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

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 r...

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Veröffentlicht in:CNS neuroscience & therapeutics 2013-10, Vol.19 (10), p.753-763
Hauptverfasser: Wei, Ning, Yu, Shan‐Ping, Gu, Xiao‐Huan, Chen, Dong‐Dong, Whalin, Matthew K., Xu, Ge‐Lin, Liu, Xin‐Feng, Wei, Ling
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container_end_page 763
container_issue 10
container_start_page 753
container_title CNS neuroscience & therapeutics
container_volume 19
creator Wei, Ning
Yu, Shan‐Ping
Gu, Xiao‐Huan
Chen, Dong‐Dong
Whalin, Matthew K.
Xu, Ge‐Lin
Liu, Xin‐Feng
Wei, Ling
description 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.
doi_str_mv 10.1111/cns.12123
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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.</description><identifier>ISSN: 1755-5930</identifier><identifier>ISSN: 1755-5949</identifier><identifier>EISSN: 1755-5949</identifier><identifier>DOI: 10.1111/cns.12123</identifier><identifier>PMID: 23731488</identifier><language>eng</language><publisher>Oxford: Wiley-Blackwell</publisher><subject>Animals ; Apoptosis ; Associated diseases and complications ; Autophagy ; Autophagy - physiology ; Biological and medical sciences ; Blood–brain barrier ; Brain damage ; Brain Ischemia - complications ; Brain Ischemia - pathology ; Cell death ; Diabetes ; Diabetes Mellitus, Experimental - complications ; Diabetes Mellitus, Experimental - pathology ; Diabetes. Impaired glucose tolerance ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Ischemic stroke ; Male ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis ; Neurology ; Original ; Rodents ; Signal Transduction - physiology ; Vascular diseases and vascular malformations of the nervous system</subject><ispartof>CNS neuroscience &amp; therapeutics, 2013-10, Vol.19 (10), p.753-763</ispartof><rights>2013 John Wiley &amp; Sons Ltd</rights><rights>2014 INIST-CNRS</rights><rights>2013 John Wiley &amp; Sons Ltd.</rights><rights>Copyright © 2013 John Wiley &amp; Sons Ltd</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5723-dec1c74e6cee6ffd1fab3806fa30a0a05502c49a79d231bc0dee53fbad27038f3</citedby><cites>FETCH-LOGICAL-c5723-dec1c74e6cee6ffd1fab3806fa30a0a05502c49a79d231bc0dee53fbad27038f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6493478/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6493478/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,1411,11541,27901,27902,45550,45551,46027,46451,53766,53768</link.rule.ids><linktorsrc>$$Uhttps://onlinelibrary.wiley.com/doi/abs/10.1111%2Fcns.12123$$EView_record_in_Wiley-Blackwell$$FView_record_in_$$GWiley-Blackwell</linktorsrc><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=27789384$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23731488$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wei, Ning</creatorcontrib><creatorcontrib>Yu, Shan‐Ping</creatorcontrib><creatorcontrib>Gu, Xiao‐Huan</creatorcontrib><creatorcontrib>Chen, Dong‐Dong</creatorcontrib><creatorcontrib>Whalin, Matthew K.</creatorcontrib><creatorcontrib>Xu, Ge‐Lin</creatorcontrib><creatorcontrib>Liu, Xin‐Feng</creatorcontrib><creatorcontrib>Wei, Ling</creatorcontrib><title>The Involvement of Autophagy Pathway in Exaggerated Ischemic Brain Damage in Diabetic Mice</title><title>CNS neuroscience &amp; therapeutics</title><addtitle>CNS Neurosci Ther</addtitle><description>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.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Associated diseases and complications</subject><subject>Autophagy</subject><subject>Autophagy - physiology</subject><subject>Biological and medical sciences</subject><subject>Blood–brain barrier</subject><subject>Brain damage</subject><subject>Brain Ischemia - complications</subject><subject>Brain Ischemia - pathology</subject><subject>Cell death</subject><subject>Diabetes</subject><subject>Diabetes Mellitus, Experimental - complications</subject><subject>Diabetes Mellitus, Experimental - pathology</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinopathies</subject><subject>Ischemic stroke</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis</subject><subject>Neurology</subject><subject>Original</subject><subject>Rodents</subject><subject>Signal Transduction - physiology</subject><subject>Vascular diseases and vascular malformations of the nervous