Selective brain hypothermia attenuates focal cerebral ischemic injury and improves long‐term neurological outcome in aged female mice
Aims This study aimed to investigate the effects of mild selective brain hypothermia on aged female ischemic mice. Methods A distal middle cerebral artery occlusion (dMCAO) model was established in aged female mice, who were then subjected to mild selective brain hypothermia immediately after the dM...
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| Veröffentlicht in: | CNS neuroscience & therapeutics 2023-01, Vol.29 (1), p.129-139 |
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| creator | Liu, Liqiang Liu, Jia Li, Ming Lyu, Junxuan Su, Wei Feng, Shejun Ji, Xunming |
| description | Aims
This study aimed to investigate the effects of mild selective brain hypothermia on aged female ischemic mice.
Methods
A distal middle cerebral artery occlusion (dMCAO) model was established in aged female mice, who were then subjected to mild selective brain hypothermia immediately after the dMCAO procedure. Neurological behavioral examinations were conducted prior to and up to 35 days post‐ischemia. Infarct volume, brain atrophy, pro‐inflammation, and anti‐inflammation microglia/macrophages phenotype and white matter injury were evaluated by immunofluorescence staining. Correlations between neurological behaviors and histological parameters were evaluated by Pearson product linear regression analysis.
Results
Sensorimotor and cognitive function tests confirmed the protective effect of mild selective brain hypothermia in elderly female ischemic mice. In addition, hypothermia decreased the infarct volume and brain atrophy induced by focal cerebral ischemia. Furthermore, hypothermia alleviated ischemia‐induced short‐term and long‐term white matter injury, which was correlated with behavioral deficits. Finally, hypothermia suppressed the harmful immunological response by promoting the transformation of pro‐inflammatory microglia/macrophages to anti‐inflammatory phenotype. This polarization was negatively correlated with neuronal loss and white matter injury.
Conclusion
Mild selective brain hypothermia promoted long‐term functional recovery by alleviating white matter damage in an aged female mouse model of ischemia.
Selective brain hypothermia alleviated ischemia‐induced neuronal loss and white matter injury, which was correlated with behavioral deficits. Furthermore, selective brain hypothermia suppressed the harmful immunological response by promoting the transformation of microglia/macrophages from the M1 to M2 phenotype. This polarization was negatively correlated with neuronal loss and white matter injury. |
| doi_str_mv | 10.1111/cns.14017 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9804044</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2733200243</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4437-5e63e7e3afdf924e952955d9ff2524d7f02bd2cddef2568e4167caaf0a59b7e13</originalsourceid><addsrcrecordid>eNp1kctuEzEUhi0EoiWw4AWQJTZlkdbXmfEGCUVcKlWwKKwtx3OcOPLYwZ4Jyq47tjwjT4LblAiQ8MaW_Z1P5_hH6Dkl57SuCxvLORWEtg_QKW2lnEsl1MPjmZMT9KSUDSEN61T3GJ3whguqZHeKvl9DADv6HeBlNj7i9X6bxjXkwRtsxhHiZEYo2CVrAraQoWIB-2LXMHiLfdxMeY9N7LEftjntKhtSXP28-TFWCY4w5RTSyt-Wp2m0aYBahM0KeuxgMAFw9cBT9MiZUODZ_T5DX969_bz4ML_69P5y8eZqboXg7VxCw6EFblzvFBOgJFNS9so5JpnoW0fYsme276FeNB0I2rTWGEeMVMsWKJ-h1wfvdloO0FuIY51Hb7MfTN7rZLz--yX6tV6lnVYdEaT2MENn94Kcvk5QRj3Uz4AQTIQ0Fc1azhkhTPCKvvwH3aQpxzpepaRqZNd1pFKvDpTNqZQM7tgMJfo2Xl3j1XfxVvbFn90fyd95VuDiAHzzAfb_N-nFx-uD8heBJ7RM</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2759658880</pqid></control><display><type>article</type><title>Selective brain hypothermia attenuates focal cerebral ischemic injury and improves long‐term neurological outcome in aged female mice</title><source>MEDLINE</source><source>Wiley Online Library Open Access</source><source>DOAJ Directory of Open Access Journals</source><source>Wiley Online Library Journals Frontfile Complete</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><creator>Liu, Liqiang ; Liu, Jia ; Li, Ming ; Lyu, Junxuan ; Su, Wei ; Feng, Shejun ; Ji, Xunming</creator><creatorcontrib>Liu, Liqiang ; Liu, Jia ; Li, Ming ; Lyu, Junxuan ; Su, Wei ; Feng, Shejun ; Ji, Xunming</creatorcontrib><description>Aims
This study aimed to investigate the effects of mild selective brain hypothermia on aged female ischemic mice.
