Type 2 diabetes is a strong risk factor for stroke. Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor in clinical use against type 2 diabetes. The aim of this study was to determine the potential antistroke efficacy of linagliptin in type 2 diabetic mice. To understand whether efficacy was mediated by glycemia regulation, a comparison with the sulfonylurea glimepiride was done. To determine whether linagliptin-mediated efficacy was dependent on a diabetic background, experiments in nondiabetic mice were performed. Type 2 diabetes was induced by feeding the mice a high-fat diet for 32 weeks. Mice were treated with linagliptin/glimepiride for 7 weeks. Stroke was induced at 4 weeks into the treatment by transient middle cerebral artery occlusion. Blood DPP-4 activity, glucagon-like peptide-1 (GLP-1) levels, glucose, body weight, and food intake were assessed throughout the experiments. Ischemic brain damage was measured by determining stroke volume and by stereologic quantifications of surviving neurons in the striatum/cortex. We show pronounced antistroke efficacy of linagliptin in type 2 diabetic and normal mice, whereas glimepiride proved efficacious against stroke in normal mice only. These results indicate a linagliptin-mediated neuroprotection that is glucose-independent and likely involves GLP-1. The findings may provide an impetus for the development of DPP-4 inhibitors for the prevention and treatment of stroke in diabetic patients.

译文

:2型糖尿病是中风的重要危险因素。 Linagliptin是临床上用于治疗2型糖尿病的二肽基肽酶4(DPP-4)抑制剂。这项研究的目的是确定利格列汀在2型糖尿病小鼠中的潜在抗中风功效。为了了解功效是否由血糖调节介导,与磺酰脲格列美脲进行了比较。为了确定利格列汀介导的功效是否取决于糖尿病背景,在非糖尿病小鼠中进行了实验。通过给小鼠喂高脂饮食32周来诱发2型糖尿病。用利格列汀/格列美脲治疗小鼠7周。在治疗的第4周,通过短暂性中脑动脉闭塞诱发中风。在整个实验过程中,评估了血液DPP-4活性,胰高血糖素样肽1(GLP-1)水平,葡萄糖,体重和食物摄入量。通过测定中风量和纹状体/皮层中存活的神经元的立体定量来测量缺血性脑损伤。我们在2型糖尿病和正常小鼠中显示了利格列汀的显着抗中风功效,而格列美脲仅在正常小鼠中被证明对中风有效。这些结果表明,由利格列汀介导的神经保护作用与葡萄糖无关,并且可能涉及GLP-1。这些发现可能为DPP-4抑制剂的开发提供动力,以预防和治疗糖尿病患者的中风。

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