{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:15:56Z","timestamp":1787062556910,"version":"build-2736575974"},"reference-count":40,"publisher":"SAGE Publications","issue":"11","license":[{"start":{"date-parts":[[2015,6,10]],"date-time":"2015-06-10T00:00:00Z","timestamp":1433894400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["J Cereb Blood Flow Metab"],"published-print":{"date-parts":[[2015,11]]},"abstract":"<jats:p>\n                    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 \u03bcg\/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\n                    <jats:sub>2<\/jats:sub>\n                    <jats:sup>\u2013<\/jats:sup>\n                    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)-\u03baBp65\/ 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- \u03baB\/ICAM-1 signaling, ER stress, and apoptosis.\n                  <\/jats:p>","DOI":"10.1038\/jcbfm.2015.126","type":"journal-article","created":{"date-parts":[[2015,6,10]],"date-time":"2015-06-10T05:09:58Z","timestamp":1433912998000},"page":"1790-1803","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":45,"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"],"prefix":"10.1177","volume":"35","author":[{"given":"Chiang-Ting","family":"Chien","sequence":"first","affiliation":[{"name":"Department of Life Science, National Taiwan Normal University, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Jia","family":"Jou","sequence":"additional","affiliation":[{"name":"Department of Chinese Medicine for Post Baccalaureate, College of Medicine, I-Shou University (Yanchao Campus), Kaohsiung, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tai-Yu","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Life Science, National Taiwan Normal University, Taipei, Taiwan"},{"name":"Department of Bioengineering, College of Engineering, Ta-Tung University, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Hui","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Biological Science and Technology, College of Medicine, I-Shou University (Yanchao Campus), Kaohsiung, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzu-Ying","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Occupational Therapy, College of Medicine, I-Shou University (Yanchao Campus), Kaohsiung, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping-Chia","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Occupational Therapy, College of Medicine, I-Shou University (Yanchao Campus), Kaohsiung, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2015,6,10]]},"reference":[{"key":"bibr1-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.106.481390"},{"key":"bibr2-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.0000053843.03997.35"},{"key":"bibr3-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.0000258041.75739.cb"},{"key":"bibr4-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1038\/414813a"},{"key":"bibr5-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-9-279"},{"key":"bibr6-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5480-05.2006"},{"key":"bibr7-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1042\/CS20090464"},{"key":"bibr8-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.49.5.741"},{"key":"bibr9-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.48.12.2358"},{"key":"bibr10-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2009.00376.x"},{"key":"bibr11-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1160\/TH14-03-0258"},{"key":"bibr12-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.102.037481"},{"key":"bibr13-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2011.51"},{"key":"bibr14-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1016\/j.metabol.2012.03.002"},{"key":"bibr15-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1016\/j.peptides.2012.06.018"},{"key":"bibr16-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1042\/CS20110374"},{"key":"bibr17-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.2337\/db12-1025"},{"key":"bibr18-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.113.004116"},{"key":"bibr19-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.2337\/db14-0302"},{"key":"bibr20-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1210\/en.2007-1743"},{"key":"bibr21-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2012.99"},{"key":"bibr22-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.3390\/molecules18066521"},{"key":"bibr23-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2009.12.002"},{"key":"bibr24-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1089\/089771502753460268"},{"key":"bibr25-jcbfm.2015.126","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1681\/ASN.V125973","volume":"12","author":"Chien CT","year":"2001","journal-title":"J Am Soc Nephrol"},{"key":"bibr26-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.107.492934"},{"key":"bibr27-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.4103\/0971-6203.48720"},{"key":"bibr28-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jcbfm.9600457"},{"key":"bibr29-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1002\/jps.24238"},{"key":"bibr30-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ijo.0802206"},{"key":"bibr31-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.1993.129"},{"key":"bibr32-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2013.169"},{"key":"bibr33-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2011.09.022"},{"key":"bibr34-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.1999.tb00214.x"},{"key":"bibr35-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-10-95"},{"key":"bibr36-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2011.51"},{"key":"bibr37-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2014.05.004"},{"key":"bibr38-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2005.05.043"},{"key":"bibr39-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2006.04.060"},{"key":"bibr40-jcbfm.2015.126","doi-asserted-by":"publisher","DOI":"10.1016\/j.jvs.2013.03.023"}],"container-title":["Journal of Cerebral Blood Flow &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1038\/jcbfm.2015.126","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1038\/jcbfm.2015.126","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1038\/jcbfm.2015.126","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T20:12:09Z","timestamp":1777493529000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1038\/jcbfm.2015.126"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,6,10]]},"references-count":40,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2015,11]]}},"alternative-id":["10.1038\/jcbfm.2015.126"],"URL":"https:\/\/doi.org\/10.1038\/jcbfm.2015.126","relation":{},"ISSN":["0271-678X","1559-7016"],"issn-type":[{"value":"0271-678X","type":"print"},{"value":"1559-7016","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,6,10]]}}}