The DPP-4 Inhibitor Linagliptin Counteracts Stroke in the Normal and Diabetic Mouse Brain

A Comparison With Glimepiride

  1. Cesare Patrone1
  1. 1Diabetes Research Unit, Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
  2. 2Department of CardioMetabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
  1. Corresponding authors: Vladimer Darsalia, vladimer.darsalia{at}ki.se, and Cesare Patrone, cesare.patrone{at}ki.se.

Abstract

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.

  • Received July 23, 2012.
  • Accepted October 27, 2012.

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  1. Diabetes vol. 62 no. 4 1289-1296
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