title: Sitagliptin, a dipeptidyl peptidase-4 inhibitor, improves recognition memory, oxidative stress and hippocampal neurogenesis and upregulates key genes involved in cognitive decline.
abstract: OBJECTIVE
  To examine whether prolonged dipeptidyl peptidase-4 (DPP-4) inhibition can reverse learning and memory impairment in high-fat-fed mice.
  
  
  METHODS
  High-fat-fed mice received oral sitagliptin (50 mg/kg body weight) once daily or saline vehicle over 21 days. An additional group of mice on standard chow received saline vehicle. Energy intake, body weight, glucose and insulin concentrations were measured at regular intervals. Glucose tolerance, insulin sensitivity, novel object recognition, DPP-4 activity, hormone analysis, hippocampal gene expression and histology were performed.
  
  
  RESULTS
  Sitagliptin decreased circulating DPP-4 activity and improved glucose tolerance, glucose-stimulated insulin secretion and insulin sensitivity, and reduced plasma triglycerides and cholesterol levels. DPP-4 inhibition improved recognition memory (1.2-fold increase) without affecting hypermoteric activity or anxiety levels. Improvement in memory and learning was linked to reduced immunostaining for 8-oxoguanine and increased doublecortin staining in the hippocampus, which were indicative of reduced brain oxidative stress and increased hippocampal neurogenesis, respectively. These effects were associated with significant upregulation of hippocampal gene expression of glucagon-like peptide-1 (GLP-1) receptor, glucose-dependent insulinotropic polypeptide receptor, synaptophysin, sirtuin 1, glycogen synthase kinase 3β, superdioxide mutase 2, nuclear factor (erythroid-derived 2)-like 2 and vascular endothelial growth factor. Total plasma and brain GLP-1 concentrations were significantly increased after sitagliptin therapy, whereas DPP-4 activity in brain tissue was not altered.
  
  
  CONCLUSIONS
  These studies show that sitagliptin can reverse memory impairment in high-fat-fed mice and is also associated with improved insulin sensitivity, enhanced hippocampal neurogenesis and reduced oxidative stress. DPP-4 inhibitors may therefore exhibit dual benefits by improving metabolic control and reducing the decline in cognitive function.
authors.affiliation: Diabetes Research Group, School of Biomedical Sciences, University of Ulster, Coleraine, UK.
authors.forename: V A
authors.initials: VA
authors.lastname: Gault
authors.forename: R
authors.initials: R
authors.lastname: Lennox
authors.forename: P R
authors.initials: PR
authors.lastname: Flatt
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D060825:Cognitive Dysfunction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D059305:Diet, High-Fat / Q000009:adverse effects; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007333:Insulin Resistance; D008297:Male; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008815:Mice, Inbred Strains; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D011897:Random Allocation; D021641:Recognition, Psychology / Q000187:drug effects; D000068900:Sitagliptin Phosphate / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D009419:Nerve Tissue Proteins; D000068900:Sitagliptin Phosphate
keywords: cognitive function; dipeptidyl peptidase-4 (DPP-4); hippocampus; neurogenesis; oxidative stress