Combined Antiapoptotic and Antioxidant Approach to Acute Neuroprotection for Stroke in Hypertensive Rats
We hypothesized that targeting key points in the ischemic cascade with combined neuroglobin (Ngb) overexpression and c-jun N-terminal kinase (JNK) inhibition (SP600125) would offer greater neuroprotection than single treatment after in vitro hypoxia/reoxygenation and in a randomized, blinded in vivo...
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| Veröffentlicht in: | Journal of cerebral blood flow and metabolism 2013-08, Vol.33 (8), p.1215-1224 |
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| container_title | Journal of cerebral blood flow and metabolism |
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| creator | Ord, Emily NJ Shirley, Rachel McClure, John D McCabe, Christopher Kremer, Eric J Macrae, I Mhairi Work, Lorraine M |
| description | We hypothesized that targeting key points in the ischemic cascade with combined neuroglobin (Ngb) overexpression and c-jun N-terminal kinase (JNK) inhibition (SP600125) would offer greater neuroprotection than single treatment after in vitro hypoxia/reoxygenation and in a randomized, blinded in vivo experimental stroke study using a clinically relevant rat strain. Male spontaneously hypertensive stroke-prone rats underwent transient middle cerebral artery occlusion (tMCAO) and were divided into the following groups: tMCAO; tMCAO + control GFP-expressing canine adenovirus-2, CAVGFP; tMCAO + Ngb-expressing CAV-2, CAVNgb; tMCAO + SP600125; tMCAO + CAVNgb + SP600125; or sham procedure. Rats were assessed till day 14 for neurologic outcome before infarct determination. In vitro, combined lentivirus-mediated Ngb overexpression + SP600125 significantly reduced oxidative stress and apoptosis compared with single treatment(s) after hypoxia/reoxygenation in B50 cells. In vivo, infarct volume was significantly reduced by CAVNgb, SP600125, and further by CAVNgb + SP600125. The number of Ngb-positive cells in the peri-infarct cortex and striatum was significantly increased 14 days after tMCAO in animals receiving CAVNgb. Neurologic outcome, measured using a 32-point neurologic score, significantly improved with CAVNgb + SP600125 compared with single treatments at 14 days after tMCAO. Combined Ngb overexpression with JNK inhibition reduced hypoxia/reoxygenation-induced oxidative stress and apoptosis in cultured neurons and reduced infarct and improved neurologic outcome more than single therapy after in vivo experimental stroke in hypertensive rats. |
| doi_str_mv | 10.1038/jcbfm.2013.70 |
| format | Article |
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Male spontaneously hypertensive stroke-prone rats underwent transient middle cerebral artery occlusion (tMCAO) and were divided into the following groups: tMCAO; tMCAO + control GFP-expressing canine adenovirus-2, CAVGFP; tMCAO + Ngb-expressing CAV-2, CAVNgb; tMCAO + SP600125; tMCAO + CAVNgb + SP600125; or sham procedure. Rats were assessed till day 14 for neurologic outcome before infarct determination. In vitro, combined lentivirus-mediated Ngb overexpression + SP600125 significantly reduced oxidative stress and apoptosis compared with single treatment(s) after hypoxia/reoxygenation in B50 cells. In vivo, infarct volume was significantly reduced by CAVNgb, SP600125, and further by CAVNgb + SP600125. The number of Ngb-positive cells in the peri-infarct cortex and striatum was significantly increased 14 days after tMCAO in animals receiving CAVNgb. Neurologic outcome, measured using a 32-point neurologic score, significantly improved with CAVNgb + SP600125 compared with single treatments at 14 days after tMCAO. Combined Ngb overexpression with JNK inhibition reduced hypoxia/reoxygenation-induced oxidative stress and apoptosis in cultured neurons and reduced infarct and improved neurologic outcome more than single therapy after in vivo experimental stroke in hypertensive rats.