|
Background and Objective: Inflammatory bowel disease(IBD)is a chronic,debilitating disease associated with severe damageto the intestinal mucosa whose etiology is still unknown. It is typified by ulcerative colitis(UC) and Crohn’s disease (CD).UC is characterized by diffuse mucosal inflammation limited to the colon, clinical manifestations were diarrhea, abdominal pain, mucus pus and blood will. Crohn disease is a chronic granulomatous inflammation, mostly segment, non-symmetrical distribution, and characterized by transmural inflammation, involvement of discontinuous segments of the intestine,and it most commonly involves the terminal ileum and proximal colon[1]. The main clinical manifestations were abdominal pain, diarrhea, fistula, anal lesions and varying degrees of symptoms. During the last few years significant advances have been achieved in the understanding of the pathogenesis of inflammatory bowel disease(IBD). Although the specific risk factors for IBD is not clear so far,a large number of clinical studies and animal experiments showed that[2,3], the abnormal immune system is the internal factor caused the inflammation and tissue damage in the genetic susceptibility individuals. Alogliptin is a highly selective DPP-4 inhibitor for the treatment of typeⅡdiabetes developed by Takeda of Japan. Its role in the treatment of diabetes research has been clear, but for the treatment of ulcerative colitis is rarely reported, and the therapy mechanism is not clear. Research has shown that[4~5], DPP-4 inhibitors could cure the colitis of Balb/C mice induced by DSS,and the concentration of GLP-2 in mice was significantly increased, and the same as in the DPP-4 knockout mice. These findings suggested that the therapeutic mechanism may be by inhibiting DPP-4 enzyme to reduce the degradation of GLP-2,and there is a significant correlation between GLP-2 and increases in cell growth of the small and large bowel. It is suggested that Alogliptin may have a therapeutic effect on mice with IBD.In this study, our objective is to investigate that the effect of Alogliptin on mice with IBD and its possible mechanism,and then to find a new path to treat the IBD.Methods:Balb/C mice were divided into six groups randomly: control group, model group of IBD, positive control group with SASP(520mg/kg) and treatment groups with Alogliptin at doses of 1 mg/kg, 0.3 mg/kg and 0.1 mg/kg. TNBS used to produce the mice colitis model enema. The mice were lightly anesthetized with ether, then were inserted a catheter with a diameter about 2 mm into the colon through the anus about 4 cm, each mouse was injected TNBS at the dose of 70mg/kg. The control group mice were injected the equal volume of saline.Then pinch the anus and put down for 5 min, and put the mice into the cage until the drug was absorbed completely. Observe the mice weight, stool consistency and occult blood condition every day to evaluate the DAI score. Determinate the myeloperoxidase (MPO) activity, and the content of serum IL-8, tumor necrosis factorα(TNF-α) and glucagon glucagon-like peptide -2 (GLP-2).Results and conclusions:(1) Compared with model group, treatment groups with Alogliptin (1mg/kg,0.3mg/kg,0.1mg/kg) and control group with SASP (520 mg/kg) could reduce the inflammatory injury in mice enteritis, decrease the DAI score, serum IL-8, TNF-αlevels, MPO activity, and increase the serum levels of GLP-2 in colitis mice. HE staining reveals that, compared with the colitis model, Alogliptin groups and SASP group mitigate the inflammatory damage in different degrees and improve the pathological changes.(2) In summary, Alogliptin has a therapeutic effect on experimental colitis in mice. It can reduce the inflammatory response, and increase the serum concentrations of GLP-2。The results indicate that the mechanism may be Alogliptin increased GLP-2 concentration to achieve the intestinal repair through inhibition of DPP-4 activity.
|