Evidence map›Paper›PMID 34076259›Full record

ArticleEuropean journal of clinical investigation2021

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

Luca Liberale, Nicole R Bonetti, Yustina M Puspitasari, Ana Vukolic, Alexander Akhmedov, Candela Diaz-Cañestro, Stephan Keller, Fabrizio Montecucco, Mario Merlini, Aurora Semerano and 8 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in European journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers, 3 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
34citing papers in PubMed, 3 pooled it
2.9field-weighted citation impact, top 9% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

34 citing papers in PubMed, 3 syntheses or guidelines pooled it, 47 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

18 authors at 7 institutions in 5 countries.

Luca LiberaleCenter for Molecular Cardiology, University of Zürich, Schlieren, Switzerland.ORCID https://orcid.org/0000-0003-1472-7975
Nicole R BonettiCenter for Molecular Cardiology, University of Zürich, Schlieren, Switzerland.
Yustina M PuspitasariCenter for Molecular Cardiology, University of Zürich, Schlieren, Switzerland.
Ana VukolicCenter for Molecular Cardiology, University of Zürich, Schlieren, Switzerland.
Alexander AkhmedovCenter for Molecular Cardiology, University of Zürich, Schlieren, Switzerland.
Candela Diaz-CañestroCenter for Molecular Cardiology, University of Zürich, Schlieren, Switzerland.
Stephan KellerCenter for Molecular Cardiology, University of Zürich, Schlieren, Switzerland.
Fabrizio MontecuccoDepartment of Internal Medicine, First Clinic of Internal Medicine, University of Genoa, Genoa, Italy.ORCID https://orcid.org/0000-0003-0823-8729
Mario MerliniBlood & Brain @ Caen-Normandie Institute, GIP Cyceron, Caen, France.
Aurora SemeranoDepartment of Neurology, San Raffaele Scientific Institute, Milano, Italy.
Giacomo GiacaloneDepartment of Neurology, San Raffaele Scientific Institute, Milano, Italy.
Marco BacigaluppiDepartment of Neurology, San Raffaele Scientific Institute, Milano, Italy.
Maria SessaDepartment of Neurology, Papa Giovanni XXIII Hospital, Bergamo, Italy.
Frank RuschitzkaDepartment of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland.
Thomas F LüscherCenter for Molecular Cardiology, University of Zürich, Schlieren, Switzerland.
Peter LibbyDivision of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Jürg H BeerCenter for Molecular Cardiology, University of Zürich, Schlieren, Switzerland.
Giovanni G CamiciCenter for Molecular Cardiology, University of Zürich, Schlieren, Switzerland.ORCID https://orcid.org/0000-0002-0523-0695
University of Zurich · CHSan Raffaele University of Rome · ITBrigham and Women's Hospital · USCyceron · FROspedale Papa Giovanni XXIII · ITOspedale Policlinico San Martino · ITUniversity Hospital of Zurich · CH

Funding

Molecular Determinants of Arterial Remodeling in AtherogenesisR01HL080472 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI LIBBY, PETER · 2005 to 2018
$5.0M
Novel mechanisms of the thrombotic complications of atherosclerosisR01HL134892 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI LIBBY, PETER · 2019 to 2022
$1.7M
Alfred and Annemarie von Sick Grants for Translational and Clinical Research Cardiology and OncologyAmerican Heart Association 18CSA34080399Foundation for Cardiovascular Research-Zurich Heart HouseNHLBI NIH HHS R01 HL080472NHLBI NIH HHS R01 HL134892RRM Charitable FundSheikh Khalifa's FoundationSwiss Heart FoundationSwiss National Science Foundation 310030_197510US National Heart, Lung, and Blood Institute 1R01HL134892US National Heart, Lung, and Blood Institute R01HL080472
6 · The paper itself

Abstract

aimsEpidemiologic 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.

methods3 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.

resultsOld 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.

conclusionsThis 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.

Indexed as

AdalimumabAgedAged, 80 and overAgingAnimalsBlood-Brain BarrierCadherinsFemaleHumansInfarction, Middle Cerebral ArteryInflammationInterleukin-1betaIschemic StrokeMaleMiceMiddle AgedAdalimumabCadherinsIL1B protein, mouseInterleukin-1betaTight Junction ProteinsTNF protein, humanTnf protein, mouseTumor Necrosis Factor-alphaTumor Necrosis Factor Inhibitorsageinginflamm-ageinginflammationischaemic strokematrix metalloproteinasesTNF-α

Identifiers

PMID34076259
PMCPMC8596431
OpenAlexW3165110865

What OpenQuestion holds

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LicenceCC BY-NC-ND
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.