TAK-242, an Antagonist for Toll-like Receptor 4, Protects against Acute Cerebral Ischemia/Reperfusion Injury in Mice
Toll-like receptor 4 (TLR4) contributes to cerebral ischemia/reperfusion (I/R) injury and is a potential target for the treatment of ischemic stroke. This experiment is to evaluate the effect of an exogenous TLR4 antagonist, TAK-242, against acute cerebral I/R injury. A mouse model of cerebral I/R w...
Gespeichert in:
| Veröffentlicht in: | Journal of cerebral blood flow and metabolism 2015-04, Vol.35 (4), p.536-542 |
|---|---|
| Hauptverfasser: | , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 542 |
|---|---|
| container_issue | 4 |
| container_start_page | 536 |
| container_title | Journal of cerebral blood flow and metabolism |
| container_volume | 35 |
| creator | Hua, Fang Tang, Huiling Wang, Jun Prunty, Megan C Hua, Xiaodong Sayeed, Iqbal Stein, Donald G |
| description | Toll-like receptor 4 (TLR4) contributes to cerebral ischemia/reperfusion (I/R) injury and is a potential target for the treatment of ischemic stroke. This experiment is to evaluate the effect of an exogenous TLR4 antagonist, TAK-242, against acute cerebral I/R injury. A mouse model of cerebral I/R was induced by transient middle cerebral artery occlusion. TAK-242 (3 mg/kg body weight) was injected intraperitoneally 1 hour after ischemia. Our results showed that the concentration of TAK-242 in plasma increased to 52.0 ng/mL 3 hours after injection, was maintained at 54.1 ng/mL 8 hours after injection, and decreased to 22.6 ng/mL 24 hours after injection. The concentration of TAK-242 in brain tissue increased to 26.1 ng/mL in ischemic hemisphere and 14.2 ng/mL in nonischemic hemisphere 3 hours after injection, and was maintained at the similar levels 24 hours after injection. We found that TAK-242 significantly reduced cerebral infarction compared with vehicle control, improved neurologic function, inhibited the phosphorylation of downstream protein kinases in TLR4 signaling pathway, and downregulated the expression of inflammatory cytokines. We conclude that TAK-242 is able to cross blood-brain barrier, blocks TLR4 signaling, mediates the expression of inflammatory cytokines, and protects the brain from acute damage induced by I/R. |
| doi_str_mv | 10.1038/jcbfm.2014.240 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4420883</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sage_id>10.1038_jcbfm.2014.240</sage_id><sourcerecordid>3641481091</sourcerecordid><originalsourceid>FETCH-LOGICAL-c553t-e051e545b2a96535709e721d31676b7651d6992839bd2bbad3880fa23220e29a3</originalsourceid><addsrcrecordid>eNqNkc1rFDEYh4Modq1ePUrAi2Bnm--ZXArL4sdiRSkreAuZmXe2WWeTNckI_e_NurVU8eApkDx58nvzQ-g5JXNKeHO-7dphN2eEijkT5AGaUSl1VROqHqIZYTWtVN18PUFPUtoSQhou5WN0wqRsFBV0hvJ68aFigp1h6_HCZ7sJ3qWMhxDxOoxjNbpvgK-gg30uW-IMf44hQ5cTthvrfEEX3ZQBLyFCG-2IV6m7hp2z51ewhzhMyQWPV347xRvsPP7oOniKHg12TPDsdj1FX96-WS_fV5ef3q2Wi8uqk5LnCoikIIVsmdVKclkTDTWjPaeqVm2tJO2V1qzhuu1Z29qeNw0ZLOOMEWDa8lN0cfTup3YHfQc-l4RmH93OxhsTrDN_nnh3bTbhhxGCkabhRfDqVhDD9wlSNjuXOhhH6yFMyZQgnNdaavofqNJCckoP1pd_odswRV9-4kAVnVJCF2p-pLoYUoow3OWmxBy6N7-6N4fuTem-XHhxf9o7_HfZBXh9BJLdwL03_637CYFNtvo</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1667956649</pqid></control><display><type>article</type><title>TAK-242, an Antagonist for Toll-like Receptor 4, Protects against Acute Cerebral Ischemia/Reperfusion Injury in Mice</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>SAGE Complete</source><source>PubMed Central</source><creator>Hua, Fang ; Tang, Huiling ; Wang, Jun ; Prunty, Megan C ; Hua, Xiaodong ; Sayeed, Iqbal ; Stein, Donald G</creator><creatorcontrib>Hua, Fang ; Tang, Huiling ; Wang, Jun ; Prunty, Megan C ; Hua, Xiaodong ; Sayeed, Iqbal ; Stein, Donald G</creatorcontrib><description>Toll-like receptor 4 (TLR4) contributes to cerebral ischemia/reperfusion (I/R) injury and is a potential target for the treatment of ischemic