</description><identifier>ISSN: 0271-678X</identifier><identifier>EISSN: 1559-7016</identifier><identifier>DOI: 10.1038/jcbfm.2013.70</identifier><identifier>PMID: 23632970</identifier><language>eng</language><publisher>London, England: SAGE Publications</publisher><subject>Animals ; Anthracenes - pharmacology ; Antioxidants - pharmacology ; Apoptosis - drug effects ; Biochemistry, Molecular Biology ; Dependovirus - genetics ; Enzyme Inhibitors - pharmacology ; Genetic Vectors ; Globins - biosynthesis ; Globins - genetics ; Green Fluorescent Proteins - metabolism ; Hypertension - complications ; Hypertension - drug therapy ; Hypoxia, Brain - pathology ; Immunohistochemistry ; Infarction, Middle Cerebral Artery - pathology ; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors ; Lentivirus - genetics ; Life Sciences ; Male ; Nerve Tissue Proteins - biosynthesis ; Nerve Tissue Proteins - genetics ; Neuroglobin ; Neuroprotective Agents - pharmacology ; Original ; Oxidative Stress - drug effects ; Plethysmography ; Rats ; Rats, Inbred SHR ; Real-Time Polymerase Chain Reaction ; Stroke - etiology ; Stroke - prevention & control ; Transduction, Genetic</subject><ispartof>Journal of cerebral blood flow and metabolism, 2013-08, Vol.33 (8), p.1215-1224</ispartof><rights>2013 ISCBFM</rights><rights>Copyright Nature Publishing Group Aug 2013</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><rights>Copyright © 2013 International Society for Cerebral Blood Flow & Metabolism, Inc. 2013 International Society for Cerebral Blood Flow & Metabolism, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c517t-76a0d20843642e4393809d7d5689464c7433f8429907e0f8f4eba0015debc7113</citedby><cites>FETCH-LOGICAL-c517t-76a0d20843642e4393809d7d5689464c7433f8429907e0f8f4eba0015debc7113</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/PMC3734772/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3734772/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,21798,27901,27902,43597,43598,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23632970$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-02193669$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Ord, Emily NJ</creatorcontrib><creatorcontrib>Shirley, Rachel</creatorcontrib><creatorcontrib>McClure, John D</creatorcontrib><creatorcontrib>McCabe, Christopher</creatorcontrib><creatorcontrib>Kremer, Eric J</creatorcontrib><creatorcontrib>Macrae, I Mhairi</creatorcontrib><creatorcontrib>Work, Lorraine M</creatorcontrib><title>Combined Antiapoptotic and Antioxidant Approach to Acute Neuroprotection for Stroke in Hypertensive Rats</title><title>Journal of cerebral blood flow and metabolism</title><addtitle>J Cereb Blood Flow Metab</addtitle><description>We hypothesized that targeting key points in the ischemic cascade with combined neuroglobin (Ngb) overexpression and c-jun N-terminal kinase (JNK) inhibition (SP600125) would offer greater neuroprotection than single treatment after in vitro hypoxia/reoxygenation and in a randomized, blinded in vivo experimental stroke study using a clinically relevant rat strain. Male spontaneously hypertensive stroke-prone rats underwent transient middle cerebral artery occlusion (tMCAO) and were divided into the following groups: tMCAO; tMCAO + control GFP-expressing canine adenovirus-2, CAVGFP; tMCAO + Ngb-expressing CAV-2, CAVNgb; tMCAO + SP600125; tMCAO + CAVNgb + SP600125; or sham procedure. Rats were assessed till day 14 for neurologic outcome before infarct determination. In vitro, combined lentivirus-mediated Ngb overexpression + SP600125 significantly reduced oxidative stress and apoptosis compared with single treatment(s) after hypoxia/reoxygenation in B50 cells. In vivo, infarct volume was significantly reduced