The role of p53 in brain edema after 24 h of experimental subarachnoid hemorrhage in a rat model
Our previous study demonstrated that p53 plays an orchestrating role in the vasospasm and apoptotic cell death after subarachnoid hemorrhage (SAH). We now hypothesize that p53 also plays an important role in brain edema by up-regulating the expression of MMP-9 via the NF-κB molecular signaling pathw...
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creator | Yan, Junhao Chen, Chunhua Hu, Qing Yang, Xiaomei Lei, Jiliang Yang, Lei Wang, Ke Qin, Lihua Huang, Hongyun Zhou, Changman |
description | Our previous study demonstrated that p53 plays an orchestrating role in the vasospasm and apoptotic cell death after subarachnoid hemorrhage (SAH). We now hypothesize that p53 also plays an important role in brain edema by up-regulating the expression of MMP-9 via the NF-κB molecular signaling pathway. Adult male rats (300–350 g) were divided into five groups (
n
=
20 each): Sham, SAH treatment with DMSO or PFT-α (0.2 mg/kg and 2.0 mg/kg), intraperitoneally. The monofilament puncture model was used to induce SAH and animals were subsequently sacrificed at 24 h. The blood–brain barrier (BBB) disruption, brain water content, MMP-9 activity, immunohistochemistry, treble fluorescence labeling, Western blot, and ultra-structural observations were performed. Evans blue extravagation, BBB diffuse leakage of IgG protein and brain water content were significantly reduced by PFT-α treatment; and the expression of p53, NF-κB and MMP-9 were significantly increased. The tight junction protein (Occludin) in endothelia cells and Collage IV in basal lamina were decreased in the brain of SAH rats, and were also modified by PFT-α treatment. Ultra-structural changes included disruption of endothelial tight junction and widening of the inter-endothelial spaces. Treble labeling showed p53 colocalized with NF-κB and MMP-9 in cerebral endothelia cells. We thus conclude that the level of p53 in cerebral microvasculature significantly affects the BBB permeability and brain edema after 24 h of SAH in rats. This can be at least partially ascribed to p53 inducing a significant up-regulation of MMP-9 via NF-κB in the endothelium, which in turn opened the tight junction by degrading Occludin and disrupting the basal lamina by degrading collagen IV. |
doi_str_mv | 10.1016/j.expneurol.2008.07.006 |
format | Article |
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n
=
20 each): Sham, SAH treatment with DMSO or PFT-α (0.2 mg/kg and 2.0 mg/kg), intraperitoneally. The monofilament puncture model was used to induce SAH and animals were subsequently sacrificed at 24 h. The blood–brain barrier (BBB) disruption, brain water content, MMP-9 activity, immunohistochemistry, treble fluorescence labeling, Western blot, and ultra-structural observations were performed. Evans blue extravagation, BBB diffuse leakage of IgG protein and brain water content were significantly reduced by PFT-α treatment; and the expression of p53, NF-κB and MMP-9 were significantly increased. The tight junction protein (Occludin) in endothelia cells and Collage IV in basal lamina were decreased in the brain of SAH rats, and were also modified by PFT-α treatment. Ultra-structural changes included disruption of endothelial tight junction and widening of the inter-endothelial spaces. Treble labeling showed p53 colocalized with NF-κB and MMP-9 in cerebral endothelia cells. We thus conclude that the level of p53 in cerebral microvasculature significantly affects the BBB permeability and brain edema after 24 h of SAH in rats. This can be at least partially ascribed to p53 inducing a significant up-regulation of MMP-9 via NF-κB in the endothelium, which in turn opened the tight junction by degrading Occludin and disrupting the basal lamina by degrading collagen IV.