Abstract
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 O2–
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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