by CAVNgb, SP600125, and further by CAVNgb + SP600125. The number of Ngb-positive cells in the peri-infarct cortex and striatum was significantly increased 14 days after tMCAO in animals receiving CAVNgb. Neurologic outcome, measured using a 32-point neurologic score, significantly improved with CAVNgb + SP600125 compared with single treatments at 14 days after tMCAO. Combined Ngb overexpression with JNK inhibition reduced hypoxia/reoxygenation-induced oxidative stress and apoptosis in cultured neurons and reduced infarct and improved neurologic outcome more than single therapy after in vivo experimental stroke in hypertensive rats.</description><subject>Animals</subject><subject>Anthracenes - pharmacology</subject><subject>Antioxidants - pharmacology</subject><subject>Apoptosis - drug effects</subject><subject>Biochemistry, Molecular Biology</subject><subject>Dependovirus - genetics</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Genetic Vectors</subject><subject>Globins - biosynthesis</subject><subject>Globins - genetics</subject><subject>Green Fluorescent Proteins - metabolism</subject><subject>Hypertension - complications</subject><subject>Hypertension - drug therapy</subject><subject>Hypoxia, Brain - pathology</subject><subject>Immunohistochemistry</subject><subject>Infarction, Middle Cerebral Artery - pathology</subject><subject>JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors</subject><subject>Lentivirus - genetics</subject><subject>Life Sciences</subject><subject>Male</subject><subject>Nerve Tissue Proteins - biosynthesis</subject><subject>Nerve Tissue Proteins - genetics</subject><subject>Neuroglobin</subject><subject>Neuroprotective Agents - pharmacology</subject><subject>Original</subject><subject>Oxidative Stress - drug effects</subject><subject>Plethysmography</subject><subject>Rats</subject><subject>Rats, Inbred SHR</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Stroke - etiology</subject><subject>Stroke - prevention & control</subject><subject>Transduction, Genetic</subject><issn>0271-678X</issn><issn>1559-7016</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqNkt2L1DAUxYMo7uzoo68S8MUVOt58tGlfhDKoIwwKfoBvIU3TnYwzSTdJB_e_t7Xrsi4--BQ4-eXcy8lB6BmBFQFWvt7rpjuuKBC2EvAALUieV5kAUjxEC6CCZIUov5-h8xj3AFCyPH-MzigrGK0ELNBu7Y-NdabFtUtW9b5PPlmNlZsV_9O2yiVc933wSu9w8rjWQzL4oxmCH8Vk9Ig53PmAv6TgfxhsHd5c9yYk46I9GfxZpfgEPerUIZqnN-cSfXv39ut6k20_vf-wrreZzolImSgUtBRKzgpODWcVK6FqRZsXZcULrgVnrCs5rSoQBrqy46ZRACRvTaMFIWyJ3sy-_dAcTauNS0EdZB_sUYVr6ZWVf984u5OX_iSZYFwIOhpczAa7e8829VZOGlBSsaKoTtOwlzfDgr8aTEzyaKM2h4Nyxg9REk7Hr6AU6H-gRORUiHGNJXpxD937IbgxtYkqoOL5mM8SZTOlg48xmO52WQJyqob8XQ05VUMKGPnnd4O5pf90YQRezUBUl-bOyH-6_QIvPcIc</recordid><startdate>20130801</startdate><enddate>20130801</enddate><creator>Ord, Emily NJ</creator><creator>Shirley, Rachel</creator><creator>McClure, John D</creator><creator>McCabe, Christopher</creator><creator>Kremer, Eric J</creator><creator>Macrae, I Mhairi</creator><creator>Work, Lorraine M</creator><general>SAGE Publications</general><general>Sage Publications Ltd</general><general>Nature Publishing Group</general><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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>7TK</scope><scope>1XC</scope><scope>5PM</scope></search><sort><creationdate>20130801</creationdate><title>Combined Antiapoptotic and Antioxidant Approach to Acute Neuroprotection for Stroke in Hypertensive Rats</title><author>Ord, Emily NJ ; Shirley, Rachel ; McClure, John D ; McCabe, Christopher ; Kremer, Eric J ; Macrae, I Mhairi ; Work, Lorraine M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c517t-76a0d20843642e4393809d7d5689464c7433f8429907e0f8f4eba0015debc7113</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Anthracenes - 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Academic</collection><collection>Neurosciences