</description><identifier>ISSN: 0014-4886</identifier><identifier>EISSN: 1090-2430</identifier><identifier>DOI: 10.1016/j.expneurol.2008.07.006</identifier><identifier>PMID: 18691572</identifier><identifier>CODEN: EXNEAC</identifier><language>eng</language><publisher>Amsterdam: Elsevier Inc</publisher><subject>Analysis of Variance ; Animals ; Biological and medical sciences ; Blood-Brain Barrier - metabolism ; Blood-Brain Barrier - pathology ; Blood–brain barrier ; Blotting, Western ; Brain - metabolism ; Brain - pathology ; Brain edema ; Brain Edema - etiology ; Brain Edema - metabolism ; Brain Edema - pathology ; Cerebrovascular Circulation - physiology ; Endothelial Cells - metabolism ; Immunohistochemistry ; Male ; Matrix Metalloproteinase 9 - metabolism ; Medical sciences ; Membrane Proteins - metabolism ; Microvessels - metabolism ; Microvessels - pathology ; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis ; Neurology ; Occludin ; p53 ; Pifithrin-α (PFT-α) ; Rats ; Rats, Sprague-Dawley ; Signal Transduction - physiology ; Subarachnoid hemorrhage ; Subarachnoid Hemorrhage - complications ; Subarachnoid Hemorrhage - metabolism ; Subarachnoid Hemorrhage - pathology ; Tumor Suppressor Protein p53 - metabolism ; Up-Regulation - physiology</subject><ispartof>Experimental neurology, 2008-11, Vol.214 (1), p.37-46</ispartof><rights>2008 Elsevier Inc.</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c497t-eb46ee7a503cfd47a3f0bd8e94f4de732197da82d548a9434bcb6a8f1d8aa0893</citedby><cites>FETCH-LOGICAL-c497t-eb46ee7a503cfd47a3f0bd8e94f4de732197da82d548a9434bcb6a8f1d8aa0893</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.expneurol.2008.07.006$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20823588$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18691572$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yan, Junhao</creatorcontrib><creatorcontrib>Chen, Chunhua</creatorcontrib><creatorcontrib>Hu, Qing</creatorcontrib><creatorcontrib>Yang, Xiaomei</creatorcontrib><creatorcontrib>Lei, Jiliang</creatorcontrib><creatorcontrib>Yang, Lei</creatorcontrib><creatorcontrib>Wang, Ke</creatorcontrib><creatorcontrib>Qin, Lihua</creatorcontrib><creatorcontrib>Huang, Hongyun</creatorcontrib><creatorcontrib>Zhou, Changman</creatorcontrib><title>The role of p53 in brain edema after 24 h of experimental subarachnoid hemorrhage in a rat model</title><title>Experimental neurology</title><addtitle>Exp Neurol</addtitle><description>Our previous study demonstrated that p53 plays an orchestrating role in the vasospasm and apoptotic cell death after subarachnoid hemorrhage (SAH). We now hypothesize that p53 also plays an important role in brain edema by up-regulating the expression of MMP-9 via the NF-κB molecular signaling pathway. Adult male rats (300–350 g) were divided into five groups (
n
=
20 each): Sham, SAH treatment with DMSO or PFT-α (0.2 mg/kg and 2.0 mg/kg), intraperitoneally. The monofilament puncture model was used to induce SAH and animals were subsequently sacrificed at 24 h. The blood–brain barrier (BBB) disruption, brain water content, MMP-9 activity, immunohistochemistry, treble fluorescence labeling, Western blot, and ultra-structural observations were performed. Evans blue extravagation, BBB diffuse leakage of IgG protein and brain water content were significantly reduced by PFT-α treatment; and the expression of p53, NF-κB and MMP-9 were significantly increased. The tight junction protein (Occludin) in endothelia cells and Collage IV in basal lamina were decreased in the brain of SAH rats, and were also modified by PFT-α treatment. Ultra-structural changes included disruption of endothelial tight junction and widening of the inter-endothelial spaces. Treble labeling showed p53 colocalized with NF-κB and MMP-9 in cerebral endothelia cells. We thus conclude that the level of p53 in cerebral microvasculature significantly affects the BBB permeability and brain edema after 24 h of SAH in rats. This can be at least partially ascribed to p53 inducing a significant up-regulation of MMP-9 via NF-κB in the endothelium, which in turn opened the tight junction by degrading Occludin and disrupting the basal lamina by degrading collagen IV.