dc.contributor.author | Clemente-Moragón, Agustín | |
dc.contributor.author | Oliver, Eduardo | |
dc.contributor.author | Calle, Daniel | |
dc.contributor.author | Cusso, Lorena | |
dc.contributor.author | Gomez, Monica | |
dc.contributor.author | Pradillo, Jesús M | |
dc.contributor.author | Castejón, Raquel | |
dc.contributor.author | Rallón, Norma | |
dc.contributor.author | Benito, José M | |
dc.contributor.author | Fernández-Ferro, José C | |
dc.contributor.author | Carneado-Ruíz, Joaquín | |
dc.contributor.author | Moro, María A | |
dc.contributor.author | Sanchez-Gonzalez, Javier | |
dc.contributor.author | Fuster, Valentín | |
dc.contributor.author | Cortes-Canteli, Marta | |
dc.contributor.author | Desco, Manuel | |
dc.contributor.author | Ibáñez, Borja | |
dc.date.accessioned | 2023-07-17T14:21:45Z | |
dc.date.available | 2023-07-17T14:21:45Z | |
dc.date.issued | 2023-02 | |
dc.identifier.citation | Br J Pharmacol. 2023 Feb;180(4):459-478 | es_ES |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/16281 | |
dc.description.abstract | BACKGROUND AND PURPOSE
Reperfusion therapy is the standard of care for ischaemic stroke; however, there is a need to identify new therapeutic targets able to ameliorate cerebral damage. Neutrophil β1 adrenoceptors (β1AR) have been linked to neutrophil migration during exacerbated inflammation. Given the central role of neutrophils in cerebral damage during stroke, we hypothesize that β1AR blockade will improve stroke outcomes.
EXPERIMENTAL APPROACH
Rats were subjected to middle cerebral artery occlusion-reperfusion to evaluate the effect on stroke of the selective β1AR blocker metoprolol (12.5 mg·kg-1 ) when injected i.v. 10 min before reperfusion.
KEY RESULTS
Magnetic resonance imaging and histopathology analysis showed that pre-reperfusion i.v. metoprolol reduced infarct size. This effect was accompanied by reduced cytotoxic oedema at 24 h and vasogenic oedema at 7 days. Metoprolol-treated rats showed reduced brain neutrophil infiltration and those which infiltrated displayed a high proportion of anti-inflammatory phenotype (N2, YM1+ ). Additional inflammatory models demonstrated that metoprolol specifically blocked neutrophil migration via β1AR and excluded a significant effect on the glia compartment. Consistently, metoprolol did not protect the brain in neutrophil-depleted rats upon stroke. In patients suffering an ischaemic stroke, β1AR blockade by metoprolol reduced circulating neutrophil-platelet co-aggregates.
CONCLUSIONS AND IMPLICATIONS
Our findings describe that β1AR blockade ameliorates cerebral damage by targeting neutrophils, identifying a novel therapeutic target to improve outcomes in patients with stroke. This therapeutic strategy is in the earliest stages of the translational pathway and should be further explored. | es_ES |
dc.description.sponsorship | This study received funding from the Instituto
de Salud Carlos III (ISCIII; PI16/02110 to
B.I. and PT20/00044 to M.D.), the European
Regional Development Fund (ERDF) “A way of
making Europe,” the Comunidad de Madrid
(S2017/BMD-3867 RENIM-CM to M.D. and
B.I.), cofunding from European structural, and
investment funds, and by Agencia Estatal de
Investigacion (PID2019-110369RB-I00 to B.I.).
B.I. is a recipient of funding from the European
Research Council (ERC) under the European
Union Horizon 2020 Research and Innovation
Programme (ERC-Consolidator Grant
agreement No. 819775). E.O. is a recipient of
funds from the Comunidad de Madrid
Programa de Atraccion de Talento (2017-T1/BMD-5185) and from a Ramon y Cajal grant (RYC2020-028884-I) funded by MCIN/
AEI/10.13039/501100011033 and by “ESF
Investing in your future.” A.C.M. is the
beneficiary of an FPU fellowship from the
Ministerio de Ciencia e Innovacion (FPU2017/01932). M.C.C. is the beneficiary of
a Miguel Servet contract (MS16/00174). The
CNIC is supported by the ISCIII, the Ministerio
de Ciencia e Innovacion and the Pro CNIC Foundation and is a Severo Ochoa Center of
Excellence (CEX2020-001041-S). | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Wiley | es_ES |
dc.type.hasVersion | VoR | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.subject.mesh | Brain Ischemia | es_ES |
dc.subject.mesh | Stroke | es_ES |
dc.subject.mesh | Ischemic Stroke | es_ES |
dc.subject.mesh | Rats | es_ES |
dc.subject.mesh | Animals | es_ES |
dc.subject.mesh | Metoprolol | es_ES |
dc.subject.mesh | Neutrophils | es_ES |
dc.subject.mesh | Neuroinflammatory Diseases | es_ES |
dc.subject.mesh | Receptors, Adrenergic | es_ES |
dc.title | Neutrophil β1 adrenoceptor blockade blunts stroke-associated neuroinflammation. | es_ES |
dc.type | research article | es_ES |
dc.rights.license | Attribution-NonCommercial-NoDerivatives 4.0 Internacional | * |
dc.identifier.pubmedID | 36181002 | es_ES |
dc.format.volume | 180 | es_ES |
dc.format.number | 4 | es_ES |
dc.format.page | 459 | es_ES |
dc.identifier.doi | 10.1111/bph.15963 | es_ES |
dc.contributor.funder | Instituto de Salud Carlos III | es_ES |
dc.contributor.funder | Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) | es_ES |
dc.contributor.funder | Comunidad de Madrid (España) | es_ES |
dc.contributor.funder | Agencia Estatal de Investigación (España) | es_ES |
dc.contributor.funder | Unión Europea. Comisión Europea. European Research Council (ERC) | es_ES |
dc.contributor.funder | Unión Europea. Comisión Europea. H2020 | es_ES |
dc.contributor.funder | Ministerio de Ciencia e Innovación (España) | es_ES |
dc.contributor.funder | Fundación ProCNIC | es_ES |
dc.contributor.funder | Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España) | es_ES |
dc.description.peerreviewed | Sí | es_ES |
dc.identifier.e-issn | 1476-5381 | es_ES |
dc.relation.publisherversion | https://doi.org/10.1111/bph.15963 | es_ES |
dc.identifier.journal | British journal of pharmacology | es_ES |
dc.repisalud.orgCNIC | CNIC::Unidades técnicas::Imagen Avanzada | es_ES |
dc.repisalud.institucion | CNIC | es_ES |
dc.rights.accessRights | open access | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PI16/02110 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PT20/00044 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/S2017/BMD-3867/RENIM-CM | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/PID2019-110369RB-I00 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/2017-T1/BMD-5185 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/RYC2020-028884-I | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/MCIN/AEI/10.13039/501100011033 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/FPU2017/01932 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/MS16/00174 | es_ES |
dc.relation.projectFECYT | info:eu-repo/grantAgreement/ES/CEX2020-001041-S | es_ES |