stroke. This experiment is to evaluate the effect of an exogenous TLR4 antagonist, TAK-242, against acute cerebral I/R injury. A mouse model of cerebral I/R was induced by transient middle cerebral artery occlusion. TAK-242 (3 mg/kg body weight) was injected intraperitoneally 1 hour after ischemia. Our results showed that the concentration of TAK-242 in plasma increased to 52.0 ng/mL 3 hours after injection, was maintained at 54.1 ng/mL 8 hours after injection, and decreased to 22.6 ng/mL 24 hours after injection. The concentration of TAK-242 in brain tissue increased to 26.1 ng/mL in ischemic hemisphere and 14.2 ng/mL in nonischemic hemisphere 3 hours after injection, and was maintained at the similar levels 24 hours after injection. We found that TAK-242 significantly reduced cerebral infarction compared with vehicle control, improved neurologic function, inhibited the phosphorylation of downstream protein kinases in TLR4 signaling pathway, and downregulated the expression of inflammatory cytokines. We conclude that TAK-242 is able to cross blood-brain barrier, blocks TLR4 signaling, mediates the expression of inflammatory cytokines, and protects the brain from acute damage induced by I/R.</description><identifier>ISSN: 0271-678X</identifier><identifier>EISSN: 1559-7016</identifier><identifier>DOI: 10.1038/jcbfm.2014.240</identifier><identifier>PMID: 25586141</identifier><language>eng</language><publisher>London, England: SAGE Publications</publisher><subject>Animals ; Brain - blood supply ; Brain - drug effects ; Brain - pathology ; Brain Ischemia - pathology ; Brain Ischemia - prevention & control ; Male ; Mice ; Mice, Inbred C57BL ; Neuroprotective Agents - pharmacokinetics ; Neuroprotective Agents - therapeutic use ; Rapid Communication ; Reperfusion Injury - pathology ; Reperfusion Injury - prevention & control ; Sulfonamides - pharmacokinetics ; Sulfonamides - therapeutic use ; Toll-Like Receptor 4 - antagonists & inhibitors</subject><ispartof>Journal of cerebral blood flow and metabolism, 2015-04, Vol.35 (4), p.536-542</ispartof><rights>2015 ISCBFM</rights><rights>Copyright Nature Publishing Group Apr 2015</rights><rights>Copyright © 2015 International Society for Cerebral Blood Flow & Metabolism, Inc. 2015 International Society for Cerebral Blood Flow & Metabolism, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c553t-e051e545b2a96535709e721d31676b7651d6992839bd2bbad3880fa23220e29a3</citedby><cites>FETCH-LOGICAL-c553t-e051e545b2a96535709e721d31676b7651d6992839bd2bbad3880fa23220e29a3</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/PMC4420883/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420883/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,21798,27901,27902,43597,43598,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25586141$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hua, Fang</creatorcontrib><creatorcontrib>Tang, Huiling</creatorcontrib><creatorcontrib>Wang, Jun</creatorcontrib><creatorcontrib>Prunty, Megan C</creatorcontrib><creatorcontrib>Hua, Xiaodong</creatorcontrib><creatorcontrib>Sayeed, Iqbal</creatorcontrib><creatorcontrib>Stein, Donald G</creatorcontrib><title>TAK-242, an Antagonist for Toll-like Receptor 4, Protects against Acute Cerebral Ischemia/Reperfusion Injury in Mice</title><title>Journal of cerebral blood flow and metabolism</title><addtitle>J Cereb Blood Flow Metab</addtitle><description>Toll-like receptor 4 (TLR4) contributes to cerebral ischemia/reperfusion (I/R) injury and is a potential target for the treatment of ischemic stroke. This experiment is to evaluate the effect of an exogenous TLR4 antagonist, TAK-242, against acute cerebral I/R injury. A mouse model of cerebral I/R was induced by transient middle cerebral artery occlusion. TAK-242 (3 mg/kg body weight) was injected intraperitoneally 1 hour after ischemia. Our results showed that the concentration of TAK-242 in plasma increased to 