TNF‐α antagonism rescues the effect of ageing on stroke: Perspectives for targeting inflamm‐ageing

Aims Epidemiologic evidence links ischemic stroke to age, yet the mechanisms that underlie the specific and independent effects of age on stroke remain elusive, impeding the development of targeted treatments. This study tested the hypothesis that age directly aggravates stroke outcomes and proposes...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:European journal of clinical investigation 2021-11, Vol.51 (11), p.e13600-n/a
Hauptverfasser: Liberale, Luca, Bonetti, Nicole R., Puspitasari, Yustina M., Vukolic, Ana, Akhmedov, Alexander, Diaz‐Cañestro, Candela, Keller, Stephan, Montecucco, Fabrizio, Merlini, Mario, Semerano, Aurora, Giacalone, Giacomo, Bacigaluppi, Marco, Sessa, Maria, Ruschitzka, Frank, Lüscher, Thomas F., Libby, Peter, Beer, Jürg H., Camici, Giovanni G.
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page n/a
container_issue 11
container_start_page e13600
container_title European journal of clinical investigation
container_volume 51
creator Liberale, Luca
Bonetti, Nicole R.
Puspitasari, Yustina M.
Vukolic, Ana
Akhmedov, Alexander
Diaz‐Cañestro, Candela
Keller, Stephan
Montecucco, Fabrizio
Merlini, Mario
Semerano, Aurora
Giacalone, Giacomo
Bacigaluppi, Marco
Sessa, Maria
Ruschitzka, Frank
Lüscher, Thomas F.
Libby, Peter
Beer, Jürg H.
Camici, Giovanni G.
description Aims Epidemiologic evidence links ischemic stroke to age, yet the mechanisms that underlie the specific and independent effects of age on stroke remain elusive, impeding the development of targeted treatments. This study tested the hypothesis that age directly aggravates stroke outcomes and proposes inflamm‐aging as a mediator and potential therapeutic target. Methods 3 months‐ (young) and 18‐20 months‐old (old) mice underwent transient middle cerebral artery occlusion (tMCAO) for 30 minutes followed by 48 hours of reperfusion. Old animals received weekly treatment with the TNF‐α neutralizing antibody adalimumab over 4 weeks before tMCAO in a separate set of experiments. Plasma levels of TNF‐ α were assessed in patients with ischemic stroke and correlated with age and outcome. Results Old mice displayed larger stroke size than young ones with increased neuromotor deficit. Immunohistochemical analysis revealed impairment of the blood‐brain barrier in old mice, i.e. increased post‐stroke degradation of endothelial tight junctions and expression of tight junctions‐digesting and neurotoxic matrix metalloproteinases. At baseline, old animals showed a broad modulation of several circulating inflammatory mediators. TNF‐α displayed the highest increase in old animals and its inhibition restored the volume of stroke, neuromotor performance, and survival rates of old mice to the levels observed in young ones. Patients with ischemic stroke showed increased TNF‐α plasma levels which correlated with worsened short‐term neurological outcome as well as with age. Conclusions This study identifies TNF‐α as a causative contributor to the deleterious effect of aging on stroke and points to inflamm‐aging as a mechanism of age‐related worsening of stroke outcomes and potential therapeutic target in this context. Thus, this work provides a basis for tailoring novel stroke therapies for the particularly vulnerable elderly population.
