title: Gliptin-mediated neuroprotection against stroke requires chronic pretreatment and is independent of glucagon-like peptide-1 receptor.
abstract: Gliptins are anti-type 2 diabetes (T2D) drugs that regulate glycaemia by preventing endogenous glucagon-like peptide-1 (GLP-1) degradation. Chronically administered gliptins before experimental stroke can also induce neuroprotection, and this effect is potentially relevant for reducing brain damage in patients with T2D and high risk of stroke. It is not known, however, whether acute gliptin treatment after stroke (mimicking a post-hospitalization treatment) is neuroprotective or whether gliptin-mediated neuroprotection occurs via GLP-1-receptor (GLP-1R) activation. To answer these two questions, wild-type and glp-1r(-/-) mice were subjected to transient middle cerebral artery occlusion (MCAO). Linagliptin was administered acutely (50 mg/kg intravenously), at MCAO time or chronically (10 mg/kg orally) for 4 weeks before and 3 weeks after MCAO. Neuroprotection was assessed by stroke volume measurement and quantification of NeuN-positive surviving neurons. Plasma/brain GLP-1 levels and dipeptidyl peptidase-4 activity were also measured. The results show that the linagliptin-mediated neuroprotection against stroke requires chronic pretreatment and does not occur via GLP-1R. The findings provide essential new knowledge with regard to the potential clinical use of gliptins against stroke, as well as a strong impetus to identify gliptin-mediated neuroprotective mechanisms.
authors: Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: V
authors: V
authors: Darsalia
authors: Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: M
authors: M
authors: Larsson
authors: Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden.|Department of Anatomy and Neurobiology, Medical University of Gdansk, Gdansk, Poland.
authors: G
authors: G
authors: Lietzau
authors: Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: D
authors: D
authors: Nathanson
authors: Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: T
authors: T
authors: Nyström
authors: Department of CardioMetabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors: T
authors: T
authors: Klein
authors: Department of Clinical Science and Education, Södersjukhuset, Internal Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: C
authors: C
authors: Patrone
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins; D018819:Dipeptidyl Peptidase 4 / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000819:agonists* / Q000097:blood / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor / Q000235:genetics / Q000378:metabolism; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D009687:Nuclear Proteins / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage / Q000627:therapeutic use; D020521:Stroke / Q000097:blood / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D014688:Venoms / Q000008:administration & dosage / Q000627:therapeutic use; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D004268:DNA-Binding Proteins; D054873:Dipeptidyl-Peptidase IV Inhibitors; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D010455:Peptides; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
keywords: DPP-4 inhibitors; GLP-1; gliptins; linagliptin; stroke; type 2 diabetes