Pharmacological evaluation of non‐nucleotide purine derivatives as P2X7 antagonists for the treatment of neuroinflammation in traumatic brain injury

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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.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.