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The DPP-4 inhibitor linagliptin counteracts stroke in the normal and diabetic mouse brain: a comparison with glimepiride.

Authors
  • Darsalia, Vladimer1
  • Ortsäter, Henrik
  • Olverling, Anna
  • Darlöf, Emilia
  • Wolbert, Petra
  • Nyström, Thomas
  • Klein, Thomas
  • Sjöholm, Åke
  • Patrone, Cesare
  • 1 Diabetes Research Unit, Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden. , (Sweden)
Type
Published Article
Journal
Diabetes
Publication Date
Apr 01, 2013
Volume
62
Issue
4
Pages
1289–1296
Identifiers
DOI: 10.2337/db12-0988
PMID: 23209191
Source
Medline
License
Unknown

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.

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