%0 Journal Article
%A Valencia, Inés
%A Pastor-Martínez, Andrea
%A Decouty-Pérez, Céline
%A Lopez-Rodriguez, Ana Belen
%A Álvarez-Rubal, María
%A Ramos Alonso, Eva
%A Calzaferri, Francesco
%A Zamorano-Fernández, Jorge
%A Giner-García, Javier
%A Palpán-Flores, Alexis J
%A Rodríguez-Domínguez, Víctor
%A Rodríguez de Cía, Javier
%A Hernández-García, Borja J
%A Romero Martínez, Manuel Alejandro
%A de Los Ríos, Cristóbal
%A Egea, Javier
%T Pharmacological evaluation of non-nucleotide purine derivatives as P2X7 antagonists for the treatment of neuroinflammation in traumatic brain injury.
%D 2025
%@ 0007-1188
%U https://hdl.handle.net/20.500.14352/121900
%X 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.
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