Methods
A distal middle cerebral artery occlusion (dMCAO) model was established in aged female mice, who were then subjected to mild selective brain hypothermia immediately after the dMCAO procedure. Neurological behavioral examinations were conducted prior to and up to 35 days post‐ischemia. Infarct volume, brain atrophy, pro‐inflammation, and anti‐inflammation microglia/macrophages phenotype and white matter injury were evaluated by immunofluorescence staining. Correlations between neurological behaviors and histological parameters were evaluated by Pearson product linear regression analysis.
Results
Sensorimotor and cognitive function tests confirmed the protective effect of mild selective brain hypothermia in elderly female ischemic mice. In addition, hypothermia decreased the infarct volume and brain atrophy induced by focal cerebral ischemia. Furthermore, hypothermia alleviated ischemia‐induced short‐term and long‐term white matter injury, which was correlated with behavioral deficits. Finally, hypothermia suppressed the harmful immunological response by promoting the transformation of pro‐inflammatory microglia/macrophages to anti‐inflammatory phenotype. This polarization was negatively correlated with neuronal loss and white matter injury.
Conclusion
Mild selective brain hypothermia promoted long‐term functional recovery by alleviating white matter damage in an aged female mouse model of ischemia.
Selective brain hypothermia alleviated ischemia‐induced neuronal loss and white matter injury, which was correlated with behavioral deficits. Furthermore, selective brain hypothermia suppressed the harmful immunological response by promoting the transformation of microglia/macrophages from the M1 to M2 phenotype. This polarization was negatively correlated with neuronal loss and white matter injury.</description><identifier>ISSN: 1755-5930</identifier><identifier>EISSN: 1755-5949</identifier><identifier>DOI: 10.1111/cns.14017</identifier><identifier>PMID: 36341958</identifier><language>eng</language><publisher>England: John Wiley & Sons, Inc</publisher><subject>Adhesives ; aged mice ; Animal memory ; Animals ; Anti-Inflammatory Agents - pharmacology ; Atrophy ; Brain - pathology ; Brain Injuries ; Brain injury ; Brain Ischemia - pathology ; Carotid arteries ; Cerebral blood flow ; Clinical trials ; Cognitive ability ; Cooling ; Female ; Females ; Hypothermia ; Hypothermia, Induced - methods ; Immune response ; Immunofluorescence ; Infarction, Middle Cerebral Artery - pathology ; Infarction, Middle Cerebral Artery - therapy ; Inflammation ; Ischemia ; ischemic stroke ; Laboratories ; Macrophages ; Males ; Mice ; Microglia ; Original ; Phenotypes ; protection ; Proteins ; Recovery of function ; Sensorimotor system ; Substantia alba ; Surgery ; Variance analysis ; Veins & arteries</subject><ispartof>CNS neuroscience & therapeutics, 2023-01, Vol.29 (1), p.129-139</ispartof><rights>2022 The Authors. published by John Wiley & Sons Ltd.</rights><rights>2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.</rights><rights>2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4437-5e63e7e3afdf924e952955d9ff2524d7f02bd2cddef2568e4167caaf0a59b7e13</citedby><cites>FETCH-LOGICAL-c4437-5e63e7e3afdf924e952955d9ff2524d7f02bd2cddef2568e4167caaf0a59b7e13</cites><orcidid>0000-0003-0293-2744 ; 0000-0001-6711-3841</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9804044/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9804044/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,1411,11541,27901,27902,45550,45551,46027,46451,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36341958$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Liqiang</creatorcontrib><creatorcontrib>Liu, Jia</creatorcontrib><creatorcontrib>Li, Ming</creatorcontrib><creatorcontrib>Lyu, Junxuan</creatorcontrib><creatorcontrib>Su, Wei</creatorcontrib><creatorcontrib>Feng, Shejun</creatorcontrib><creatorcontrib>Ji, Xunming</creatorcontrib><title>Selective brain hypothermia attenuates focal cerebral ischemic injury and improves long‐term neurological outcome in aged female mice</title><title>CNS neuroscience & therapeutics</title><addtitle>CNS Neurosci Ther</addtitle><description>Aims
This study aimed to investigate the effects of mild selective brain hypothermia on aged female ischemic mice.
