Pharmacological evaluation of non-nucleotide purine derivatives as P2X7 antagonists for the treatment of neuroinflammation in traumatic brain injury
Background and purpose: Traumatic brain injury (TBI) is considered to be a leadingcause of mortality and disability worldwide. After TBI, innate immunity is rapidly acti-vated in response to damage-associated molecular patterns, such as ATP release,recognised by P2X7 receptors. The P2X7-NLRP3 inflam...
| Autores: | , , , , , , , , , , , , , , , |
|---|---|
| Formato: | artículo |
| Fecha de publicación: | 2025 |
| País: | España |
| Recursos: | Universidad Complutense de Madrid (UCM) |
| Repositorio: | Docta Complutense |
| Idioma: | inglés |
| OAI Identifier: | oai:docta.ucm.es:20.500.14352/123825 |
| Acesso em linha: | https://hdl.handle.net/20.500.14352/123825 |
| Access Level: | acceso abierto |
| Palavra-chave: | 61 615.01/.03 577.2 612.8 Interleukin-1 beta Neuroinflammation P2X7 receptor Traumatic brain injury Ciencias Biomédicas Farmacología (Farmacia) Biología molecular (Farmacia) Neurociencias (Farmacia) 3214 Toxicología 3209.90 Farmacología Experimental 3213.08 Neurocirugía |
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| dc.title.none.fl_str_mv |
Pharmacological evaluation of non-nucleotide purine derivatives as P2X7 antagonists for the treatment of neuroinflammation in traumatic brain injury |
| title |
Pharmacological evaluation of non-nucleotide purine derivatives as P2X7 antagonists for the treatment of neuroinflammation in traumatic brain injury |
| spellingShingle |
Pharmacological evaluation of non-nucleotide purine derivatives as P2X7 antagonists for the treatment of neuroinflammation in traumatic brain injury Valencia, Inés 61 615.01/.03 577.2 612.8 Interleukin-1 beta Neuroinflammation P2X7 receptor Traumatic brain injury Ciencias Biomédicas Farmacología (Farmacia) Biología molecular (Farmacia) Neurociencias (Farmacia) 3214 Toxicología 3209.90 Farmacología Experimental 3213.08 Neurocirugía |
| title_short |
Pharmacological evaluation of non-nucleotide purine derivatives as P2X7 antagonists for the treatment of neuroinflammation in traumatic brain injury |
| title_full |
Pharmacological evaluation of non-nucleotide purine derivatives as P2X7 antagonists for the treatment of neuroinflammation in traumatic brain injury |
| title_fullStr |
Pharmacological evaluation of non-nucleotide purine derivatives as P2X7 antagonists for the treatment of neuroinflammation in traumatic brain injury |
| title_full_unstemmed |
Pharmacological evaluation of non-nucleotide purine derivatives as P2X7 antagonists for the treatment of neuroinflammation in traumatic brain injury |
| title_sort |
Pharmacological evaluation of non-nucleotide purine derivatives as P2X7 antagonists for the treatment of neuroinflammation in traumatic brain injury |
| dc.creator.none.fl_str_mv |
Valencia, Inés Pastor-Martínez, Andrea Decouty-Pérez, Céline López-Rodriguez, Ana Belén Álvarez-Rubal, María Ramos Alonso, Eva Calzaferri, Francesco Zamorano-Fernández, Jorge Giner-García, Javier Palpán-Flores, Alexis J Rodriguez-Dominguez, Victor Rodríguez de Cía, Javier Hernández-García, Borja J Romero Martínez, Manuel Alejandro De Los Rios, Cristobal Egea, Javier |
| author |
Valencia, Inés |
| author_facet |
Valencia, Inés Pastor-Martínez, Andrea Decouty-Pérez, Céline López-Rodriguez, Ana Belén Álvarez-Rubal, María Ramos Alonso, Eva Calzaferri, Francesco Zamorano-Fernández, Jorge Giner-García, Javier Palpán-Flores, Alexis J Rodriguez-Dominguez, Victor Rodríguez de Cía, Javier Hernández-García, Borja J Romero Martínez, Manuel Alejandro De Los Rios, Cristobal Egea, Javier |
| author_role |
author |
| author2 |
Pastor-Martínez, Andrea Decouty-Pérez, Céline López-Rodriguez, Ana Belén Álvarez-Rubal, María Ramos Alonso, Eva Calzaferri, Francesco Zamorano-Fernández, Jorge Giner-García, Javier Palpán-Flores, Alexis J Rodriguez-Dominguez, Victor Rodríguez de Cía, Javier Hernández-García, Borja J Romero Martínez, Manuel Alejandro De Los Rios, Cristobal Egea, Javier |
| author2_role |
author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Universidad Complutense de Madrid |
| dc.subject.none.fl_str_mv |
