Glucagon-like peptide-1 (GLP-1) receptor activation in the brain provides neuroprotection. Exendin-4 (Ex-4), a GLP-1 analog, has seen limited clinical usage because of its short half-life. We developed long-lasting Ex-4-loaded poly(D,L-lactide-co-glycolide) microspheres (PEx-4) and explored its neuroprotective potential against cerebral ischemia in diabetic rats. Compared with Ex-4, PEx-4 in the gradually degraded microspheres sustained higher Ex-4 levels in the plasma and cerebrospinal fluid for at least 2 weeks and improved diabetes-induced glycemia after a single subcutaneous administration (20 μg/day). Ten minutes of bilateral carotid artery occlusion (CAO) combined with hemorrhage-induced hypotension (around 30 mm Hg) significantly decreased cerebral blood flow and microcirculation in male Wistar rats subjected to streptozotocin-induced diabetes. CAO increased cortical O 2 - levels by chemiluminescence amplification and prefrontal cortex edema by T2-weighted magnetic resonance imaging analysis. CAO significantly increased aquaporin 4 and glial fibrillary acidic protein expression and led to cognition deficits. CAO downregulated phosphorylated Akt/endothelial nitric oxide synthase (p-Akt/p-eNOS) signaling and enhanced nuclear factor (NF)-κBp65/intercellular adhesion molecule-1 (ICAM-1) expression, endoplasmic reticulum (ER) stress, and apoptosis in the cerebral cortex. PEx-4 was more effective than Ex-4 to improve CAO-induced oxidative injury and cognitive deficits. The neuroprotection provided by PEx-4 was through p-Akt/p-eNOS pathways, which suppressed CAO-enhanced NF-κB/ICAM-1 signaling, ER stress, and apoptosis.
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