{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T13:51:09Z","timestamp":1790171469976,"version":"4.1.0"},"reference-count":48,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T00:00:00Z","timestamp":1750204800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec><jats:title>Background and purpose<\/jats:title><jats:p>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\u2010associated molecular patterns, such as ATP release, recognised by P2X7 receptors. The P2X7\u2010NLRP3 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental approach<\/jats:title><jats:p>P2X7 receptors were studied by genetic and pharmacological approaches. Six non\u2010nucleotide purine derivatives were evaluated as P2X7 antagonists. Compounds that prevented LPS\u2009+\u2009ATP\u2010induced IL\u20101\u03b2 release from primary glial cultures were investigated in the closed\u2010head injury TBI model <jats:italic>in vivo<\/jats:italic> in male mice. Finally, we evaluated soluble (s)P2X7 receptor plasmatic levels in a cohort of TBI patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key results<\/jats:title><jats:p><jats:italic>P2rx7<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice showed an exaggerated inflammatory response 24\u2009h post\u2010TBI compared to control mice. However, animals treated with the selective P2X7 antagonist JNJ\u201047965567 (30\u2009mg\u2009kg<jats:sup>\u22121<\/jats:sup>\u00a0i.p.) 30\u2009min post\u2010TBI showed improved neurological and inflammatory parameters. The purine derivative ITH15004 was the most potent compound reducing IL\u20101\u03b2 production <jats:italic>in vitro<\/jats:italic>. When administered <jats:italic>in vivo<\/jats:italic> 30\u2009min post\u2010TBI, ITH15004 (1 mg kg<jats:sup>\u22121<\/jats:sup> i.p.) improved both neuro\u2010behavioural and inflammatory markers at 24\u2009h. In TBI patients, we showed a tendency towards increase in circulating sP2X7 receptor levels at 24 and 72\u2009h post\u2010TBI.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and implications<\/jats:title><jats:p>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\u2010dependent neuroinflammation <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.70108","type":"journal-article","created":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T19:50:38Z","timestamp":1750276238000},"page":"4693-4709","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pharmacological evaluation of non\u2010nucleotide purine derivatives as P2X7 antagonists for the treatment of neuroinflammation in traumatic brain injury"],"prefix":"10.1111","volume":"182","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6741-8554","authenticated-orcid":false,"given":"In\u00e9s","family":"Valencia","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Neuroinflammation and Neuronal Plasticity Research Unit, Hospital Universitario Santa Cristina. 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