doi_str_mv 10.1111/eci.13600
format Article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8596431</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2582294305</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4430-e43ba31113142fc3c7755374bedf157ec78bcf2b56e902ace658a587a5a6e4733</originalsourceid><addsrcrecordid>eNp1kUtOHDEQhq0oURgeCy4QWcoqi2b8bHdnESka8RgJAQtYW25Tbkym2xO7B8SOI3AVLsIhOAkmDYgs8KYW9flzlX-EtinZoflMwfodyktCPqFJrrJgvGSf0YQQKgpWK7aG1lO6JIRUlLOvaI0Lokom6wlqT4_2Hm_vHu6x6QfTht6nDkdIdgUJDxeAwTmwAw4OmxZ83-LQ4zTE8Ad-4hOIaZm7_irDLkQ8mNjC8Ez53i1M12X1eG0TfXFmkWDrpW6gs73d09lBcXi8P5_9PiysEJwUIHhjeN6JU8Gc5VYpKbkSDZw7KhVYVTXWsUaWUBNmLJSyMrJSRpoShOJ8A_0avctV08G5hX6IZqGX0Xcm3uhgvP6_0_sL3YYrXcm6FJxmwfcXQQx_8ycM-jKsYp9n1kxWjNV5TJmpHyNlY0gpgnt7gRL9nInOmeh_mWT22_uR3sjXEDIwHYFrv4Cbj016dzYflU9FepnB</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2582294305</pqid></control><display><type>article</type><title>TNF‐α antagonism rescues the effect of ageing on stroke: Perspectives for targeting inflamm‐ageing</title><source>Wiley-Blackwell Journals</source><source>MEDLINE</source><creator>Liberale, Luca ; Bonetti, Nicole R. ; Puspitasari, Yustina M. ; Vukolic, Ana ; Akhmedov, Alexander ; Diaz‐Cañestro, Candela ; Keller, Stephan ; Montecucco, Fabrizio ; Merlini, Mario ; Semerano, Aurora ; Giacalone, Giacomo ; Bacigaluppi, Marco ; Sessa, Maria ; Ruschitzka, Frank ; Lüscher, Thomas F. ; Libby, Peter ; Beer, Jürg H. ; Camici, Giovanni G.</creator><creatorcontrib>Liberale, Luca ; Bonetti, Nicole R. ; Puspitasari, Yustina M. ; Vukolic, Ana ; Akhmedov, Alexander ; Diaz‐Cañestro, Candela ; Keller, Stephan ; Montecucco, Fabrizio ; Merlini, Mario ; Semerano, Aurora ; Giacalone, Giacomo ; Bacigaluppi, Marco ; Sessa, Maria ; Ruschitzka, Frank ; Lüscher, Thomas F. ; Libby, Peter ; Beer, Jürg H. ; Camici, Giovanni G.</creatorcontrib><description>Aims Epidemiologic evidence links ischemic stroke to age, yet the mechanisms that underlie the specific and independent effects of age on stroke remain elusive, impeding the development of targeted treatments. This study tested the hypothesis that age directly aggravates stroke outcomes and proposes inflamm‐aging as a mediator and potential therapeutic target. Methods 3 months‐ (young) and 18‐20 months‐old (old) mice underwent transient middle cerebral artery occlusion (tMCAO) for 30 minutes followed by 48 hours of reperfusion. Old animals received weekly treatment with the TNF‐α neutralizing antibody adalimumab over 4 weeks before tMCAO in a separate set of experiments. Plasma levels of TNF‐ α were assessed in patients with ischemic stroke and correlated with age and outcome. Results Old mice displayed larger stroke size than young ones with increased neuromotor deficit. Immunohistochemical analysis revealed impairment of the blood‐brain barrier in old mice, i.e. increased post‐stroke degradation of endothelial tight junctions and expression of tight junctions‐digesting and neurotoxic matrix metalloproteinases. At baseline, old animals showed a broad modulation of several circulating inflammatory mediators. TNF‐α displayed the highest increase in old animals and its inhibition restored the volume of stroke, neuromotor performance, and survival rates of old mice to the levels observed in young ones. Patients with ischemic stroke showed increased TNF‐α plasma levels which correlated with worsened short‐term neurological outcome as well as with age. Conclusions This study identifies TNF‐α as a causative contributor to the deleterious effect of aging on stroke and points to inflamm‐aging as a mechanism of age‐related worsening of stroke outcomes and potential therapeutic target in this context. Thus, this work provides a basis for tailoring novel stroke therapies for the particularly vulnerable elderly population.