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。利格列汀是临床抗2型糖尿病的二肽peptidase-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。为了了解疗效是否由血糖调节介导,与磺酰脲类格列美脲进行了比较。为了确定利格列汀介导的疗效是否取决于糖尿病背景,在非糖尿病小鼠中进行了实验。通过给小鼠喂食高脂饮食32周而诱发2型糖尿病。用利格列汀/格列美脲治疗小鼠7周。短暂性大脑中动脉闭塞在治疗4周时诱发中风。在整个实验中评估血液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。通过确定中风量和纹状体/皮质中存活神经元的立体定量来测量缺血性脑损伤。我们显示了利格列汀在2型糖尿病和正常小鼠中的明显抗中风功效,而格列美脲仅在正常小鼠中被证明对中风有效。这些结果表明利格列汀介导的神经保护作用是不依赖葡萄糖的并且可能涉及GLP-1。这些发现可能为糖尿病患者预防和治疗中风的DPP-4抑制剂的开发提供动力。

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