52.0 ng/mL 3 hours after injection, was maintained at 54.1 ng/mL 8 hours after injection, and decreased to 22.6 ng/mL 24 hours after injection. The concentration of TAK-242 in brain tissue increased to 26.1 ng/mL in ischemic hemisphere and 14.2 ng/mL in nonischemic hemisphere 3 hours after injection, and was maintained at the similar levels 24 hours after injection. We found that TAK-242 significantly reduced cerebral infarction compared with vehicle control, improved neurologic function, inhibited the phosphorylation of downstream protein kinases in TLR4 signaling pathway, and downregulated the expression of inflammatory cytokines. We conclude that TAK-242 is able to cross blood-brain barrier, blocks TLR4 signaling, mediates the expression of inflammatory cytokines, and protects the brain from acute damage induced by I/R.</description><subject>Animals</subject><subject>Brain - blood supply</subject><subject>Brain - drug effects</subject><subject>Brain - pathology</subject><subject>Brain Ischemia - pathology</subject><subject>Brain Ischemia - prevention & control</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Neuroprotective Agents - pharmacokinetics</subject><subject>Neuroprotective Agents - therapeutic use</subject><subject>Rapid Communication</subject><subject>Reperfusion Injury - pathology</subject><subject>Reperfusion Injury - prevention & control</subject><subject>Sulfonamides - pharmacokinetics</subject><subject>Sulfonamides - therapeutic use</subject><subject>Toll-Like Receptor 4 - antagonists & inhibitors</subject><issn>0271-678X</issn><issn>1559-7016</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqNkc1rFDEYh4Modq1ePUrAi2Bnm--ZXArL4sdiRSkreAuZmXe2WWeTNckI_e_NurVU8eApkDx58nvzQ-g5JXNKeHO-7dphN2eEijkT5AGaUSl1VROqHqIZYTWtVN18PUFPUtoSQhou5WN0wqRsFBV0hvJ68aFigp1h6_HCZ7sJ3qWMhxDxOoxjNbpvgK-gg30uW-IMf44hQ5cTthvrfEEX3ZQBLyFCG-2IV6m7hp2z51ewhzhMyQWPV347xRvsPP7oOniKHg12TPDsdj1FX96-WS_fV5ef3q2Wi8uqk5LnCoikIIVsmdVKclkTDTWjPaeqVm2tJO2V1qzhuu1Z29qeNw0ZLOOMEWDa8lN0cfTup3YHfQc-l4RmH93OxhsTrDN_nnh3bTbhhxGCkabhRfDqVhDD9wlSNjuXOhhH6yFMyZQgnNdaavofqNJCckoP1pd_odswRV9-4kAVnVJCF2p-pLoYUoow3OWmxBy6N7-6N4fuTem-XHhxf9o7_HfZBXh9BJLdwL03_637CYFNtvo</recordid><startdate>20150401</startdate><enddate>20150401</enddate><creator>Hua, Fang</creator><creator>Tang, Huiling</creator><creator>Wang, Jun</creator><creator>Prunty, Megan C</creator><creator>Hua, Xiaodong</creator><creator>Sayeed, Iqbal</creator><creator>Stein, Donald G</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>5PM</scope></search><sort><creationdate>20150401</creationdate><title>TAK-242, an Antagonist for Toll-like Receptor 4, Protects against Acute Cerebral Ischemia/Reperfusion Injury in Mice</title><author>Hua, Fang ; Tang, Huiling ; Wang, Jun ; Prunty, Megan C ; Hua, Xiaodong ; Sayeed, Iqbal ; Stein, Donald G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c553t-e051e545b2a96535709e721d31676b7651d6992839bd2bbad3880fa23220e29a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Brain - blood supply</topic><topic>Brain - drug effects</topic><topic>Brain - pathology</topic><topic>Brain Ischemia - pathology</topic><topic>Brain Ischemia - prevention & control</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Neuroprotective Agents - pharmacokinetics</topic><topic>Neuroprotective Agents - therapeutic use</topic><topic>Rapid Communication</topic><topic>Reperfusion Injury - pathology</topic><topic>Reperfusion Injury - prevention & control</topic><topic>Sulfonamides - pharmacokinetics</topic><topic>Sulfonamides - therapeutic use</topic><topic>Toll-Like Receptor 4 - antagonists & inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hua, Fang</creatorcontrib><creatorcontrib>Tang, Huiling</creatorcontrib><creatorcontrib>Wang, Jun</creatorcontrib><creatorcontrib>Prunty, Megan C</creatorcontrib><creatorcontrib>Hua, Xiaodong</creatorcontrib><creatorcontrib>Sayeed, Iqbal</creatorcontrib><creatorcontrib>Stein, Donald