system</subject><issn>1755-5930</issn><issn>1755-5949</issn><issn>1755-5949</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkUtv1DAUhSMEoqWw4A-gSAgJFtP6EcfOBqlMC4xUHhJlw8a6ca4TV3kMdjJl_j0OMwwPCQl7YUvn07k-PknymJJTGteZ6cMpZZTxO8kxlUIsRJEVdw93To6SByHcEJIzVaj7yRHjktNMqePky3WD6arfDO0GO-zHdLDp-TQO6wbqbfoRxuYWtqnr08tvUNfoYcQqXQXTYOdM-spDlC6ggxpn6MJBiWMU3jmDD5N7FtqAj_bnSfL59eX18u3i6sOb1fL8amGEZHxRoaFGZpgbxNzailoouSK5BU4gbiEIM1kBsqgYp6UhFaLgtoSKScKV5SfJy53veio7rExM4aHVa-868Fs9gNN_Kr1rdD1sdJ4VPJMqGjzfG_jh64Rh1J0LBtsWehymoGkmlMgoF9l_oFyJvMgYiejTv9CbYfJ9_ImZkowQymfqxY4yfgjBoz28mxI9l6tjufpHuZF98nvQA_mzzQg82wMQDLTWQ29c-MVJqQqu5hRnO-7Wtbj990S9fP9pN_o7i0O7Nw</recordid><startdate>201310</startdate><enddate>201310</enddate><creator>Wei, Ning</creator><creator>Yu, Shan‐Ping</creator><creator>Gu, Xiao‐Huan</creator><creator>Chen, Dong‐Dong</creator><creator>Whalin, Matthew K.</creator><creator>Xu, Ge‐Lin</creator><creator>Liu, Xin‐Feng</creator><creator>Wei, Ling</creator><general>Wiley-Blackwell</general><general>John Wiley &amp; Sons, Inc</general><general>John Wiley and Sons Inc</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>K9.</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201310</creationdate><title>The Involvement of Autophagy Pathway in Exaggerated Ischemic Brain Damage in Diabetic Mice</title><author>Wei, Ning ; Yu, Shan‐Ping ; Gu, Xiao‐Huan ; Chen, Dong‐Dong ; Whalin, Matthew K. ; Xu, Ge‐Lin ; Liu, Xin‐Feng ; Wei, Ling</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5723-dec1c74e6cee6ffd1fab3806fa30a0a05502c49a79d231bc0dee53fbad27038f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Associated diseases and complications</topic><topic>Autophagy</topic><topic>Autophagy - physiology</topic><topic>Biological and medical sciences</topic><topic>Blood–brain barrier</topic><topic>Brain damage</topic><topic>Brain Ischemia - complications</topic><topic>Brain Ischemia - pathology</topic><topic>Cell death</topic><topic>Diabetes</topic><topic>Diabetes Mellitus, Experimental - complications</topic><topic>Diabetes Mellitus, Experimental - pathology</topic><topic>Diabetes. Impaired glucose tolerance</topic><topic>Endocrine pancreas. Apud cells (diseases)</topic><topic>Endocrinopathies</topic><topic>Ischemic stroke</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis</topic><topic>Neurology</topic><topic>Original</topic><topic>Rodents</topic><topic>Signal Transduction - physiology</topic><topic>Vascular diseases and vascular malformations of the nervous system</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wei, Ning</creatorcontrib><creatorcontrib>Yu, Shan‐Ping</creatorcontrib><creatorcontrib>Gu, Xiao‐Huan</creatorcontrib><creatorcontrib>Chen, Dong‐Dong</creatorcontrib><creatorcontrib>Whalin, Matthew K.</creatorcontrib><creatorcontrib>Xu, Ge‐Lin</creatorcontrib><creatorcontrib>Liu, Xin‐Feng</creatorcontrib><creatorcontrib>Wei, Ling</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>CNS neuroscience &amp; therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Wei, Ning</au><au>Yu, Shan‐Ping</au><au>Gu, Xiao‐Huan</au><au>Chen, Dong‐Dong</au><au>Whalin, Matthew K.</au><au>Xu, Ge‐Lin</au><au>Liu, Xin‐Feng</au><au>Wei, Ling</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Involvement of Autophagy Pathway in Exaggerated Ischemic Brain Damage in Diabetic Mice</atitle><jtitle>CNS neuroscience &amp; therapeutics</jtitle><addtitle>CNS Neurosci Ther</addtitle><date>2013-10</date><risdate>2013</risdate><volume>19</volume><issue>10</issue><spage>753</spage><epage>763</epage><pages>753-763</pages><issn>1755-5930</issn><issn>1755-5949</issn><eissn>1755-5949</eissn><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.</abstract><cop>Oxford</cop><pub>Wiley-Blackwell</pub><pmid>23731488</pmid><doi>10.1111/cns.12123</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record>
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source Wiley Online Library Open Access
subjects Animals
Apoptosis
Associated diseases and complications
Autophagy
Autophagy - physiology
Biological and medical sciences
Blood–brain barrier
Brain damage
Brain Ischemia - complications
Brain Ischemia - pathology
Cell death
Diabetes
Diabetes Mellitus, Experimental - complications
Diabetes Mellitus, Experimental - pathology
Diabetes. Impaired glucose tolerance
Endocrine pancreas. Apud cells (diseases)
Endocrinopathies
Ischemic stroke
Male
Medical sciences
Mice
Mice, Inbred C57BL
Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis
Neurology
Original
Rodents
Signal Transduction - physiology
Vascular diseases and vascular malformations of the nervous system
title The Involvement of Autophagy Pathway in Exaggerated Ischemic Brain Damage in Diabetic Mice
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