Ghrelin attenuates septic brain damage in mice

Abstract

Objective To research the effect of ghrelin on sepsis-induced brain damage and the underlying mechanism by examining the integrity of the blood-brain barrier, cerebral water content, inflammatory cytokines (tumor necrosis factor α or TNF-α and interleukin-1β or IL-1β), oxidative stress, neuronal apoptosis, and p-Akt and anti-apoptotic proteins (Bcl-20) in the PI3K/AKt pathway. Methods Two hundred and forty male C57BL/6J mice were randomized into four groups: the control group, the operation group, the operation+ ghrelin group, and the operation+ ghrelin+ LY294002 (LY) group.Cecal ligation and puncture were performed in male C57BL/6 J mice to establish the sepsis model.Ghrelin was administrated intraperitoneally at a dose of 80 g/kg.Blood brain barrier (BBB) integrity, brain water content, inflammatory cytokines (TNF-α and IL-1β), oxidative stress (SOD and MDA), and neuronal apoptosis were assessed.In addition, the expression levels of Akt, phospho-Akt (Ser473) (p-Akt), Bcl-2, and Bax were detected by Western blot. Results The 7-day survival rate in the control group was 100%.At day 7 after CLP surgery, the survival rate decreased dramatically to 28% (versus the control group, P< 0.05). The survival rate increased markedly to 50% in the CLP + ghrelin group (versus the CLP group, P < 0.05). LY administration nullified the protective effect of ghrelin, as indicated by the decreased survival rate (24%) in the CLP + ghrelin + LY group (versus the CLP+ ghrelin group, P< 0.05). Ghrelin attenuated brain edema and neuronal apoptosis, but enhanced BBB integrity (all P< 0.05). It also increased the activity of SOD, and decreased the production of TNF-α, the production of IL-1β, and the level of MDA (all P< 0.05). In addition, Western blotting detected increased expression of p-Akt and Bcl-2 and decreased expression of Bax by Ghrelin (all P< 0.05). The protective effects of ghrelin observed above were nullified by LY, a PI3K inhibitor(P< 0.05). Conclusions Ghrelin alleviates brain damage in sepsis via PI3K/Akt signaling activation. Key words: Ghrelin; Sepsis; PI3K/Akt