Exendin-4 Protected against Cognitive Dysfunction in Hyperglycemic Mice Receiving an Intrahippocampal Lipopolysaccharide Injection
Open Access
- 23 July 2012
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 7 (7), e39656
- https://doi.org/10.1371/journal.pone.0039656
Abstract
Chronic hyperglycemia-associated inflammation plays critical roles in disease initiation and the progression of diabetic complications, including Alzheimer’s disease (AD). However, the association of chronic hyperglycemia with acute inflammation of the central nervous system in the progression of AD still needs to be elucidated. In addition, recent evidence suggests that Glucagon-like peptide-1 receptor (GLP-1R) protects against neuronal damage in the brain. Therefore, the neuroprotective effects of the GLP-1R agonist exendin-4 (EX-4) against hyperglycemia/lipopolysaccharides (LPS) damage were also evaluated in this study. Ten days after streptozotocin (STZ) or vehicle (sodium citrate) treatment in mice, EX-4 treatment (10 µg/kg/day) was applied to the mice before intrahippocampal CA1 injection of LPS or vehicle (saline) and continued for 28 days. This study examined the molecular alterations in these mice after LPS and EX4 application, respectively. The mouse cognitive function was evaluated during the last 6 days of EX-4 treatment. The results showed that the activation of NF-κB-related inflammatory responses induced cognitive dysfunction in both the hyperglycemic mice and the mice that received acute intrahippocampal LPS injection. Furthermore, acute intrahippocampal LPS injection exacerbated the impairment of spatial learning and memory through a strong decrease in monoaminergic neurons and increases in astrocytes activation and apoptosis in the hyperglycemic mice. However, EX-4 treatment protected against the cognitive dysfunction resulting from hyperglycemia or/and intrahippocampal LPS injection. These findings reveal that both hyperglycemia and intrahippocampal LPS injection induced cognitive dysfunction via activation of NF-κB-related inflammatory responses. However, acute intrahippocampal LPS injection exacerbated the progression of cognitive dysfunction in the hyperglycemic mice via a large increase in astrocytes activation-related responses. Furthermore, EX-4 might be considered as a potential adjuvant entity to protect against neurodegenerative diseases.Keywords
This publication has 60 references indexed in Scilit:
- Astrocytes Secrete Exosomes Enriched with Proapoptotic Ceramide and Prostate Apoptosis Response 4 (PAR-4)Journal of Biological Chemistry, 2012
- Non-Steroidal Anti-Inflammatory Drugs and Cognitive Function: Are Prostaglandins at the Heart of Cognitive Impairment in Dementia and Delirium ?Journal of Neuroimmune Pharmacology, 2011
- Astrocytes are important mediators of Aβ-induced neurotoxicity and tau phosphorylation in primary cultureCell Death & Disease, 2011
- Inflammation Induced by Infection Potentiates Tau Pathological Features in Transgenic MiceThe American Journal of Pathology, 2011
- Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stressFree Radical Biology & Medicine, 2011
- Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrineProceedings of the National Academy of Sciences, 2010
- Mechanisms Underlying Inflammation in NeurodegenerationCell, 2010
- Cyclooxygenase-1 and -2 Differentially Modulate Lipopolysaccharide-Induced Blood–Brain Barrier Disruption through Matrix Metalloproteinase ActivityJournal of Cerebral Blood Flow & Metabolism, 2009
- Inflammation, microglia, and alzheimer's diseaseNeurobiology of Disease, 2009
- Systemic LPS causes chronic neuroinflammation and progressive neurodegenerationGlia, 2007