</description><identifier>ISSN: 0014-2972</identifier><identifier>EISSN: 1365-2362</identifier><identifier>DOI: 10.1111/eci.13600</identifier><identifier>PMID: 34076259</identifier><language>eng</language><publisher>England: Blackwell Publishing Ltd</publisher><subject>Adalimumab - pharmacology ; Age ; Age factors ; Aged ; Aged, 80 and over ; ageing ; Aging ; Aging - drug effects ; Aging - metabolism ; Animals ; Antibodies ; Blood-brain barrier ; Blood-Brain Barrier - metabolism ; Cadherins - metabolism ; Cerebral blood flow ; Epidemiology ; Female ; Geriatrics ; Humans ; Infarction, Middle Cerebral Artery - metabolism ; Inflammation ; Inflammation - metabolism ; inflamm‐ageing ; Interleukin-1beta - metabolism ; ischaemic stroke ; Ischemia ; Ischemic Stroke - metabolism ; Male ; Matrix metalloproteinase ; Matrix metalloproteinases ; Mice ; Middle Aged ; Monoclonal antibodies ; Neurotoxicity ; Occlusion ; Older people ; Original ; Patients ; Plasma levels ; Recovery of Function ; Reperfusion ; Reperfusion Injury - metabolism ; Stroke ; Survival ; Therapeutic applications ; Therapeutic targets ; Tight Junction Proteins - metabolism ; Tight junctions ; TNF‐α ; Tumor necrosis factor ; Tumor Necrosis Factor Inhibitors - pharmacology ; Tumor Necrosis Factor-alpha - drug effects ; Tumor Necrosis Factor-alpha - metabolism</subject><ispartof>European journal of clinical investigation, 2021-11, Vol.51 (11), p.e13600-n/a</ispartof><rights>2021 The Authors. published by John Wiley &amp; Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.</rights><rights>2021 The Authors. European Journal of Clinical Investigation published by John Wiley &amp; Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.</rights><rights>2021. This article is published under http://creativecommons.org/licenses/by-nc-nd/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-c4430-e43ba31113142fc3c7755374bedf157ec78bcf2b56e902ace658a587a5a6e4733</citedby><cites>FETCH-LOGICAL-c4430-e43ba31113142fc3c7755374bedf157ec78bcf2b56e902ace658a587a5a6e4733</cites><orcidid>0000-0002-0523-0695 ; 0000-0003-1472-7975 ; 0000-0003-0823-8729</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Feci.13600$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Feci.13600$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34076259$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liberale, Luca</creatorcontrib><creatorcontrib>Bonetti, Nicole R.</creatorcontrib><creatorcontrib>Puspitasari, Yustina M.</creatorcontrib><creatorcontrib>Vukolic, Ana</creatorcontrib><creatorcontrib>Akhmedov, Alexander</creatorcontrib><creatorcontrib>Diaz‐Cañestro, Candela</creatorcontrib><creatorcontrib>Keller, Stephan</creatorcontrib><creatorcontrib>Montecucco, Fabrizio</creatorcontrib><creatorcontrib>Merlini, Mario</creatorcontrib><creatorcontrib>Semerano, Aurora</creatorcontrib><creatorcontrib>Giacalone, Giacomo</creatorcontrib><creatorcontrib>Bacigaluppi, Marco</creatorcontrib><creatorcontrib>Sessa, Maria</creatorcontrib><creatorcontrib>Ruschitzka, Frank</creatorcontrib><creatorcontrib>Lüscher, Thomas F.</creatorcontrib><creatorcontrib>Libby, Peter</creatorcontrib><creatorcontrib>Beer, Jürg H.</creatorcontrib><creatorcontrib>Camici, Giovanni G.