Exendin-4-loaded PLGA microspheres relieve cerebral ischemia/reperfusion injury and neurologic deficits through long-lasting bioactivity-mediated phosphorylated Akt/eNOS signaling in rats

被引:52
作者
Chien, Chiang-Ting [1 ]
Jou, Ming-Jia [2 ]
Cheng, Tai-Yu [1 ,3 ]
Yang, Chih-Hui [4 ]
Yu, Tzu-Ying [5 ]
Li, Ping-Chia [5 ]
机构
[1] Natl Taiwan Normal Univ, Dept Life Sci, Taipei, Taiwan
[2] I Shou Univ, Coll Med, Dept Chinese Med Post Baccalaureate, Kaohsiung 82445, Taiwan
[3] Tatung Univ, Coll Engn, Dept Bioengn, Taipei 104, Taiwan
[4] I Shou Univ, Coll Med, Dept Biol Sci & Technol, Kaohsiung 82445, Taiwan
[5] I Shou Univ, Coll Med, Dept Occupat Therapy, Kaohsiung 82445, Taiwan
关键词
diabetes; ischemia/reperfusion; neuroinflammation; exendin-4 PLGA microsphere; GLUCAGON-LIKE PEPTIDE-1; DIABETIC-RATS; OXIDATIVE STRESS; RECEPTOR AGONIST; ISCHEMIC-STROKE; NITRIC-OXIDE; BRAIN-INJURY; C-PEPTIDE; INSULIN; ACTIVATION;
D O I
10.1038/jcbfm.2015.126
中图分类号
R5 [内科学];
学科分类号
100201 [内科学];
摘要
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.
引用
收藏
页码:1790 / 1803
页数:14
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