Exendin-4-Loaded PLGA Microspheres Relieve Cerebral Ischemia/Reperfusion Injury and Neurologic Deficits through Long-Lasting Bioactivity-Mediated Phosphorylated Akt/eNOS Signaling in Rats

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 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.

Apelin-13 Protects against Ischemic Blood-Brain Barrier Damage through the Effects of Aquaporin-4

“…Put together, with the general existence of crosstalk among the MAPK family, we speculate that different signal transduction pathways may be activated by different stimulations to regulate AQP4 expression. Moreover, the PI3K/Akt pathway was also demonstrated to regulate AQP4 expression [35]. As a result, it is not hard to explain our findings about AQP4 regulation pathways.…”

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

“…The timing of drug administration varied between studies. Eight studies administered GLP‐1RAs pre‐ischaemia , eight post‐ischaemia and four both pre‐ and post‐ischaemia . For the seven studies involving DPP‐4Is, one study applied the drugs pre‐ischaemia , one post‐ischaemia and five studies both pre‐ and post‐ischaemia .…”

Salvinorin A ameliorates cerebral vasospasm through activation of endothelial nitric oxide synthase in a rat model of subarachnoid hemorrhage

“…A previous study showed that the upregulation of AQP‐4 expression was involved in neuroinflammation and formation of the brain edema after stroke . SA decreased the expression of AQP‐4 protein in the hippocampus and basilar artery, which might contribute to the alleviation of brain injury after SAH.…”