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...

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Detalles Bibliográficos
Autores: 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
Tipo de recurso: artículo
Fecha de publicación:2025
País:España
Institución:Universidad Complutense de Madrid (UCM)
Repositorio:Docta Complutense
Idioma:inglés
OAI Identifier:oai:docta.ucm.es:20.500.14352/123825
Acceso en línea:https://hdl.handle.net/20.500.14352/123825
Access Level:acceso abierto
Palabra clave: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
Descripción
Sumario: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.

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