The glucagon-like peptide-1 receptor agonist reduces inflammation and blood-brain barrier breakdown in an astrocyte-dependent manner in experimental stroke

Abstract

BackgroundPreserving the integrity of the blood-brain barrier (BBB) is beneficial to avoid further brain damage after acute ischemic stroke (AIS). Astrocytes, an important component of the BBB, promote BBB breakdown in subjects with AIS by secreting inflammatory factors. The glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) protects the BBB and reduces brain inflammation from cerebral ischemia, and GLP-1R is expressed on astrocytes. However, the effect of Ex-4 on astrocytes in subjects with AIS remains unclear.MethodsIn the present study, we investigated the effect of Ex-4 on astrocytes cultured under oxygen-glucose deprivation (OGD) plus reoxygenation conditions and determined whether the effect influences bEnd.3 cells. We used various methods, including permeability assays, western blotting, immunofluorescence staining, and gelatin zymography, in vitro and in vivo.ResultsEx-4 reduced OGD-induced astrocyte-derived vascular endothelial growth factor (VEGF-A), matrix metalloproteinase-9 (MMP-9), chemokine monocyte chemoattractant protein-1 (MCP-1), and chemokine C-X-C motif ligand 1 (CXCL-1). The reduction in astrocyte-derived VEGF-A and MMP-9 was related to the increased expression of tight junction proteins (TJPs) in bEnd.3 cells. Ex-4 improved neurologic deficit scores, reduced the infarct area, and ameliorated BBB breakdown as well as decreased astrocyte-derived VEGF-A, MMP-9, CXCL-1, and MCP-1 levels in ischemic brain tissues from rats subjected to middle cerebral artery occlusion. Ex-4 reduced the activation of the JAK2/STAT3 signaling pathway in astrocytes following OGD.ConclusionBased on these findings, ischemia-induced inflammation and BBB breakdown can be improved by Ex-4 through an astrocyte-dependent manner.

Butyrate-producing human gut symbiont, Clostridium butyricum, and its role in health and disease

“…GLP-1 is neuroprotective in models of brain injury and protects the BBB, potentially via modulation of tight junctions. [90][91][92] Indeed, C. butyricum treatment in the TBI model also increased the expression of the GLP-1 receptor in both the brain and the gut, 38 supporting the notion that C. butyricum mediates barrier function via GLP-1 signaling.…”

Inhibition of microglial receptor‐interacting protein kinase 1 ameliorates neuroinflammation following cerebral ischaemic stroke

“…These findings suggest that RIPK1 plays a role in mediating the secretion of inflammatory factors in M1 phenotypic microglia after OGD. RhTrx‐1 therapy inhibits the expression of microglial RIPK1 and regulates the expression of M1/M2 phenotype of microglia, which ultimately plays a neuroprotective role 45,46 . Besides, inhibition of inflammation during ischaemic stroke contributes to reduce ischaemic infarction 24,30,41 .…”

“…RhTrx-1 therapy inhibits the expression of microglial RIPK1 and regulates the expression of M1/M2 phenotype of microglia, which ultimately plays a neuroprotective role. 45,46 Besides, inhibition of inflammation during ischaemic stroke contributes to reduce ischaemic infarction. 24,30,41 Based on this evidence, we further in- 20 Ma et al demonstrated that rhTrx-1 exerts an antioxidative effect against neurological dysfunction and cerebral infarction.…”

Central nervous system diseases associated with blood brain barrier breakdown - A Comprehensive update of existing literatures

“…Ischemic stroke exhibits extravasation of blood-borne cells, chemicals, and luid into brain parenchyma across the impaired BBB as a result of increased paracellular and transcellular permeability and endothelial degeneration [89]. Astrocytes, an important component of the BBB, promotes BBB breakdown in subjects with acute ischemic stroke by secreting in lammatory factors [90].Several factors which determine BBB permeability followed by breakdown are mitochondrial bioenergetics, microRNAs, MMPs (MMP-2 and MMP-9), cytokines (IL-1β, MIF, IL-9 ), chemokines (MCP-1), i mmune cells , adhesion proteins (ICAM-1, V CAM-1) [91,94].Recent studies support the role of CCL2 in BBB disruption following ICH throu gh CCL2-CCR2-p38 MAPK path way [92]. Dysfunction of tight junctions and endothelial cells is associated with BBB disruption following aneurysmal SAH.…”