</description><subject>Analysis of Variance</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Blood-Brain Barrier - metabolism</subject><subject>Blood-Brain Barrier - pathology</subject><subject>Blood–brain barrier</subject><subject>Blotting, Western</subject><subject>Brain - metabolism</subject><subject>Brain - pathology</subject><subject>Brain edema</subject><subject>Brain Edema - etiology</subject><subject>Brain Edema - metabolism</subject><subject>Brain Edema - pathology</subject><subject>Cerebrovascular Circulation - physiology</subject><subject>Endothelial Cells - metabolism</subject><subject>Immunohistochemistry</subject><subject>Male</subject><subject>Matrix Metalloproteinase 9 - metabolism</subject><subject>Medical sciences</subject><subject>Membrane Proteins - metabolism</subject><subject>Microvessels - metabolism</subject><subject>Microvessels - pathology</subject><subject>Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis</subject><subject>Neurology</subject><subject>Occludin</subject><subject>p53</subject><subject>Pifithrin-α (PFT-α)</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Signal Transduction - physiology</subject><subject>Subarachnoid hemorrhage</subject><subject>Subarachnoid Hemorrhage - complications</subject><subject>Subarachnoid Hemorrhage - metabolism</subject><subject>Subarachnoid Hemorrhage - pathology</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Up-Regulation - physiology</subject><issn>0014-4886</issn><issn>1090-2430</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkcuO1DAQRS0EYpqGXwBvgFVC-ZHYWY5GvKSR2Axrq2JXSFp5NHaC4G_4Fr4MN90adrCp2py6t6ouYy8ElAJE_eZQ0vfjTFtcxlIC2BJMCVA_YDsBDRRSK3jIdgBCF9ra-oo9SekAAI2W5jG7ErZuRGXkjuFdTzyrEF86fqwUH2beRsyVAk3IsVspcql__exPRHalOEw0rzjytLUY0ffzMgTe07TE2OMXOkkgj7jyaQk0PmWPOhwTPbv0Pfv87u3dzYfi9tP7jzfXt4XXjVkLanVNZLAC5bugDaoO2mCp0Z0OZJQUjQloZai0xUYr3fq2RtuJYBHBNmrPXp91j3H5ulFa3TQkT-OIMy1bckapWtb6D_nqn6RolLZV9tgzcwZ9XFKK1LljPh7jDyfAnXJwB3efgzvl4MC4nEOefH6x2NqJwt-5y-Mz8PICYPI4dhFnP6R7ToKVqrI2c9dnjvLrvg0UXfIDzZ7CEMmvLizDf5f5DfTyq24</recordid><startdate>20081101</startdate><enddate>20081101</enddate><creator>Yan, Junhao</creator><creator>Chen, Chunhua</creator><creator>Hu, Qing</creator><creator>Yang, Xiaomei</creator><creator>Lei, Jiliang</creator><creator>Yang, Lei</creator><creator>Wang, Ke</creator><creator>Qin, Lihua</creator><creator>Huang, Hongyun</creator><creator>Zhou, Changman</creator><general>Elsevier Inc</general><general>Elsevier</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>7X8</scope></search><sort><creationdate>20081101</creationdate><title>The role of p53 in brain edema after 24 h of experimental subarachnoid hemorrhage in a rat model</title><author>Yan, Junhao ; Chen, Chunhua ; Hu, Qing ; Yang, Xiaomei ; Lei, Jiliang ; Yang, Lei ; Wang, Ke ; Qin, Lihua ; Huang, Hongyun ; Zhou, Changman</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c497t-eb46ee7a503cfd47a3f0bd8e94f4de732197da82d548a9434bcb6a8f1d8aa0893</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Analysis of Variance</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Blood-Brain Barrier - metabolism</topic><topic>Blood-Brain Barrier - pathology</topic><topic>Blood–brain barrier</topic><topic>Blotting, Western</topic><topic>Brain - metabolism</topic><topic>Brain - pathology</topic><topic>Brain edema</topic><topic>Brain Edema - etiology</topic><topic>Brain Edema - metabolism</topic><topic>Brain Edema - pathology</topic><topic>Cerebrovascular Circulation - physiology</topic><topic>Endothelial Cells - metabolism</topic><topic>Immunohistochemistry</topic><topic>Male</topic><topic>Matrix Metalloproteinase 9 - metabolism</topic><topic>Medical sciences</topic><topic>Membrane Proteins - metabolism</topic><topic>Microvessels - metabolism</topic><topic>Microvessels - pathology</topic><topic>Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis</topic><topic>Neurology</topic><topic>Occludin</topic><topic>p53</topic><topic>Pifithrin-α (PFT-α)</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Signal Transduction - physiology</topic><topic>Subarachnoid hemorrhage</topic><topic>Subarachnoid Hemorrhage - complications</topic><topic>Subarachnoid Hemorrhage - metabolism</topic><topic>Subarachnoid Hemorrhage - pathology</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Up-Regulation - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yan, Junhao</creatorcontrib><creatorcontrib>Chen, Chunhua</creatorcontrib><creatorcontrib>Hu, Qing</creatorcontrib><creatorcontrib>Yang, Xiaomei</creatorcontrib><creatorcontrib>Lei, Jiliang</creatorcontrib><creatorcontrib>Yang, Lei</creatorcontrib><creatorcontrib>Wang, Ke</creatorcontrib><creatorcontrib>Qin, Lihua</creatorcontrib><creatorcontrib>Huang, Hongyun</creatorcontrib><creatorcontrib>Zhou, Changman</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>MEDLINE - Academic</collection><jtitle>Experimental neurology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yan, Junhao</au><au>Chen, Chunhua</au><au>Hu, Qing</au><au>Yang, Xiaomei</au><au>Lei, Jiliang</au><au>Yang, Lei</au><au>Wang, Ke</au><au>Qin, Lihua</au><au>Huang, Hongyun</au><au>Zhou, Changman</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The role of p53 in brain edema after 24 h of experimental subarachnoid hemorrhage in a rat model</atitle><jtitle>Experimental neurology</jtitle><addtitle>Exp Neurol</addtitle><date>2008-11-01</date><risdate>2008</risdate><volume>214</volume><issue>1</issue><spage>37</spage><epage>46</epage><pages>37-46</pages><issn>0014-4886</issn><eissn>1090-2430</eissn><coden>EXNEAC</coden><abstract>Our previous study demonstrated that p53 plays an orchestrating role in the vasospasm and apoptotic cell death after subarachnoid hemorrhage (SAH). We now hypothesize that p53 also plays an important role in brain edema by up-regulating the expression of MMP-9 via the NF-κB molecular signaling pathway. Adult male rats (300–350 g) were divided into five groups (
n
=
20 each): Sham, SAH treatment with DMSO or PFT-α (0.2 mg/kg and 2.0 mg/kg), intraperitoneally. The monofilament puncture model was used to induce SAH and animals were subsequently sacrificed at 24 h. The blood–brain barrier (BBB) disruption, brain water content, MMP-9 activity, immunohistochemistry, treble fluorescence labeling, Western blot, and ultra-structural observations were performed. Evans blue extravagation, BBB diffuse leakage of IgG protein and brain water content were significantly reduced by PFT-α treatment; and the expression of p53, NF-κB and MMP-9 were significantly increased. The tight junction protein (Occludin) in endothelia cells and Collage IV in basal lamina were decreased in the brain of SAH rats, and were also modified by PFT-α treatment. Ultra-structural changes included disruption of endothelial tight junction and widening of the inter-endothelial spaces. Treble labeling showed p53 colocalized with NF-κB and MMP-9 in cerebral endothelia cells. We thus conclude that the level of p53 in cerebral microvasculature significantly affects the BBB permeability and brain edema after 24 h of SAH in rats. This can be at least partially ascribed to p53 inducing a significant up-regulation of MMP-9 via NF-κB in the endothelium, which in turn opened the tight junction by degrading Occludin and disrupting the basal lamina by degrading collagen IV.</abstract><cop>Amsterdam</cop><pub>Elsevier Inc</pub><pmid>18691572</pmid><doi>10.1016/j.expneurol.2008.07.006</doi><tpages>10</tpages></addata></record> |
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subjects | Analysis of Variance Animals Biological and medical sciences Blood-Brain Barrier - metabolism Blood-Brain Barrier - pathology Blood–brain barrier Blotting, Western Brain - metabolism Brain - pathology Brain edema Brain Edema - etiology Brain Edema - metabolism Brain Edema - pathology Cerebrovascular Circulation - physiology Endothelial Cells - metabolism Immunohistochemistry Male Matrix Metalloproteinase 9 - metabolism Medical sciences Membrane Proteins - metabolism Microvessels - metabolism Microvessels - pathology Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis Neurology Occludin p53 Pifithrin-α (PFT-α) Rats Rats, Sprague-Dawley Signal Transduction - physiology Subarachnoid hemorrhage Subarachnoid Hemorrhage - complications Subarachnoid Hemorrhage - metabolism Subarachnoid Hemorrhage - pathology Tumor Suppressor Protein p53 - metabolism Up-Regulation - physiology |
title | The role of p53 in brain edema after 24 h of experimental subarachnoid hemorrhage in a rat model |
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