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Sitagliptin, a dipeptidyl peptidase‐4 inhibitor, improves recognition memory, oxidative stress and hippocampal neurogenesis and upregulates key genes involved in cognitive decline
Author(s) -
Gault V. A.,
Lennox R.,
Flatt P. R.
Publication year - 2015
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/dom.12432
Subject(s) - endocrinology , medicine , neurogenesis , insulin , biology , chemistry , microbiology and biotechnology
Aim 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. Conclusion 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.