G</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection (ProQuest)</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>Neurosciences Abstracts</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>Hua, Fang</au><au>Tang, Huiling</au><au>Wang, Jun</au><au>Prunty, Megan C</au><au>Hua, Xiaodong</au><au>Sayeed, Iqbal</au><au>Stein, Donald G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TAK-242, an Antagonist for Toll-like Receptor 4, Protects against Acute Cerebral Ischemia/Reperfusion Injury in Mice</atitle><jtitle>Journal of cerebral blood flow and metabolism</jtitle><addtitle>J Cereb Blood Flow Metab</addtitle><date>2015-04-01</date><risdate>2015</risdate><volume>35</volume><issue>4</issue><spage>536</spage><epage>542</epage><pages>536-542</pages><issn>0271-678X</issn><eissn>1559-7016</eissn><abstract>Toll-like receptor 4 (TLR4) contributes to cerebral ischemia/reperfusion (I/R) injury and is a potential target for the treatment of ischemic stroke. This experiment is to evaluate the effect of an exogenous TLR4 antagonist, TAK-242, against acute cerebral I/R injury. A mouse model of cerebral I/R was induced by transient middle cerebral artery occlusion. TAK-242 (3 mg/kg body weight) was injected intraperitoneally 1 hour after ischemia. Our results showed that the concentration of TAK-242 in plasma increased to 52.0 ng/mL 3 hours after injection, was maintained at 54.1 ng/mL 8 hours after injection, and decreased to 22.6 ng/mL 24 hours after injection. The concentration of TAK-242 in brain tissue increased to 26.1 ng/mL in ischemic hemisphere and 14.2 ng/mL in nonischemic hemisphere 3 hours after injection, and was maintained at the similar levels 24 hours after injection. We found that TAK-242 significantly reduced cerebral infarction compared with vehicle control, improved neurologic function, inhibited the phosphorylation of downstream protein kinases in TLR4 signaling pathway, and downregulated the expression of inflammatory cytokines. We conclude that TAK-242 is able to cross blood-brain barrier, blocks TLR4 signaling, mediates the expression of inflammatory cytokines, and protects the brain from acute damage induced by I/R.</abstract><cop>London, England</cop><pub>SAGE Publications</pub><pmid>25586141</pmid><doi>10.1038/jcbfm.2014.240</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0271-678X |
| ispartof | Journal of cerebral blood flow and metabolism, 2015-04, Vol.35 (4), p.536-542 |
| issn | 0271-678X 1559-7016 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4420883 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; SAGE Complete; PubMed Central |
| subjects | Animals Brain - blood supply Brain - drug effects Brain - pathology Brain Ischemia - pathology Brain Ischemia - prevention & control Male Mice Mice, Inbred C57BL Neuroprotective Agents - pharmacokinetics Neuroprotective Agents - therapeutic use Rapid Communication Reperfusion Injury - pathology Reperfusion Injury - prevention & control Sulfonamides - pharmacokinetics Sulfonamides - therapeutic use Toll-Like Receptor 4 - antagonists & inhibitors |
| title | TAK-242, an Antagonist for Toll-like Receptor 4, Protects against Acute Cerebral Ischemia/Reperfusion Injury in Mice |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-13T06%3A49%3A27IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=TAK-242,%20an%20Antagonist%20for%20Toll-like%20Receptor%204,%20Protects%20against%20Acute%20Cerebral%20Ischemia/Reperfusion%20Injury%20in%20Mice&rft.jtitle=Journal%20of%20cerebral%20blood%20flow%20and%20metabolism&rft.au=Hua,%20Fang&rft.date=2015-04-01&rft.volume=35&rft.issue=4&rft.spage=536&rft.epage=542&rft.pages=536-542&rft.issn=0271-678X&rft.eissn=1559-7016&rft_id=info:doi/10.1038/jcbfm.2014.240&rft_dat=%3Cproquest_pubme%3E3641481091%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1667956649&rft_id=info:pmid/25586141&rft_sage_id=10.1038_jcbfm.2014.240&rfr_iscdi=true |