Exendin-4-loaded PLGA microspheres relieve cerebral ischemia/reperfusion injury and neurologic deficits through long-lasting bioactivity-mediated phosphorylated Akt/eNOS signaling in rats
Exendin-4-loaded PLGA microspheres relieve cerebral ischemia/reperfusion injury and neurologic deficits through long-lasting bioactivity-mediated phosphorylated Akt/eNOS signaling in rats
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DOI：
10.1038/jcbfm.2015.126
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发表时间：
2015-11-01
影响因子：
6.3
通讯作者：
Li, Ping-Chia
中科院分区：
文献类型：
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作者：
Chien, Chiang-Ting;Jou, Ming-Jia;Li, Ping-Chia
大脑中胰高血糖素样肽 1 (GLP-1) 受体的激活可提供神经保护。 Exendin-4 (Ex-4) 是一种 GLP-1 类似物，由于其半衰期短，其临床应用受到限制。我们开发了长效负载 Ex-4 的聚（D,L-丙交酯-乙交酯）微球 (PEx-4)，并探索了其对糖尿病大鼠脑缺血的神经保护潜力。与Ex-4相比，逐渐降解的微球中的PEx-4在血浆和脑脊液中维持较高的Ex-4水平至少2周，并且在单次皮下给药（20μg/天）后改善了糖尿病引起的血糖。链脲佐菌素诱导的糖尿病雄性 Wistar 大鼠中，十分钟的双侧颈动脉闭塞 (CAO) 结合出血引起的低血压（约 30 mm Hg）显着降低了脑血流量和微循环。 CAO 通过化学发光放大增加皮质 O-2(-) 水平，通过 T2 加权磁共振成像分析增加前额皮质水肿。 CAO 显着增加水通道蛋白 4 和神经胶质原纤维酸性蛋白的表达，并导致认知缺陷。 CAO 下调磷酸化 Akt/内皮一氧化氮合酶 (p-Akt/p-eN05) 信号传导，增强核因子 (NF)-kappa Bp65/细胞间粘附分子-1 (ICAM-1) 表达、内质网 (ER) 应激和大脑皮层细胞凋亡。 PEx-4 比 Ex-4 更能有效改善 CAO 诱导的氧化损伤和认知缺陷。 PEx-4 通过 p-Akt/p-eNOS 途径提供神经保护，抑制 CAO 增强的 NF-kappa B/ICAM-1 信号传导、ER 应激和细胞凋亡。
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-Iactide-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 mu g/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-eN05) signaling and enhanced nuclear factor (NF)-kappa Bp65/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-kappa B/ICAM-1 signaling, ER stress, and apoptosis.