Methods
A distal middle cerebral artery occlusion (dMCAO) model was established in aged female mice, who were then subjected to mild selective brain hypothermia immediately after the dMCAO procedure. Neurological behavioral examinations were conducted prior to and up to 35 days post‐ischemia. Infarct volume, brain atrophy, pro‐inflammation, and anti‐inflammation microglia/macrophages phenotype and white matter injury were evaluated by immunofluorescence staining. Correlations between neurological behaviors and histological parameters were evaluated by Pearson product linear regression analysis.
Results
Sensorimotor and cognitive function tests confirmed the protective effect of mild selective brain hypothermia in elderly female ischemic mice. In addition, hypothermia decreased the infarct volume and brain atrophy induced by focal cerebral ischemia. Furthermore, hypothermia alleviated ischemia‐induced short‐term and long‐term white matter injury, which was correlated with behavioral deficits. Finally, hypothermia suppressed the harmful immunological response by promoting the transformation of pro‐inflammatory microglia/macrophages to anti‐inflammatory phenotype. This polarization was negatively correlated with neuronal loss and white matter injury.
Conclusion
Mild selective brain hypothermia promoted long‐term functional recovery by alleviating white matter damage in an aged female mouse model of ischemia.
Selective brain hypothermia alleviated ischemia‐induced neuronal loss and white matter injury, which was correlated with behavioral deficits. Furthermore, selective brain hypothermia suppressed the harmful immunological response by promoting the transformation of microglia/macrophages from the M1 to M2 phenotype. This polarization was negatively correlated with neuronal loss and white matter injury.</description><subject>Adhesives</subject><subject>aged mice</subject><subject>Animal memory</subject><subject>Animals</subject><subject>Anti-Inflammatory Agents - pharmacology</subject><subject>Atrophy</subject><subject>Brain - pathology</subject><subject>Brain Injuries</subject><subject>Brain injury</subject><subject>Brain Ischemia - pathology</subject><subject>Carotid arteries</subject><subject>Cerebral blood flow</subject><subject>Clinical trials</subject><subject>Cognitive ability</subject><subject>Cooling</subject><subject>Female</subject><subject>Females</subject><subject>Hypothermia</subject><subject>Hypothermia, Induced - methods</subject><subject>Immune response</subject><subject>Immunofluorescence</subject><subject>Infarction, Middle Cerebral Artery - pathology</subject><subject>Infarction, Middle Cerebral Artery - therapy</subject><subject>Inflammation</subject><subject>Ischemia</subject><subject>ischemic stroke</subject><subject>Laboratories</subject><subject>Macrophages</subject><subject>Males</subject><subject>Mice</subject><subject>Microglia</subject><subject>Original</subject><subject>Phenotypes</subject><subject>protection</subject><subject>Proteins</subject><subject>Recovery of function</subject><subject>Sensorimotor system</subject><subject>Substantia alba</subject><subject>Surgery</subject><subject>Variance analysis</subject><subject>Veins & arteries</subject><issn>1755-5930</issn><issn>1755-5949</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kctuEzEUhi0EoiWw4AWQJTZlkdbXmfEGCUVcKlWwKKwtx3OcOPLYwZ4Jyq47tjwjT4LblAiQ8MaW_Z1P5_hH6Dkl57SuCxvLORWEtg_QKW2lnEsl1MPjmZMT9KSUDSEN61T3GJ3whguqZHeKvl9DADv6HeBlNj7i9X6bxjXkwRtsxhHiZEYo2CVrAraQoWIB-2LXMHiLfdxMeY9N7LEftjntKhtSXP28-TFWCY4w5RTSyt-Wp2m0aYBahM0KeuxgMAFw9cBT9MiZUODZ_T5DX969_bz4ML_69P5y8eZqboXg7VxCw6EFblzvFBOgJFNS9so5JpnoW0fYsme276FeNB0I2rTWGEeMVMsWKJ-h1wfvdloO0FuIY51Hb7MfTN7rZLz--yX6tV6lnVYdEaT2MENn94Kcvk5QRj3Uz4AQTIQ0Fc1azhkhTPCKvvwH3aQpxzpepaRqZNd1pFKvDpTNqZQM7tgMJfo2Xl3j1XfxVvbFn90fyd95VuDiAHzzAfb_N-nFx-uD8heBJ7RM</recordid><startdate>202301</startdate><enddate>202301</enddate><creator>Liu, Liqiang</creator><creator>Liu, Jia</creator><creator>Li, Ming</creator><creator>Lyu, Junxuan</creator><creator>Su, Wei</creator><creator>Feng, Shejun</creator><creator>Ji, Xunming</creator><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</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>3V.</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</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>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-0293-2744</orcidid><orcidid>https://orcid.org/0000-0001-6711-3841</orcidid></search><sort><creationdate>202301</creationdate><title>Selective brain hypothermia attenuates focal cerebral ischemic injury and improves long‐term neurological outcome in aged female mice</title><author>Liu, Liqiang ; Liu, Jia ; Li, Ming ; Lyu, Junxuan ; Su, Wei ; Feng, Shejun ; Ji, Xunming</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4437-5e63e7e3afdf924e952955d9ff2524d7f02bd2cddef2568e4167caaf0a59b7e13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Adhesives</topic><topic>aged mice</topic><topic>Animal memory</topic><topic>Animals</topic><topic>Anti-Inflammatory Agents - pharmacology</topic><topic>Atrophy</topic><topic>Brain - pathology</topic><topic>Brain Injuries</topic><topic>Brain injury</topic><topic>Brain Ischemia - pathology</topic><topic>Carotid arteries</topic><topic>Cerebral blood flow</topic><topic>Clinical trials</topic><topic>Cognitive ability</topic><topic>Cooling</topic><topic>Female</topic><topic>Females</topic><topic>Hypothermia</topic><topic>Hypothermia, Induced - methods</topic><topic>Immune response</topic><topic>Immunofluorescence</topic><topic>Infarction, Middle Cerebral Artery - pathology</topic><topic>Infarction, Middle Cerebral Artery - therapy</topic><topic>Inflammation</topic><topic>Ischemia</topic><topic>ischemic stroke</topic><topic>Laboratories</topic><topic>Macrophages</topic><topic>Males</topic><topic>Mice</topic><topic>Microglia</topic><topic>Original</topic><topic>Phenotypes</topic><topic>protection</topic><topic>Proteins</topic><topic>Recovery of function</topic><topic>Sensorimotor system</topic><topic>Substantia alba</topic><topic>Surgery</topic><topic>Variance analysis</topic><topic>Veins & arteries</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Liqiang</creatorcontrib><creatorcontrib>Liu, Jia</creatorcontrib><creatorcontrib>Li, Ming</creatorcontrib><creatorcontrib>Lyu, Junxuan</creatorcontrib><creatorcontrib>Su, Wei</creatorcontrib><creatorcontrib>Feng, Shejun</creatorcontrib><creatorcontrib>Ji, Xunming</creatorcontrib><collection>Wiley Online Library Open Access</collection><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>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</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</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>Biological Science Database</collection><collection>Publicly Available Content 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>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>CNS neuroscience & therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Liqiang</au><au>Liu, Jia</au><au>Li, Ming</au><au>Lyu, Junxuan</au><au>Su, Wei</au><au>Feng, Shejun</au><au>Ji, Xunming</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Selective brain hypothermia attenuates focal cerebral ischemic injury and improves long‐term neurological outcome in aged female mice</atitle><jtitle>CNS neuroscience & therapeutics</jtitle><addtitle>CNS Neurosci Ther</addtitle><date>2023-01</date><risdate>2023</risdate><volume>29</volume><issue>1</issue><spage>129</spage><epage>139</epage><pages>129-139</pages><issn>1755-5930</issn><eissn>1755-5949</eissn><abstract>Aims