Abstracts</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of cerebral blood flow and metabolism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ord, Emily NJ</au><au>Shirley, Rachel</au><au>McClure, John D</au><au>McCabe, Christopher</au><au>Kremer, Eric J</au><au>Macrae, I Mhairi</au><au>Work, Lorraine M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Combined Antiapoptotic and Antioxidant Approach to Acute Neuroprotection for Stroke in Hypertensive Rats</atitle><jtitle>Journal of cerebral blood flow and metabolism</jtitle><addtitle>J Cereb Blood Flow Metab</addtitle><date>2013-08-01</date><risdate>2013</risdate><volume>33</volume><issue>8</issue><spage>1215</spage><epage>1224</epage><pages>1215-1224</pages><issn>0271-678X</issn><eissn>1559-7016</eissn><abstract>We hypothesized that targeting key points in the ischemic cascade with combined neuroglobin (Ngb) overexpression and c-jun N-terminal kinase (JNK) inhibition (SP600125) would offer greater neuroprotection than single treatment after in vitro hypoxia/reoxygenation and in a randomized, blinded in vivo experimental stroke study using a clinically relevant rat strain. Male spontaneously hypertensive stroke-prone rats underwent transient middle cerebral artery occlusion (tMCAO) and were divided into the following groups: tMCAO; tMCAO + control GFP-expressing canine adenovirus-2, CAVGFP; tMCAO + Ngb-expressing CAV-2, CAVNgb; tMCAO + SP600125; tMCAO + CAVNgb + SP600125; or sham procedure. Rats were assessed till day 14 for neurologic outcome before infarct determination. In vitro, combined lentivirus-mediated Ngb overexpression + SP600125 significantly reduced oxidative stress and apoptosis compared with single treatment(s) after hypoxia/reoxygenation in B50 cells. In vivo, infarct volume was significantly reduced by CAVNgb, SP600125, and further by CAVNgb + SP600125. The number of Ngb-positive cells in the peri-infarct cortex and striatum was significantly increased 14 days after tMCAO in animals receiving CAVNgb. Neurologic outcome, measured using a 32-point neurologic score, significantly improved with CAVNgb + SP600125 compared with single treatments at 14 days after tMCAO. Combined Ngb overexpression with JNK inhibition reduced hypoxia/reoxygenation-induced oxidative stress and apoptosis in cultured neurons and reduced infarct and improved neurologic outcome more than single therapy after in vivo experimental stroke in hypertensive rats.</abstract><cop>London, England</cop><pub>SAGE Publications</pub><pmid>23632970</pmid><doi>10.1038/jcbfm.2013.70</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0271-678X |
| ispartof | Journal of cerebral blood flow and metabolism, 2013-08, Vol.33 (8), p.1215-1224 |
| issn | 0271-678X 1559-7016 |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; SAGE Complete; PubMed Central |
| subjects | Animals Anthracenes - pharmacology Antioxidants - pharmacology Apoptosis - drug effects Biochemistry, Molecular Biology Dependovirus - genetics Enzyme Inhibitors - pharmacology Genetic Vectors Globins - biosynthesis Globins - genetics Green Fluorescent Proteins - metabolism Hypertension - complications Hypertension - drug therapy Hypoxia, Brain - pathology Immunohistochemistry Infarction, Middle Cerebral Artery - pathology JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors Lentivirus - genetics Life Sciences Male Nerve Tissue Proteins - biosynthesis Nerve Tissue Proteins - genetics Neuroglobin Neuroprotective Agents - pharmacology Original Oxidative Stress - drug effects Plethysmography Rats Rats, Inbred SHR Real-Time Polymerase Chain Reaction Stroke - etiology Stroke - prevention & control Transduction, Genetic |
| title | Combined Antiapoptotic and Antioxidant Approach to Acute Neuroprotection for Stroke in Hypertensive Rats |
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