RT Journal Article
T1 Pharmacological evaluation of non-nucleotide purine derivatives as P2X7 antagonists for the treatment of neuroinflammation in traumatic brain injury.
A1 Valencia, Inés
A1 Pastor-Martínez, Andrea
A1 Decouty-Pérez, Céline
A1 Lopez-Rodriguez, Ana Belen
A1 Álvarez-Rubal, María
A1 Ramos Alonso, Eva
A1 Calzaferri, Francesco
A1 Zamorano-Fernández, Jorge
A1 Giner-García, Javier
A1 Palpán-Flores, Alexis J
A1 Rodríguez-Domínguez, Víctor
A1 Rodríguez de Cía, Javier
A1 Hernández-García, Borja J
A1 Romero Martínez, Manuel Alejandro
A1 de Los Ríos, Cristóbal
A1 Egea, Javier
AB Background and purpose:Traumatic brain injury (TBI) is considered to be a leading cause of mortality and disability worldwide. After TBI, innate immunity is rapidly activated in response to damage-associated molecular patterns, such as ATP release, recognised by P2X7 receptors. The P2X7-NLRP3 inflammasome axis has been identified as one of the main players in neuroinflammation. This study aimed to validate P2X7 receptors as therapeutic target for traumatic brain injury.Experimental approach:P2X7 receptors were studied by genetic and pharmacological approaches. Six non-nucleotide purine derivatives were evaluated as P2X7 antagonists. Compounds that prevented LPS + ATP-induced IL-1β release from primary glial cultures were investigated in the closed-head injury TBI model in vivo in male mice. Finally, we evaluated soluble (s)P2X7 receptor plasmatic levels in a cohort of TBI patients.Key results:P2rx7−/− mice showed an exaggerated inflammatory response 24 h post-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 improved neurological and inflammatory parameters. The purine derivative ITH15004 was the most potent compound reducing IL-1β production in vitro. When administered in vivo 30 min post-TBI, ITH15004 (1 mg kg−1 i.p.) improved both neuro-behavioural and inflammatory markers at 24 h. In TBI patients, we showed a tendency towards increase in circulating sP2X7 receptor levels at 24 and 72 h post-TBI.Conclusions and implications:These results highlight the importance of P2X7 receptors in the acute phase of TBI and present ITH15004 as a promising pharmacological tool to counteract P2X7 receptor-dependent neuroinflammation in vivo.
PB Nature Publishing Group
SN 0007-1188
YR 2025
FD 2025
LK https://hdl.handle.net/20.500.14352/121900
UL https://hdl.handle.net/20.500.14352/121900
LA eng
NO Valencia, I., Pastor-Martínez, A., Decouty-Pérez, C., Lopez-Rodriguez, A. B., Álvarez-Rubal, M., Ramos, E., Calzaferri, F., Zamorano-Fernández, J., Giner-García, J., Palpán-Flores, A. J., Rodríguez-Domínguez, V., Rodríguez de Cía, J., Hernández-García, B. J., Romero, A., de los Ríos, C., & Egea, J. (2025). Pharmacological evaluation of non-nucleotide purine derivatives as P2X7 antagonists for the treatment of neuroinflammation in traumatic brain injury. British Journal of Pharmacology, 1–17. https://doi.org/10.1111/bph.70108
NO Justificación de autores:Javier Egea conceptualised and administered the work. Javier Egea and Inés Valencia supervised the research activity planning. Inés Valencia, Andrea Pastor-Martínez, Céline Decouty-Pérez, Ana Belen Lopez-Rodriguez, María Álvarez-Rubal, Eva Ramos, Javier Rodríguez de Cía and Alejandro Romero performed the experiments. Inés Valencia and Andrea Pastor-Martínez performed formal analysis of the results. Francesco Calzaferri and Cristóbal de los Ríos developed compound synthesis methodology. Jorge Zamorano-Fernández, Javier Giner-García, Alexis J. Palpán-Flores and Víctor Rodríguez-Domínguez provided patients samples. Javier Egea and Inés Valencia drafted the manuscript. All authors participated in reviewing and editing the last version of the manuscript.Becas:PID2022-140164OB-C21CNS2022/135290CD22/00101FI23/00135
NO Fundación Mutua Madrileña
NO Instituto de Salud Carlos III
NO Ministerio de Ciencia, Innovación y Universidades (España)
NO European Commission
DS Docta Complutense
RD 13 sept 2025