Exendin-4 Protected against Cognitive Dysfunction in Hyperglycemic Mice Receiving an Intrahippocampal Lipopolysaccharide Injection

• Published in: PloS one Vol. 7; no. 7; p. e39656
• Main Authors: Huang, Hei-Jen, Chen, Yen-Hsu, Liang, Keng-Chen, Jheng, Yu-Syuan, Jhao, Jhih-Jhen, Su, Ming-Tsan, Lee-Chen, Guey-Jen, Hsieh-Li, Hsiu Mei
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.07.2012; Public Library of Science (PLoS)
• Subjects: Activation; Advertising executives; Alzheimer's disease; Animals; Apoptosis; Apoptosis - drug effects; Astrocytes; Astrocytes - drug effects; Astrocytes - pathology; Bailouts; Biology; Blood Glucose - metabolism; Blood pressure; Brain damage; Brain injury; Central nervous system; Citric acid; Cognition - drug effects; Cognition Disorders - complications; Cognition Disorders - prevention & control; Cognitive ability; Complications; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - metabolism; Cytokines; Damage assessment; Dementia; Diabetes; Diabetes mellitus; Drug dosages; Gene expression; Glucagon; Glucagon-like peptide 1; Glucose; Hippocampus; Hyperglycemia; Hyperglycemia - chemically induced; Hyperglycemia - metabolism; Hyperglycemia - pathology; Hyperglycemia - physiopathology; Hypoglycemic Agents - pharmacology; Inflammation; Injection; Injections; Insulin; Insulin - blood; Interleukin-1beta - metabolism; Ischemia; Kinases; Leukocyte Common Antigens - metabolism; Life sciences; Lipopolysaccharides; Lipopolysaccharides - administration & dosage; Lipopolysaccharides - pharmacology; Male; Medicine; Membrane Proteins - metabolism; Memory - drug effects; Metabolism; Mice; Mice, Inbred C57BL; Mitogens; Nervous system diseases; Neurodegeneration; Neurodegenerative diseases; Neurological diseases; Neurons; Neurons - drug effects; Neurons - pathology; Neuroprotection; NF-kappa B - metabolism; NF-κB protein; Nursing; Peptides; Peptides - pharmacology; Phosphorylation; Proteins; Rodents; Social and Behavioral Sciences; Sodium; Sodium citrate; Spatial Behavior - drug effects; Spatial Behavior - physiology; Spatial discrimination learning; Spatial memory; Streptozocin; Streptozocin - adverse effects; Superoxide Dismutase - metabolism; Up-Regulation - drug effects; Venoms - pharmacology; Taiwan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0039656

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.