This study aimed to investigate the effects of mild selective brain hypothermia on aged female ischemic mice.
Methods
A distal middle cerebral artery occlusion (dMCAO) model was established in aged female mice, who were then subjected to mild selective brain hypothermia immediately after the dMCAO procedure. Neurological behavioral examinations were conducted prior to and up to 35 days post‐ischemia. Infarct volume, brain atrophy, pro‐inflammation, and anti‐inflammation microglia/macrophages phenotype and white matter injury were evaluated by immunofluorescence staining. Correlations between neurological behaviors and histological parameters were evaluated by Pearson product linear regression analysis.
Results
Sensorimotor and cognitive function tests confirmed the protective effect of mild selective brain hypothermia in elderly female ischemic mice. In addition, hypothermia decreased the infarct volume and brain atrophy induced by focal cerebral ischemia. Furthermore, hypothermia alleviated ischemia‐induced short‐term and long‐term white matter injury, which was correlated with behavioral deficits. Finally, hypothermia suppressed the harmful immunological response by promoting the transformation of pro‐inflammatory microglia/macrophages to anti‐inflammatory phenotype. This polarization was negatively correlated with neuronal loss and white matter injury.
Conclusion
Mild selective brain hypothermia promoted long‐term functional recovery by alleviating white matter damage in an aged female mouse model of ischemia.
Selective brain hypothermia alleviated ischemia‐induced neuronal loss and white matter injury, which was correlated with behavioral deficits. Furthermore, selective brain hypothermia suppressed the harmful immunological response by promoting the transformation of microglia/macrophages from the M1 to M2 phenotype. This polarization was negatively correlated with neuronal loss and white matter injury.</abstract><cop>England</cop><pub>John Wiley & Sons, Inc</pub><pmid>36341958</pmid><doi>10.1111/cns.14017</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0003-0293-2744</orcidid><orcidid>https://orcid.org/0000-0001-6711-3841</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Wiley Online Library Open Access; DOAJ Directory of Open Access Journals; Wiley Online Library Journals Frontfile Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Adhesives aged mice Animal memory Animals Anti-Inflammatory Agents - pharmacology Atrophy Brain - pathology Brain Injuries Brain injury Brain Ischemia - pathology Carotid arteries Cerebral blood flow Clinical trials Cognitive ability Cooling Female Females Hypothermia Hypothermia, Induced - methods Immune response Immunofluorescence Infarction, Middle Cerebral Artery - pathology Infarction, Middle Cerebral Artery - therapy Inflammation Ischemia ischemic stroke Laboratories Macrophages Males Mice Microglia Original Phenotypes protection Proteins Recovery of function Sensorimotor system Substantia alba Surgery Variance analysis Veins & arteries |
| title | Selective brain hypothermia attenuates focal cerebral ischemic injury and improves long‐term neurological outcome in aged female mice |
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