61 615.01/.03 577.2 612.8 Interleukin-1 beta Neuroinflammation P2X7 receptor Traumatic brain injury Ciencias Biomédicas Farmacología (Farmacia) Biología molecular (Farmacia) Neurociencias (Farmacia) 3214 Toxicología 3209.90 Farmacología Experimental 3213.08 Neurocirugía |
| topic |
61 615.01/.03 577.2 612.8 Interleukin-1 beta Neuroinflammation P2X7 receptor Traumatic brain injury Ciencias Biomédicas Farmacología (Farmacia) Biología molecular (Farmacia) Neurociencias (Farmacia) 3214 Toxicología 3209.90 Farmacología Experimental 3213.08 Neurocirugía |
| description |
Background and purpose: Traumatic brain injury (TBI) is considered to be a leadingcause of mortality and disability worldwide. After TBI, innate immunity is rapidly acti-vated in response to damage-associated molecular patterns, such as ATP release,recognised by P2X7 receptors. The P2X7-NLRP3 inflammasome axis has been identi-fied as one of the main players in neuroinflammation. This study aimed to validateP2X7 receptors as therapeutic target for traumatic brain injury. Experimental approach: P2X7 receptors were studied by genetic and pharmacologi-cal approaches. Six non-nucleotide purine derivatives were evaluated as P2X7 antag-onists. Compounds that prevented LPS + ATP-induced IL-1β release from primaryglial cultures were investigated in the closed-head injury TBI model in vivo in malemice. Finally, we evaluated soluble (s)P2X7 receptor plasmatic levels in a cohort ofTBI patients. Key results: P2rx7 / mice showed an exaggerated inflammatory response 24 hpost-TBI compared to control mice. However, animals treated with the selective P2X7 antagonist JNJ-47965567 (30 mg kg 1 i.p.) 30 min post-TBI showed improvedneurological and inflammatory parameters. The purine derivative ITH15004 was themost potent compound reducing IL-1β production in vitro. When administered in vivo30 min post-TBI, ITH15004 (1 mg kg 1 i.p.) improved both neuro-behavioural andinflammatory markers at 24 h. In TBI patients, we showed a tendency towardsincrease in circulating sP2X7 receptor levels at 24 and 72 h post-TBI. Conclusions and implications: These results highlight the importance of P2X7 recep-tors in the acute phase of TBI and present ITH15004 as a promising pharmacologicaltool to counteract P2X7 receptor-dependent neuroinflammation in vivo. |
| publishDate |
2025 |
| dc.date.none.fl_str_mv |
2025 2025-01-01 2025 2025-01-01 |
| dc.type.none.fl_str_mv |
journal article http://purl.org/coar/resource_type/c_6501 VoR http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| dc.type.openaire.fl_str_mv |
info:eu-repo/semantics/article |
| format |
article |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/20.500.14352/123825 |
| url |
https://hdl.handle.net/20.500.14352/123825 |
| dc.language.none.fl_str_mv |
Inglés eng |
| language_invalid_str_mv |
Inglés |
| language |
eng |
| dc.relation.none.fl_str_mv |
Instituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII) PI19%2F00082 LAS PROTEINAS DEL INFLAMASOMA COMO NUEVAS DIANAS MOLECULARES PARA EL DIAGNOSTICO, PRONOSTICO Y TRATAMIENTO DEL TRAUMATISMO CRANEOENCEFALICO Instituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 Plan Estatal de Investigación Científica, Técnica y de Innovación 2021-2023 PI22%2F00362 La proteína amiloide sérica A1 como nueva diana molecular para la detección del daño secundario, pronóstico y tratamiento del traumatismo craneoencefálico. Agencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023 PID2022-140164OB-C21 NEUROTOXICIDAD INDUCIDA POR MECLORETAMINA, MECANISMOS MOLECULARES DE NEUROTOXICIDAD Y ABORDAJE TERAPEUTICO CON MELATONINA European Commission http://dx.doi.org/10.13039/501100000780 Horizon 2020 Framework Programme 766124 |
| dc.rights.none.fl_str_mv |
open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| dc.rights.openaire.fl_str_mv |
info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
open access http://purl.org/coar/access_right/c_abf2 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ |
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openAccess |
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application/pdf |
| dc.publisher.none.fl_str_mv |
Wiley |
| publisher.none.fl_str_mv |
Wiley |
