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 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 infla...
| Autores: | , , , , , , , , , , , , , , , |
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| 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:20.500.14352/121900 |
| Acesso em linha: | https://hdl.handle.net/20.500.14352/121900 |
| Access Level: | acceso abierto |
| Palavra-chave: | 615.03 616.8 Interleukin‐1 beta Neuroinflammation P2X7 receptor Traumatic brain injury Farmacología (Medicina) 3209.90 Farmacología Experimental 3205.07 Neurología |
| Resumo: | 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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