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

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-1r^KO) mice but were partially reversed in insulin-like growth factor 1 (IGF-1) receptor knockdown (Igf-1r^KD) 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-1r^KO astrocytes but was reversed in Igf-1r^KO 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.

Keywords: Astrocytes; GLP-1(9–36); Insulin-like growth factor 1 receptor; Neuroinflammation; Stroke.