Prostaglandin/Cyclooxygenase Pathway in Ghrelin-Induced Gastroprotection against Ischemia-Reperfusion Injury

Abstract

Ghrelin is involved in the control of food intake, but its role in gastroprotection against the formation of gastric mucosal injury has been little elucidated. We studied the effects of peripheral (i.p.) and central (i.c.v.) administration of ghrelin on gastric secretion and gastric mucosal lesions induced by 3 h of ischemia/reperfusion (I/R) with or without inhibition of ghrelin growth hormone secretagogue type 1a receptor (GHS-R1a) by using ghrelin antagonist, D-Lys 3 -GHRP-6; blockade of cycloox-and COX-2 (rofecoxib); and bilateral vagotomy or capsaicin denervation. I/R produced typical gastric erosions, a significant fall in the gastric blood flow (GBF), an increase in gastric myeloperoxidase (MPO) activity and malonyldialdehyde (MDA) content, and the up-regulation of mucosal ghrelin mRNA. Ghrelin dose-dependently increased gastric acid secretion and significantly reduced I/R-induced gastric erosions, while producing a significant rise in the GBF and mucosal PGE 2 generation and a significant fall in MPO activity and MDA content. The protective and hyperemic activities of ghrelin were significantly attenuated in rats pretreated with D-Lys 3 -GHRP-6 and capsaicin denervation and completely abolished by vagotomy. Indomethacin, SC560, and rofecoxib, selective COX-1 and COX-2 inhibitors, attenuated ghrelin-induced protection that was restored by supplying the methyl analog of prostaglandin (PG) E 2 . The expression of mRNA for COX-1 was unaffected by ghrelin, but COX-2 mRNA and COX-2 protein were detectable in I/R injured mucosa and further up-regulated by exogenous ghrelin. We conclude that ghrelin exhibits gastroprotective and hyperemic activities against I/R-induced erosions, the effects that are mediated by hormone activation of GHS-R1a receptors, COX-PG system, and vagal-sensory nerves.

Effect of in ovo ghrelin administration on serum malondialdehyde level in newly-hatched chickens

“…Results of the present study were in agreement with the findings of Işeri and Brzozowski et al [17,18] who reported lowering effect of ghrelin on serum MDA in mammalian species. Also, obtained results are in accordance with in ovo studies of Schaal [21] and Wang et al [22] who have investigated other anti-oxidant compounds.…”

“…Reports of Işeri et al [17] indicated anti-oxidative activity of ghrelin and its ameliorative ability for alendronate-induced oxidative stress, as MDA comes back to the control level after ghrelin infusion. Also, Brzozowski et al [18] reported its gastroprotective and hyperemic activities against ischemia-reperfusion-induced erosions and a decrease in relative MDA level. Increase in aerobic metabolism and lipid peroxidation in chick embryo makes high demands for anti-oxidative protection.…”

Ghrelin attenuates intestinal ischemia/reperfusion injury in mice by activating the mTOR signaling pathway

“…Previous studies have shown that ghrelin inhibits leptininduced pro-inflammatory cytokine [interleukin (IL)-1β, tumor necrosis factor (TNF)-α and IL-6] expression by human T cells and monocytes (20) and suppresses nuclear factor (NF)-κB activation in human endothelial cells (21). It has been reported that ghrelin attenuates the formation of I/R-induced gastric lesions and other types of organ damage (22)(23)(24)(25), with a decrease in TNF-α and IL-6 expression (26). mTOR activation has also been shown to inhibit the production of pro-inflammatory cytokines and to enhance the release of anti-inflammatory cytokines by blocking NF-κB activation and increasing signal transducer and activator of transcription 3 (STAT3) activity (27).…”

Roles of NADPH Oxidase in Occurrence of Gastric Damage and Expression of Cyclooxygenase-2 During Ischemia/Reperfusion in Rat Stomachs

“…However, COX-1 has demonstrated inconsistent findings with regard to its role in gastric mucosa damaged by I /R with some studies assigning it a protective or neutral role (33,60) and another giving it an aggressive role (59). The discrepancy between these results could be attributed to differences among animal species, methods of I /R induction, doses of SC-560 chosen, durations of the ischemia and reperfusion, and experimental conditions employed.…”