TY - JOUR

T1 - Effects of the glucagon-like polypeptide-1 analogue (Val8)GLP-1 on learning, progenitor cell proliferation and neurogenesis in the C57B/16 mouse brain

AU - McGovern, Stephen F. J.

AU - Hunter, Kerry

AU - Hölscher, Christian

N1 - Copyright © 2012 Elsevier B.V. All rights reserved.

PY - 2012/9/14

Y1 - 2012/9/14

N2 - Type 2 diabetes (T2DM) has been identified as a risk factor for Alzheimer's disease. Here, we tested the properties of the glucagon-like polypetide-1 (GLP-1) analogue (Val8)GLP-1, a drug originally developed as a treatment for T2DM at a range of doses (2.5 nmol; 25 nmol; 100 nmol; or 250 nmol/kg bw ip.) in an acute memory study in wild type C57B/l6 mice. We also tested (Val8)GLP-1 and the GLP-1 receptor antagonist exendin (9-39) in a chronic study (3 weeks at 25 nmol/kg bw ip. once-daily). We found that (Val8)GLP-1 crossed the blood brain barrier readily and that peripheral injection increased levels in the brain 30 min post-injection ip. but not 2h post-injection in rats. In the acute study, the low dose of 2.5 nmol/kg ip. enhanced motor activity in the open field task, while total distance travelled, exploratory behaviour and anxiety was not affected at any dose. Learning an object recognition task was not affected either. In the chronic study, no effect was observed in the open field assessment. The antagonist exendin (9-39) impaired object recognition learning and spatial learning in a water maze task, demonstrating the importance of GLP-1 signalling in memory formation. Locomotor activity was also affected in some cases. Blood sugar levels and insulin sensitivity was not affected in chronically treated mice. Neuronal stem cells and neurogenesis was enhanced by (Val8)GLP-1 in the dentate gyrus of wild type mice. The results demonstrate that (Val8)GLP-1 is safe in a range of doses, crosses the BBB and has potentially beneficial effects in the CNS by enhancing neurogenesis.

AB - Type 2 diabetes (T2DM) has been identified as a risk factor for Alzheimer's disease. Here, we tested the properties of the glucagon-like polypetide-1 (GLP-1) analogue (Val8)GLP-1, a drug originally developed as a treatment for T2DM at a range of doses (2.5 nmol; 25 nmol; 100 nmol; or 250 nmol/kg bw ip.) in an acute memory study in wild type C57B/l6 mice. We also tested (Val8)GLP-1 and the GLP-1 receptor antagonist exendin (9-39) in a chronic study (3 weeks at 25 nmol/kg bw ip. once-daily). We found that (Val8)GLP-1 crossed the blood brain barrier readily and that peripheral injection increased levels in the brain 30 min post-injection ip. but not 2h post-injection in rats. In the acute study, the low dose of 2.5 nmol/kg ip. enhanced motor activity in the open field task, while total distance travelled, exploratory behaviour and anxiety was not affected at any dose. Learning an object recognition task was not affected either. In the chronic study, no effect was observed in the open field assessment. The antagonist exendin (9-39) impaired object recognition learning and spatial learning in a water maze task, demonstrating the importance of GLP-1 signalling in memory formation. Locomotor activity was also affected in some cases. Blood sugar levels and insulin sensitivity was not affected in chronically treated mice. Neuronal stem cells and neurogenesis was enhanced by (Val8)GLP-1 in the dentate gyrus of wild type mice. The results demonstrate that (Val8)GLP-1 is safe in a range of doses, crosses the BBB and has potentially beneficial effects in the CNS by enhancing neurogenesis.

KW - Animals

KW - Blood-Brain Barrier

KW - Brain

KW - Cell Proliferation

KW - Enzyme-Linked Immunosorbent Assay

KW - Glucagon-Like Peptide 1

KW - Immunohistochemistry

KW - Learning

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Neural Stem Cells

KW - Neurogenesis

KW - Peptide Fragments

KW - Rats

KW - Rats, Sprague-Dawley

U2 - 10.1016/j.brainres.2012.07.029

DO - 10.1016/j.brainres.2012.07.029

M3 - Journal article

C2 - 22867941

VL - 1473

SP - 204

EP - 213

JO - Brain Research

JF - Brain Research

SN - 0006-8993

ER -