title: Linagliptin enhances neural stem cell proliferation after stroke in type 2 diabetic mice.
abstract: Dipeptidyl peptidase 4 (DPP-4) inhibitors are current drugs for the treatment of type 2 diabetes (T2D) based on their main property to enhance endogenous glucagon-like peptide-1 (GLP-1) levels, thus increasing insulin secretion. However, the mechanism of action of DPP-4 inhibition in extra pancreatic tissues has been poorly investigated and it might occur differently from that induced by GLP-1R agonists. Increased adult neurogenesis by GLP-1R agonists has been suggested to play a role in functional recovery in animal models of brain disorders. We recently showed that the DPP-4 inhibitor linagliptin reduces brain damage after stroke in normal and type 2 diabetic (T2D) mice. The aim of this study was to determine whether linagliptin impacts stroke-induced neurogenesis. T2D was induced by 25 weeks of high-fat diet. Linagliptin treatment was carried out for 7 weeks. Standard diet fed-mice were used as controls. Stroke was induced by middle cerebral artery occlusion 4 weeks into the linagliptin treatment. Neural stem cell (NSC) proliferation/neuroblast formation and striatal neurogenesis/gliogenesis were assessed 3 weeks after stroke. The effect of linagliptin on NSC viability was also determined in vitro. The results show that linagliptin enhances NSC proliferation in T2D mice but not in normal mice. Linagliptin did not increase NSC number in vitro indicating that the effect of linagliptin on NSC proliferation in T2D is indirect. Neurogenesis and gliogenesis were not affected. In conclusion, we found no correlation between acute neuroprotection (occurring in both T2D and normal mice) and increased NSC proliferation (occurring only in T2D mice). However, our results show that linagliptin evokes a differential response on NSC proliferation after stroke in normal and T2D mice suggesting that DPP-4 inhibition effect in the CNS might go beyond the well known increase of GLP-1.
authors.affiliation: Karolinska Institutet, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Stockholm, Sweden.
authors.forename: Vladimer
authors.initials: V
authors.lastname: Darsalia
authors.affiliation: Karolinska Institutet, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Olverling
authors.affiliation: Karolinska Institutet, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Stockholm, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Larsson
authors.affiliation: Karolinska Institutet, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Stockholm, Sweden.
authors.forename: Shiva
authors.initials: S
authors.lastname: Mansouri
authors.affiliation: Karolinska Institutet, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Stockholm, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Nathanson
authors.affiliation: Karolinska Institutet, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Stockholm, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Nyström
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klein
authors.affiliation: University of South Alabama, College of Medicine, Department of Biochemistry and Molecular Biology, Mobile, AL, USA; Department of Internal Medicine, Diabetes Research Unit, Södertälje Hospital, Södertälje, Sweden.
authors.forename: Åke
authors.initials: Å
authors.lastname: Sjöholm
authors.affiliation: Karolinska Institutet, Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Stockholm, Sweden. Electronic address: cesare.patrone@ki.se.
authors.forename: Cesare
authors.initials: C
authors.lastname: Patrone
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000201:enzymology / Q000473:pathology; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D000069476:Linagliptin; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects*; D011687:Purines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D020521:Stroke / Q000150:complications* / Q000201:enzymology / Q000473:pathology*; D013329:Structure-Activity Relationship
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D011687:Purines; D011799:Quinazolines; D000069476:Linagliptin; D018819:Dipeptidyl Peptidase 4
keywords: DPP-4 inhibitor; GLP-1; High fat diet; Linagliptin; MCAO; Stroke