Sitagliptin, a DPP-4 inhibitor, improves recognition memory, oxidative stress, hippocampal neurogenesis and up-regulates key genes involved in cognitive decline

This is only in mice so don't expect any use to come from this for 50 years.
http://www.ncbi.nlm.nih.gov/pubmed/25580570

Gault VA¹, Lennox R, Flatt PR.

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Abstract

AIM:

Increasing evidence suggests an important link between diabetes and cognitive decline with insulin resistance and oxidative stress as possible common factors. In this study, we examined whether prolonged DPP-4 inhibition could reverse learning and memory impairment in high-fat fed mice.

METHODS:

High-fat fed mice received sitagliptin (50 mg/kg bw) orally (po) 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, 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 (DCX) staining in the hippocampus indicative of reduced brain oxidative stress and increased hippocampal neurogenesis, respectively. These effects were associated with significant up-regulation of hippocampal gene expression of GLP-1R, GIPR, Synaptophysin, SIRT1, GSK-3β, SOD2, Nrf2, and VEGF. Total plasma and brain GLP-1 concentrations were significantly increased following sitagliptin therapy whereas DPP-4 activity in brain tissue was not altered.

CONCLUSION:

These studies demonstrate that sitagliptin can reverse memory impairment in high-fat fed mice in association with improved insulin sensitivity, enhanced hippocampal neurogenesis and reduced oxidative stress. Therefore, DPP-4 inhibitors may exhibit dual benefits by improving metabolic control and declining cognitive function.