</creatorcontrib><title>TNF‐α antagonism rescues the effect of ageing on stroke: Perspectives for targeting inflamm‐ageing</title><title>European journal of clinical investigation</title><addtitle>Eur J Clin Invest</addtitle><description>Aims Epidemiologic evidence links ischemic stroke to age, yet the mechanisms that underlie the specific and independent effects of age on stroke remain elusive, impeding the development of targeted treatments. This study tested the hypothesis that age directly aggravates stroke outcomes and proposes inflamm‐aging as a mediator and potential therapeutic target. Methods 3 months‐ (young) and 18‐20 months‐old (old) mice underwent transient middle cerebral artery occlusion (tMCAO) for 30 minutes followed by 48 hours of reperfusion. Old animals received weekly treatment with the TNF‐α neutralizing antibody adalimumab over 4 weeks before tMCAO in a separate set of experiments. Plasma levels of TNF‐ α were assessed in patients with ischemic stroke and correlated with age and outcome. Results Old mice displayed larger stroke size than young ones with increased neuromotor deficit. Immunohistochemical analysis revealed impairment of the blood‐brain barrier in old mice, i.e. increased post‐stroke degradation of endothelial tight junctions and expression of tight junctions‐digesting and neurotoxic matrix metalloproteinases. At baseline, old animals showed a broad modulation of several circulating inflammatory mediators. TNF‐α displayed the highest increase in old animals and its inhibition restored the volume of stroke, neuromotor performance, and survival rates of old mice to the levels observed in young ones. Patients with ischemic stroke showed increased TNF‐α plasma levels which correlated with worsened short‐term neurological outcome as well as with age. Conclusions This study identifies TNF‐α as a causative contributor to the deleterious effect of aging on stroke and points to inflamm‐aging as a mechanism of age‐related worsening of stroke outcomes and potential therapeutic target in this context. Thus, this work provides a basis for tailoring novel stroke therapies for the particularly vulnerable elderly population.</description><subject>Adalimumab - pharmacology</subject><subject>Age</subject><subject>Age factors</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>ageing</subject><subject>Aging</subject><subject>Aging - drug effects</subject><subject>Aging - metabolism</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Blood-brain barrier</subject><subject>Blood-Brain Barrier - metabolism</subject><subject>Cadherins - metabolism</subject><subject>Cerebral blood flow</subject><subject>Epidemiology</subject><subject>Female</subject><subject>Geriatrics</subject><subject>Humans</subject><subject>Infarction, Middle Cerebral Artery - metabolism</subject><subject>Inflammation</subject><subject>Inflammation - metabolism</subject><subject>inflamm‐ageing</subject><subject>Interleukin-1beta - metabolism</subject><subject>ischaemic stroke</subject><subject>Ischemia</subject><subject>Ischemic Stroke - metabolism</subject><subject>Male</subject><subject>Matrix metalloproteinase</subject><subject>Matrix metalloproteinases</subject><subject>Mice</subject><subject>Middle Aged</subject><subject>Monoclonal antibodies</subject><subject>Neurotoxicity</subject><subject>Occlusion</subject><subject>Older people</subject><subject>Original</subject><subject>Patients</subject><subject>Plasma levels</subject><subject>Recovery of Function</subject><subject>Reperfusion</subject><subject>Reperfusion Injury - metabolism</subject><subject>Stroke</subject><subject>Survival</subject><subject>Therapeutic applications</subject><subject>Therapeutic targets</subject><subject>Tight Junction Proteins - metabolism</subject><subject>Tight junctions</subject><subject>TNF‐α</subject><subject>Tumor necrosis factor</subject><subject>Tumor Necrosis Factor Inhibitors - pharmacology</subject><subject>Tumor Necrosis Factor-alpha - drug effects</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><issn>0014-2972</issn><issn>1365-2362</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNp1kUtOHDEQhq0oURgeCy4QWcoqi2b8bHdnESka8RgJAQtYW25Tbkym2xO7B8SOI3AVLsIhOAkmDYgs8KYW9flzlX-EtinZoflMwfodyktCPqFJrrJgvGSf0YQQKgpWK7aG1lO6JIRUlLOvaI0Lokom6wlqT4_2Hm_vHu6x6QfTht6nDkdIdgUJDxeAwTmwAw4OmxZ83-LQ4zTE8Ad-4hOIaZm7_irDLkQ8mNjC8Ez53i1M12X1eG0TfXFmkWDrpW6gs73d09lBcXi8P5_9PiysEJwUIHhjeN6JU8Gc5VYpKbkSDZw7KhVYVTXWsUaWUBNmLJSyMrJSRpoShOJ8A_0avctV08G5hX6IZqGX0Xcm3uhgvP6_0_sL3YYrXcm6FJxmwfcXQQx_8ycM-jKsYp9n1kxWjNV5TJmpHyNlY0gpgnt7gRL9nInOmeh_mWT22_uR3sjXEDIwHYFrv4Cbj016dzYflU9FepnB</recordid><startdate>202111</startdate><enddate>202111</enddate><creator>Liberale, Luca</creator><creator>Bonetti, Nicole R.</creator><creator>Puspitasari, Yustina M.</creator><creator>Vukolic, Ana</creator><creator>Akhmedov, Alexander</creator><creator>Diaz‐Cañestro, Candela</creator><creator>Keller, Stephan</creator><creator>Montecucco, Fabrizio</creator><creator>Merlini, Mario</creator><creator>Semerano, Aurora</creator><creator>Giacalone, Giacomo</creator><creator>Bacigaluppi, Marco</creator><creator>Sessa, Maria</creator><creator>Ruschitzka, Frank</creator><creator>Lüscher, Thomas F.</creator><creator>Libby, Peter</creator><creator>Beer, Jürg H.</creator><creator>Camici, Giovanni G.</creator><general>Blackwell Publishing Ltd</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</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>7QO</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-0523-0695</orcidid><orcidid>https://orcid.org/0000-0003-1472-7975</orcidid><orcidid>https://orcid.org/0000-0003-0823-8729</orcidid></search><sort><creationdate>202111</creationdate><title>TNF‐α antagonism rescues the effect of ageing on stroke: Perspectives for targeting inflamm‐ageing</title><author>Liberale, Luca ; Bonetti, Nicole R. ; Puspitasari, Yustina M. ; Vukolic, Ana ; Akhmedov, Alexander ; Diaz‐Cañestro, Candela ; Keller, Stephan ; Montecucco, Fabrizio ; Merlini, Mario ; Semerano, Aurora ; Giacalone, Giacomo ; Bacigaluppi, Marco ; Sessa, Maria ; Ruschitzka, Frank ; Lüscher, Thomas F. ; Libby, Peter ; Beer, Jürg H. ; Camici, Giovanni G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4430-e43ba31113142fc3c7755374bedf157ec78bcf2b56e902ace658a587a5a6e4733</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adalimumab - pharmacology</topic><topic>Age</topic><topic>Age factors</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>ageing</topic><topic>Aging</topic><topic>Aging - drug effects</topic><topic>Aging - metabolism</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Blood-brain barrier</topic><topic>Blood-Brain Barrier - metabolism</topic><topic>Cadherins - metabolism</topic><topic>Cerebral blood flow</topic><topic>Epidemiology</topic><topic>Female</topic><topic>Geriatrics</topic><topic>Humans</topic><topic>Infarction, Middle Cerebral Artery - metabolism</topic><topic>Inflammation</topic><topic>Inflammation - metabolism</topic><topic>inflamm‐ageing</topic><topic>Interleukin-1beta - metabolism</topic><topic>ischaemic stroke</topic><topic>Ischemia</topic><topic>Ischemic Stroke - metabolism</topic><topic>Male</topic><topic>Matrix metalloproteinase</topic><topic>Matrix metalloproteinases</topic><topic>Mice</topic><topic>Middle Aged</topic><topic>Monoclonal antibodies</topic><topic>Neurotoxicity</topic><topic>Occlusion</topic><topic>Older people</topic><topic>Original</topic><topic>Patients</topic><topic>Plasma levels</topic><topic>Recovery of Function</topic><topic>Reperfusion</topic><topic>Reperfusion Injury - metabolism</topic><topic>Stroke</topic><topic>Survival</topic><topic>Therapeutic applications</topic><topic>Therapeutic targets</topic><topic>Tight Junction Proteins - metabolism</topic><topic>Tight junctions</topic><topic>TNF‐α</topic><topic>Tumor necrosis factor</topic><topic>Tumor Necrosis Factor Inhibitors - pharmacology</topic><topic>Tumor Necrosis Factor-alpha - drug effects</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liberale, Luca</creatorcontrib><creatorcontrib>Bonetti, Nicole R.</creatorcontrib><creatorcontrib>Puspitasari, Yustina M.</creatorcontrib><creatorcontrib>Vukolic, Ana</creatorcontrib><creatorcontrib>Akhmedov, Alexander</creatorcontrib><creatorcontrib>Diaz‐Cañestro, Candela</creatorcontrib><creatorcontrib>Keller, Stephan</creatorcontrib><creatorcontrib>Montecucco, Fabrizio</creatorcontrib><creatorcontrib>Merlini, Mario</creatorcontrib><creatorcontrib>Semerano, Aurora</creatorcontrib><creatorcontrib>Giacalone, Giacomo</creatorcontrib><creatorcontrib>Bacigaluppi, Marco</creatorcontrib><creatorcontrib>Sessa, Maria</creatorcontrib><creatorcontrib>Ruschitzka, Frank</creatorcontrib><creatorcontrib>Lüscher, Thomas F.</creatorcontrib><creatorcontrib>Libby, Peter</creatorcontrib><creatorcontrib>Beer, Jürg H.</creatorcontrib><creatorcontrib>Camici, Giovanni G.</creatorcontrib><collection>Wiley_OA刊</collection><collection>Wiley Online Library website</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>European journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liberale, Luca</au><au>Bonetti, Nicole R.</au><au>Puspitasari, Yustina M.</au><au>Vukolic, Ana</au><au>Akhmedov, Alexander</au><au>Diaz‐Cañestro, Candela</au><au>Keller, Stephan</au><au>Montecucco, Fabrizio</au><au>Merlini, Mario</au><au>Semerano, Aurora</au><au>Giacalone, Giacomo</au><au>Bacigaluppi, Marco</au><au>Sessa, Maria</au><au>Ruschitzka, Frank</au><au>Lüscher, Thomas F.</au><au>Libby, Peter</au><au>Beer, Jürg H.</au><au>Camici, Giovanni G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TNF‐α antagonism rescues the effect of ageing on stroke: Perspectives for targeting inflamm‐ageing</atitle><jtitle>European journal of clinical investigation</jtitle><addtitle>Eur J Clin Invest</addtitle><date>2021-11</date><risdate>2021</risdate><volume>51</volume><issue>11</issue><spage>e13600</spage><epage>n/a</epage><pages>e13600-n/a</pages><issn>0014-2972</issn><eissn>1365-2362</eissn><abstract>Aims Epidemiologic evidence links ischemic stroke to age, yet the mechanisms that underlie the specific and independent effects of age on stroke remain elusive, impeding the development of targeted treatments. This study tested the hypothesis that age directly aggravates stroke outcomes and proposes inflamm‐aging as a mediator and potential therapeutic target. Methods 3 months‐ (young) and 18‐20 months‐old (old) mice underwent transient middle cerebral artery occlusion (tMCAO) for 30 minutes followed by 48 hours of reperfusion. Old animals received weekly treatment with the TNF‐α neutralizing antibody adalimumab over 4 weeks before tMCAO in a separate set of experiments. Plasma levels of TNF‐ α were assessed in patients with ischemic stroke and correlated with age and outcome. Results Old mice displayed larger stroke size than young ones with increased neuromotor deficit. Immunohistochemical analysis revealed impairment of the blood‐brain barrier in old mice, i.e. increased post‐stroke degradation of endothelial tight junctions and expression of tight junctions‐digesting and neurotoxic matrix metalloproteinases. At baseline, old animals showed a broad modulation of several circulating inflammatory mediators. TNF‐α displayed the highest increase in old animals and its inhibition restored the volume of stroke, neuromotor performance, and survival rates of old mice to the levels observed in young ones. Patients with ischemic stroke showed increased TNF‐α plasma levels which correlated with worsened short‐term neurological outcome as well as with age. Conclusions This study identifies TNF‐α as a causative contributor to the deleterious effect of aging on stroke and points to inflamm‐aging as a mechanism of age‐related worsening of stroke outcomes and potential therapeutic target in this context. Thus, this work provides a basis for tailoring novel stroke therapies for the particularly vulnerable elderly population.</abstract><cop>England</cop><pub>Blackwell Publishing Ltd</pub><pmid>34076259</pmid><doi>10.1111/eci.13600</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0002-0523-0695</orcidid><orcidid>https://orcid.org/0000-0003-1472-7975</orcidid><orcidid>https://orcid.org/0000-0003-0823-8729</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0014-2972
ispartof European journal of clinical investigation, 2021-11, Vol.51 (11), p.e13600-n/a
issn 0014-2972
1365-2362
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8596431
source Wiley-Blackwell Journals; MEDLINE
subjects Adalimumab - pharmacology
Age
Age factors
Aged
Aged, 80 and over
ageing
Aging
Aging - drug effects
Aging - metabolism
Animals
Antibodies
Blood-brain barrier
Blood-Brain Barrier - metabolism
Cadherins - metabolism
Cerebral blood flow
Epidemiology
Female
Geriatrics
Humans
Infarction, Middle Cerebral Artery - metabolism
Inflammation
Inflammation - metabolism
inflamm‐ageing
Interleukin-1beta - metabolism
ischaemic stroke
Ischemia
Ischemic Stroke - metabolism
Male
Matrix metalloproteinase
Matrix metalloproteinases
Mice
Middle Aged
Monoclonal antibodies
Neurotoxicity
Occlusion
Older people
Original
Patients
Plasma levels
Recovery of Function
Reperfusion
Reperfusion Injury - metabolism
Stroke
Survival
Therapeutic applications
Therapeutic targets
Tight Junction Proteins - metabolism
Tight junctions
TNF‐α
Tumor necrosis factor
Tumor Necrosis Factor Inhibitors - pharmacology
Tumor Necrosis Factor-alpha - drug effects
Tumor Necrosis Factor-alpha - metabolism
title TNF‐α antagonism rescues the effect of ageing on stroke: Perspectives for targeting inflamm‐ageing
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T07%3A03%3A35IST&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=TNF%E2%80%90%CE%B1%20antagonism%20rescues%20the%20effect%20of%20ageing%20on%20stroke:%20Perspectives%20for%20targeting%20inflamm%E2%80%90ageing&rft.jtitle=European%20journal%20of%20clinical%20investigation&rft.au=Liberale,%20Luca&rft.date=2021-11&rft.volume=51&rft.issue=11&rft.spage=e13600&rft.epage=n/a&rft.pages=e13600-n/a&rft.issn=0014-2972&rft.eissn=1365-2362&rft_id=info:doi/10.1111/eci.13600&rft_dat=%3Cproquest_pubme%3E2582294305%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=2582294305&rft_id=info:pmid/34076259&rfr_iscdi=true