Glucagon-like peptide-1 cleavage product GLP-1(9-36) reduces neuroinflammation from stroke via the activation of insulin-like growth factor 1 receptor in astrocytes.

Abstract

Glucagon-like peptide-1 (GLP-1) is an endogenous gut hormone and a key regulator in maintaining glucose homeostasis by stimulating insulin secretion. Its natural cleavage product GLP-1 (9-36), which was formerly considered a "bio-inactive" metabolite mainly due to its low affinity for GLP-1 receptor, possesses unique properties such as cardiovascular protection. Little is known about the effects and mechanisms of GLP-1 (9-36) in cerebral ischemia and reperfusion injury. Here, we report that systemic application of GLP-1 (9-36) in adult mice facilitated functional recovery and reduced infarct volume, astrogliosis, and neuronal apoptosis following middle cerebral artery occlusion and reperfusion. Interestingly, these effects were still observed in GLP-1 receptor knockout (Glp-1rKO) mice but were partially reversed in insulin-like growth factor 1 (IGF-1) receptor knockdown (Igf-1rKD) mice. Primary astrocytes were cultured and subjected to oxygen-glucose deprivation/reoxygenation (OGD/R), and enzyme-linked immunosorbent assay indicated that GLP-1 (9-36) pretreatment reduces tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 levels. This effect was not diminished in Glp-1rKO astrocytes but was reversed in Igf-1rKO astrocytes, emphasizing that the anti-inflammatory effect of GLP-1 (9-36) in astrocytes is independent of GLP-1 receptor signaling and is instead mediated by IGF-1 receptor. Immunoprecipitation experiments showed that GLP-1 (9-36) directly interacts with IGF-1 receptor in astrocytes. Western blot data indicated that GLP-1 (9-36) activates IGF-1 receptor and downstream PI3K-AKT pathway in astrocytes upon OGD/R injury, which was abrogated by preincubation with IGF-1 receptor autophosphorylation inhibitor picropodophyllin. Thus, our findings suggest that GLP-1 (9-36) improved stroke outcome by reducing inflammation in astrocytes via interaction with IGF-1 receptor.

• Authors: Jing Huang, Yunhan Liu, Liusiyuan Cheng, Jihong Li, Tangrui Zhang, Gang Zhao, Huinan Zhang
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 887 Pg. 173581 (Nov 15 2020) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 32949596 (Publication Type: Journal Article)
• Copyright: Copyright © 2020. Published by Elsevier B.V.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Cytokines
• IGF1R protein, human
• Igf1r protein, mouse
• glucagon-like peptide-1 (9-36)-amide
• Glucagon-Like Peptide 1
• Receptor, IGF Type 1
• Glucose

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology, therapeutic use)
• Astrocytes (drug effects)
• Behavior, Animal (drug effects)
• Cell Hypoxia
• Cytokines (metabolism)
• Encephalitis (drug therapy, etiology, psychology)
• Gene Knockdown Techniques
• Glucagon-Like Peptide 1 (analogs & derivatives, genetics, metabolism, pharmacology, therapeutic use)
• Glucose (deficiency)
• Mice
• Mice, Knockout
• Primary Cell Culture
• Receptor, IGF Type 1 (agonists, genetics)
• Signal Transduction (drug effects)
• Stroke (complications, drug therapy, psychology)