| dc.source.none.fl_str_mv |
reponame:Docta Complutense instname:Universidad Complutense de Madrid (UCM) |
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Universidad Complutense de Madrid (UCM) |
| reponame_str |
Docta Complutense |
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Docta Complutense |
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|
| repository.mail.fl_str_mv |
|
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1869407501219266560 |
| spelling |
Pharmacological evaluation of non-nucleotide purine derivatives as P2X7 antagonists for the treatment of neuroinflammation in traumatic brain injuryValencia, InésPastor-Martínez, AndreaDecouty-Pérez, CélineLópez-Rodriguez, Ana BelénÁlvarez-Rubal, MaríaRamos Alonso, EvaCalzaferri, FrancescoZamorano-Fernández, JorgeGiner-García, JavierPalpán-Flores, Alexis JRodriguez-Dominguez, VictorRodríguez de Cía, JavierHernández-García, Borja JRomero Martínez, Manuel AlejandroDe Los Rios, CristobalEgea, Javier61615.01/.03577.2612.8Interleukin-1 betaNeuroinflammationP2X7 receptorTraumatic brain injuryCiencias BiomédicasFarmacología (Farmacia)Biología molecular (Farmacia)Neurociencias (Farmacia)3214 Toxicología3209.90 Farmacología Experimental3213.08 NeurocirugíaBackground and purpose: Traumatic brain injury (TBI) is considered to be a leadingcause of mortality and disability worldwide. After TBI, innate immunity is rapidly acti-vated in response to damage-associated molecular patterns, such as ATP release,recognised by P2X7 receptors. The P2X7-NLRP3 inflammasome axis has been identi-fied as one of the main players in neuroinflammation. This study aimed to validateP2X7 receptors as therapeutic target for traumatic brain injury. Experimental approach: P2X7 receptors were studied by genetic and pharmacologi-cal approaches. Six non-nucleotide purine derivatives were evaluated as P2X7 antag-onists. Compounds that prevented LPS + ATP-induced IL-1β release from primaryglial cultures were investigated in the closed-head injury TBI model in vivo in malemice. Finally, we evaluated soluble (s)P2X7 receptor plasmatic levels in a cohort ofTBI patients. Key results: P2rx7 / mice showed an exaggerated inflammatory response 24 hpost-TBI compared to control mice. However, animals treated with the selective P2X7 antagonist JNJ-47965567 (30 mg kg 1 i.p.) 30 min post-TBI showed improvedneurological and inflammatory parameters. The purine derivative ITH15004 was themost potent compound reducing IL-1β production in vitro. When administered in vivo30 min post-TBI, ITH15004 (1 mg kg 1 i.p.) improved both neuro-behavioural andinflammatory markers at 24 h. In TBI patients, we showed a tendency towardsincrease in circulating sP2X7 receptor levels at 24 and 72 h post-TBI. Conclusions and implications: These results highlight the importance of P2X7 recep-tors in the acute phase of TBI and present ITH15004 as a promising pharmacologicaltool to counteract P2X7 receptor-dependent neuroinflammation in vivo.WileyUniversidad Complutense de Madrid20252025-01-0120252025-01-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.14352/123825reponame:Docta Complutenseinstname:Universidad Complutense de Madrid (UCM)InglésengInstituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII) PI19%2F00082 LAS PROTEINAS DEL INFLAMASOMA COMO NUEVAS DIANAS MOLECULARES PARA EL DIAGNOSTICO, PRONOSTICO Y TRATAMIENTO DEL TRAUMATISMO CRANEOENCEFALICOInstituto de Salud Carlos III http://dx.doi.org/10.13039/501100004587 Plan Estatal de Investigación Científica, Técnica y de Innovación 2021-2023 PI22%2F00362 La proteína amiloide sérica A1 como nueva diana molecular para la detección del daño secundario, pronóstico y tratamiento del traumatismo craneoencefálico.Agencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023 PID2022-140164OB-C21 NEUROTOXICIDAD INDUCIDA POR MECLORETAMINA, MECANISMOS MOLECULARES DE NEUROTOXICIDAD Y ABORDAJE TERAPEUTICO CON MELATONINAEuropean Commission http://dx.doi.org/10.13039/501100000780 Horizon 2020 Framework Programme 766124open accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:docta.ucm.es:20.500.14352/1238252026-06-02T12:44:21Z |
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15.812429 |