Valencia, InésPastor-Martínez, AndreaDecouty-Pérez, CélineLopez-Rodriguez, Ana BelenÁlvarez-Rubal, MaríaRamos Alonso, EvaCalzaferri, FrancescoZamorano-Fernández, JorgeGiner-García, JavierPalpán-Flores, Alexis JRodríguez-Domínguez, VíctorRodríguez de Cía, JavierHernández-García, Borja JRomero Martínez, Manuel Alejandrode Los Ríos, CristóbalEgea, Javier2025-06-262025-06-262025Valencia, 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.701080007-118810.1111/bph.70108https://hdl.handle.net/20.500.14352/121900Justificación 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-C21 CNS2022/135290 CD22/00101 FI23/00135Background 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.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/journal article1476-5381https://doi.org/10.1111/bph.7010840533073open access615.03616.8Interleukin‐1 betaNeuroinflammationP2X7 receptorTraumatic brain injuryFarmacología (Medicina)3209.90 Farmacología Experimental3205.07 Neurología