Glucagon-Like Peptide-1 Strengthens the Barrier Integrity in Primary Cultures of Rat Brain Endothelial Cells Under Basal and Hyperglycemia Conditions

Abstract

The objective of the present study was to determine the effects of glucagon-like peptide-1 (GLP-1) on barrier functions and to assess the underlying mechanism using an in vitro blood-brain barrier (BBB) model comprised of a primary culture of rat brain capillary endothelial cells (RBECs). GLP-1 increased transendothelial electrical resistance and decreased the permeability of sodium fluorescein in RBECs in a dose- and time-dependent manner. The effects on these barrier functions were significantly reduced in the presence of the GLP-1 receptor antagonist exendin-3 (9-39) and the protein kinase A (PKA) inhibitor H-89. Western blot analysis showed that GLP-1 increased the amount of occludin and claudin-5. GLP-1 analogs are approved for treatment of type 2 diabetes mellitus, and thus, we examined the effects of GLP-1 on hyperglycemia-induced BBB damage. GLP-1 inhibited the increase in production of reactive oxygen species under hyperglycemia conditions and improved the BBB integrity induced by hyperglycemia. As GLP-1 stabilized the integrity of the BBB, probably via cAMP/PKA signaling, the possibility that GLP-1 acts as a BBB-protective drug should be considered.

Clostridium butyricum exerts a neuroprotective effect in a mouse model of traumatic brain injury via the gut‐brain axis

“…Activated GLP‐1R can exert multifarious neuroprotective effects in Alzheimer's, Parkinson's diseases and stroke by combining with GLP‐1 or long‐acting GLP‐1R agonists. Consistent with studies showing that GLP‐1 can stabilize the integrity of the BBB, activating GLP‐1R may be one of the mechanisms by which Cb attenuated BBB impairment in TBI mice. Our results showed that Cb treatment could exert neuroprotective activity, which may be via stimulating secretion of GLP‐1 and subsequently activating GLP‐1R in the brain.…”

Impact of Metabolic Diseases on Cerebral Circulation: Structural and Functional Consequences

“…Studies in db/db mice and in vitro models showed increased activation of protein kinase Cβ (PKCβ), and when treated with the selective PKCβ inhibitor LY-317615, BBB leakiness and macrophage infiltration were prevented (226, 233). Fukuda et al observed inhibition of ROS and improvement in the integrity of the BBB in hyperglycemia when treated with glucagon-like peptide 1 (GLP-1) agonist, a newer class of antidiabetic agents, suggesting this might be a BBB-protective treatment for diabetic patients (97). …”

Neuroprotective Mechanisms of Glucagon‐like Peptide‐1‐based Therapies in Ischaemic Stroke: A Systematic Review based on Pre‐Clinical Studies

“…How GLP‐1 might decrease risk of cerebrovascular disease or improve memory is not fully understood. GLP‐1 may modulate various pathophysiological mechanisms by affecting brain glucose levels , the blood–brain barrier (BBB) or the central regulation of heart rate and blood pressure. Different GLP‐1RAs might have variable effects based on different compound structures, modes of administration and pharmacokinetics.…”