Sitagliptin attenuates intestinal ischemia/reperfusion injury via cAMP/PKA, PI3K/Akt pathway in a glucagon-like peptide 1 receptor-dependent manner

Aims: This study investigated the effect of sitagliptin prophylactic treatment on intestinal I/R rat model and explored the possible underlying mechanism. Main methods: Forty-five male Sprague-Dawley rats were randomly assigned to 3 groups: Sham group (operation without clamping), I/R group (operation with clamping) and sitagliptin pretreated group (300 mg/kg/day; p.o.) for 2 weeks before I/R insult. Intestinal I/R was performed by clamping the superior mesenteric artery for 30 min, followed by 60 min reperfusion after removal of clamping. At the end of the experimental period, all rats were sacrificed for histopathological, biochemical, PCR and western blot assessment. Key findings: Pretreatment with sitagliptin remarkably alleviated the pathological changes induced by I/R in the jejunum, suppressed upregulated NF-kappa B, TNF-alpha, IL-1 beta and MPO caused by I/R. Moreover, sitagliptin decreased the Bax/Bcl-2 ratio and accordingly suppressed apoptotic tissue damage as reflected by a caspase-3 level reduction in rat intestine subjected to I/R injury. Interestingly, sitagliptin could obviously increase the active GLP1 level and GLP-1 receptor mRNA expression in the jejunum of I/R rats. This was associated with the augmentation of the cAMP level and enhancement of PKA activity. Simultaneously, sitagliptin treatment was able to increase the protein expression levels of phosphorylated PI3K and Akt. Significance: Sitagliptin has shown protective effects against intestinal I/R injury in rats through reduction of intestinal inflammation and apoptosis. The molecular mechanisms may be partially correlated with activation of cAMP/PKA and PI3K/Akt signaling pathway by the GLP-1/GLP-1 receptor.