The metabolite GLP ‐1 (9‐36) is neuroprotective and anti‐inflammatory in cellular models of neurodegeneration

AbstractGlucagon-like peptide-1 (GLP-1) is best known for its insulinotropic action following food intake. Its metabolite, GLP-1 (9-36), was assumed biologically inactive due to low GLP-1 receptor (GLP-1R) affinity and non-insulinotropic properties; however, recent studies contradict this assumption. Increased use of FDA approved GLP-1 analogues for treating metabolic disorders and neurodegenerative diseases raises interest in GLP-1 (9-36) ’s biological role. We use human SH-SY5Y neuroblastoma cells and a GLP-1R overexpressing variety (#9), in both undifferentiated and differentiated states, to evaluate the neurotrophic/neuroprotective effects of GLP-1 (9-36) against toxic glutamate exposure and other oxidative stress models (via th e MTS, LDH or ROS assays). In addition, we examine GLP-1 (9-36)’s signaling pathways, including cyclic-adenosine monophosphate (cAMP), protein kinase-A (PKA), and 5’ adenosine monophosphate activated protein kinase (AMPK) via use of ELISA, pharmacological inhibitors, or GLP-1R antagonist. Human HMC3 and mouse IMG microglial cell lines were used to study the anti-inflammatory effects of GLP-1 (9-36) against lipopolysaccharide (LPS) (via ELISA). Finally, we applied GLP-1 (9-36) to primary dissociation cultures challenged with α-synuclein or amyloid-β and assessed survival and morphology vi a immunochemistry. We demonstrate evidence of GLP-1R, cAMP, PKA, and AMPK mediated neurotrophic and neuroprotective effects of GLP-1 (9-36). The metabolit...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: ORIGINAL ARTICLE Source Type: research