title: 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 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.
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Chiang-Ting
authors.initials: CT
authors.lastname: Chien
authors.affiliation: Department of Chinese Medicine for Post Baccalaureate, College of Medicine, I-Shou University (Yanchao Campus), Kaohsiung, Taiwan.
authors.forename: Ming-Jia
authors.initials: MJ
authors.lastname: Jou
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.|Department of Bioengineering, College of Engineering, Ta-Tung University, Taipei, Taiwan.
authors.forename: Tai-Yu
authors.initials: TY
authors.lastname: Cheng
authors.affiliation: Department of Biological Science and Technology, College of Medicine, I-Shou University (Yanchao Campus), Kaohsiung, Taiwan.
authors.forename: Chih-Hui
authors.initials: CH
authors.lastname: Yang
authors.affiliation: Department of Occupational Therapy, College of Medicine, I-Shou University (Yanchao Campus), Kaohsiung, Taiwan.
authors.forename: Tzu-Ying
authors.initials: TY
authors.lastname: Yu
authors.affiliation: Department of Occupational Therapy, College of Medicine, I-Shou University (Yanchao Campus), Kaohsiung, Taiwan.
authors.forename: Ping-Chia
authors.initials: PC
authors.lastname: Li
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000523:psychology; D002339:Carotid Arteries / Q000187:drug effects; D016893:Carotid Stenosis / Q000188:drug therapy / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology / Q000523:psychology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D004337:Drug Carriers; D000077270:Exenatide; D007279:Injections, Subcutaneous; D019344:Lactic Acid; D008279:Magnetic Resonance Imaging; D008297:Male; D008833:Microcirculation; D008863:Microspheres; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects*; D051058:Oncogene Protein v-akt / Q000187:drug effects*; D010455:Peptides / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000523:psychology; D015398:Signal Transduction / Q000187:drug effects; D014688:Venoms / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D004337:Drug Carriers; D018696:Neuroprotective Agents; D010455:Peptides; D014688:Venoms; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D000077270:Exenatide; D052250:Nitric Oxide Synthase Type III; D051058:Oncogene Protein v-akt