glucagon-like-peptide-1 and Encephalitis

Glucagon-like peptide-1 (GLP-1) is a hormone mainly secreted from enteroendocrine L cells. GLP-1 and its receptor are also expressed in the brain. GLP-1 signaling has pivotal roles in regulating neuroinflammation and memory function, but it is unclear how GLP-1 improves memory function by regulating neuroinflammation. Here, we demonstrated that GLP-1 enhances neural structure by inhibiting lipopolysaccharide (LPS)-induced inflammation in microglia with the effects of GLP-1 itself on neurons. Inflammatory secretions of BV-2 microglia by LPS aggravated mitochondrial function and cell survival, as well as neural structure in Neuro-2a neurons. In inflammatory condition, GLP-1 suppressed the secretion of tumor necrosis factor-alpha (TNF-α)-associated cytokines and chemokines in BV-2 microglia and ultimately enhanced neurite complexity (neurite length, number of neurites from soma, and secondary branches) in Neuro-2a neurons. We confirmed that GLP-1 improves neurite complexity, dendritic spine morphogenesis, and spine development in TNF-α-treated primary cortical neurons based on altered expression levels of the factors related to neurite growth and spine morphology. Given that our data that GLP-1 itself enhances neurite complexity and spine morphology in neurons, we suggest that GLP-1 has a therapeutic potential in central nervous system diseases.

Topics: Animals; Cell Death; Cells, Cultured; Cytokines; Encephalitis; Glucagon-Like Peptide 1; Lipopolysaccharides; Mice, Inbred C57BL; Microglia; Neurons; Rats, Sprague-Dawley

Glucagon-like peptide-1 (GLP-1) is derived from the processing of proglucagon in intestinal L-cells and releases insulin from pancreatic β-cells as an incretin. The GLP-1 receptor has been proposed as a possible therapeutic target for the treatment of Alzheimer's disease, in which neuroinflammation is critical in the pathogenesis. The present study investigates whether GLP-1 (7-36) amide, an active fragment of GLP-1, protected against synaptic impairments induced by inflammation-related injurious agents (lipopolysaccharide [LPS], interleukin-1β [IL-1β], and H2 O2). In the Y-maze test, LPS (10 μg/mouse, i.c.v) significantly decreased the percentage alternation. Pretreatment with GLP-1 (7-36) amide (0.09-0.9 nmol/mouse, i.c.v.) prevented an impairment in spontaneous alternation performance. Pretreatment with LPS (10 μg/ml, 2 hr) impaired LTP induction but not paired-pulse facilitation in the CA1 region of rat hippocampal slices. This impairment was prevented by cotreatment with GLP-1 (7-36) amide (50 nM). IL-1β (0.57 nM) or H2 O2 (50 μM) also impaired LTP induction. This impairment was prevented by GLP-1 (7-36) amide (50 nM). These results suggest that GLP-1 (7-36) amide improves the synaptic impairments induced by inflammation-related injurious agents in the CA1 region of the hippocampus.

Topics: Analysis of Variance; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Electric Stimulation; Encephalitis; Excitatory Postsynaptic Potentials; Glucagon-Like Peptide 1; Hippocampus; Hydrogen Peroxide; In Vitro Techniques; Learning Disabilities; Lipopolysaccharides; Long-Term Potentiation; Male; Maze Learning; Motor Activity; Rats, Wistar; Synapses

Glia play an important role in neurotoxicity in neurodegenerative diseases. In this study, we investigated the expression of glucagon-like peptide-1 (GLP-1) and its receptor, and the effects of GLP-1 on lipopolysaccharide (LPS)-induced IL-1beta mRNA expression and IL-1beta production in glia. GLP-1-like immunoreactivity was observed in amoeboid microglia, but not ramified microglia or astrocytes. GLP-1 binding and GLP-1 receptor mRNA expression were observed in both astrocytes and microglia. GLP-1-induced morphological changes in microglia from the ramified type to the amoeboid type, suggesting an increase in production and release of endogenous GLP-1. GLP-1 prevented the LPS-induced IL-1beta mRNA expression, which effect was, in turn, inhibited by pretreatment with SQ22536, an adenylate cyclase inhibitor. GLP-1 also increased cAMP concentration and cAMP response element-binding protein phosphorylation in astrocytes. These results suggest that GLP-1 may be a modulator of inflammation in the central nervous system.

Topics: Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Animals; Astrocytes; Brain; Cell Shape; Cells, Cultured; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Encephalitis; Gene Expression; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Inflammation Mediators; Interleukin-1; Lipopolysaccharides; Microglia; Phosphorylation; Protein Binding; Rats; Rats, Wistar; Receptors, Glucagon; RNA, Messenger; Up-Regulation