The Involvement of Autophagy Pathway in Exaggerated Ischemic Brain Damage in Diabetic Mice

• Type of Material: Article
• Authors: Ning Wei, Nanjing University; Shan Ping Yu, Emory University; Xiao-Huan Gu, Emory University; Dong-Dong Chen, Emory University; Matthew Whalin, Emory University; Ge-Lin Xu, Nanjing University; Xin-Feng Liu, Nanjing University; Ling Wei, Emory University
• Language: English
• Date: 2013-10-01
• Publisher: Wiley Open Access
• Publication Version: Final Published Version
• Copyright Statement: © 2013 John Wiley & Sons Ltd.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1111/cns.12123
• Title of Journal or Parent Work: CNS Neuroscience and Therapeutics
• ISSN: 1755-5930
• Volume: 19
• Issue: 10
• Start Page: 753
• End Page: 763
• Grant/Funding Information: This work was supported by NIH grants NS057255 (LW), NS075338 (LW), NS062097 (LW), NS0458710 (SPY), and an AHA Established Investigator Award (LW).; This work was also supported by the NIH grant C06 RR015455 from the Extramural Research Facilities Program of the National Center for Research Resources.
• Keywords: BARREL CORTEX; RATS; Blood-brain barrier; Cell death; STROKE; Diabetes; PANCREATIC BETA-CELLS; DOUBLE-EDGED-SWORD; LC3; Pharmacology & Pharmacy; Science & Technology; Neurosciences; APOPTOSIS; DEATH; FOCAL CEREBRAL-ISCHEMIA; Life Sciences & Biomedicine; Neurosciences & Neurology; CORTICAL-NEURONS; Autophagy; Ischemic stroke
• Research Categories: Biology, Neuroscience; Health Sciences, Pharmacology

Abstract

Summary: Background: Patients with Diabetes are at greater risk for ischemic stroke and usually suffer more severe ischemic brain damage than nondiabetic patients. However, the underlying mechanism of the exaggerated injury is not well defined. Aims: Macroautophagy (hereafter called autophagy in this report) plays a key role in cellular homeostasis and may contribute to cell death as well. Our aim was to determine whether autophagy was involved in the enhanced susceptibility of diabetic brain cells to ischemic injury and explore it as a possible target for the treatment of stroke in a diabetic condition. Results: A type II diabetic mouse model generated by combined administration of streptozotocin and nicotinamide showed enlarged infarct volume, increased cell death and excessive blood-brain barrier (BBB) disruption compared with nondiabetic stroke mice. After ischemic stroke, both diabetic and nondiabetic mice showed enhanced autophagosome formation and autophagic flux as demonstrated by increased expression of autophagy signals Beclin 1, microtubule-associated protein light-chain II (LC3-II), and decreased autophagy-specific substrate p62. The increased autophagic activity was significantly higher in diabetic stroke mice than that in nondiabetic stroke mice. The autophagy inhibitor 3-methyladenine (3-MA) attenuated the exaggerated brain injury and improved functional recovery. Conclusions: These data suggest that autophagy contributes to exacerbated brain injury in diabetic condition, and autophagy-mediated cell death may be a therapeutic target in diabetic stroke.