title: The DPP-4 inhibitor linagliptin counteracts stroke in the normal and diabetic mouse brain: a comparison with glimepiride.
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.
authors.affiliation: Diabetes Research Unit, Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Vladimer
authors.initials: V
authors.lastname: Darsalia
authors.forename: Henrik
authors.initials: H
authors.lastname: Ortsäter
authors.forename: Anna
authors.initials: A
authors.lastname: Olverling
authors.forename: Emilia
authors.initials: E
authors.lastname: Darlöf
authors.forename: Petra
authors.initials: P
authors.lastname: Wolbert
authors.forename: Thomas
authors.initials: T
authors.lastname: Nyström
authors.forename: Thomas
authors.initials: T
authors.lastname: Klein
authors.forename: Åke
authors.initials: Å
authors.lastname: Sjöholm
authors.forename: Cesare
authors.initials: C
authors.lastname: Patrone
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000188:drug therapy; D004041:Dietary Fats / Q000009:adverse effects; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D000069476:Linagliptin; D008297:Male; D051379:Mice; D009765:Obesity / Q000150:complications / Q000209:etiology; D011687:Purines / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D020521:Stroke / Q000209:etiology / Q000517:prevention & control*; D013453:Sulfonylurea Compounds / Q000627:therapeutic use*
chemical_list: D004041:Dietary Fats; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D011687:Purines; D011799:Quinazolines; D013453:Sulfonylurea Compounds; D000069476:Linagliptin; C057619:glimepiride