulated expression of bcl-2 and translocation of bax, probably through inhibiting NF-nB activation [12]. However, conflicting results have also been reported on the effect of PDTC on p53 gene [12,13].…”

The role of nuclear factor-κB in the effect of angiotensin II in the paraventricular nucleus in protecting the gastric mucosa from ischemia-reperfusion injury in rats

“…This result is supported by other reports that NF-κB is activated in gastric tissue injury caused by GI-R or acetic acid. 15,44 Furthermore, NF-κB can be activated in the brain, 17,19 myocardium, 16 lungs, 20 and many other tissues following ischemiareperfusion. The activation of NF-κB involves removal of the inhibitory subunit IκB-α from a latent cytoplasmic complex.…”

“…13 When cells are subjected to stimuli, NF-κB translocates to the nucleus and activates the transcription of genes related to the immune infl ammatory and stress response. 14 It has been reported that NF-κB is activated and translocated during ischemia-reperfusion of the stomach, 15 and of other organs such as the heart (myocardium), 16 brain, [17][18][19] lung, 20 kidney, 21,22 and intestine. 23 Since some factors, such as NF-κB, 24 regulate the development of GI-R injury, including apoptosis, infl ammation, and angiogenesis, we postulated that this pathway may play a major role in GI-R injury and the protective effects of Ang II in the PVN on GI-R injury.…”