Sitagliptin, a dipeptidyl peptidase-4 inhibitor, improves recognition memory, oxidative stress and hippocampal neurogenesis and upregulates key genes involved in cognitive decline

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Abstract

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.
LanguageEnglish
Pages403-413
JournalDiabetes Obes Metab.
Volume17
Issue number4
DOIs
Publication statusPublished - 1 Apr 2015

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Dipeptidyl-Peptidase IV Inhibitors
Dipeptidyl Peptidase 4
Neurogenesis
Oxidative Stress
Up-Regulation
Insulin Resistance
Glucose
Genes
Fats
Brain
Sirtuin 1
Intramolecular Transferases
Body Weight
Learning
Insulin
Gene Expression
Glycogen Synthase Kinases
Synaptophysin
Glucagon-Like Peptide 1
Energy Intake

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@article{8256ab12eea141e980645531271ee0ff,
title = "Sitagliptin, a dipeptidyl peptidase-4 inhibitor, improves recognition memory, oxidative stress and hippocampal neurogenesis and upregulates key genes involved in cognitive decline",
abstract = "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.",
author = "Victor Gault and R Lennox and Peter Flatt",
year = "2015",
month = "4",
day = "1",
doi = "10.1111/dom.12432",
language = "English",
volume = "17",
pages = "403--413",
journal = "Diabetes, Obesity and Metabolism",
issn = "1463-1326",
number = "4",

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TY - JOUR

T1 - Sitagliptin, a dipeptidyl peptidase-4 inhibitor, improves recognition memory, oxidative stress and hippocampal neurogenesis and upregulates key genes involved in cognitive decline

AU - Gault, Victor

AU - Lennox, R

AU - Flatt, Peter

PY - 2015/4/1

Y1 - 2015/4/1

N2 - 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.

AB - 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.

U2 - 10.1111/dom.12432

DO - 10.1111/dom.12432

M3 - Article

VL - 17

SP - 403

EP - 413

JO - Diabetes, Obesity and Metabolism

T2 - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

SN - 1463-1326

IS - 4

ER -