Valencia Inés, Pastor-Martínez Andrea, Decouty-Pérez Céline, Lopez-Rodriguez Ana Belen, Álvarez-Rubal María, Ramos Eva, Calzaferri Francesco, Zamorano-Fernández Jorge, Giner-García Javier, Palpán-Flores Alexis J, Rodríguez-Domínguez Víctor, Rodríguez de Cía Javier, Hernández-García Borja J, Romero Alejandro, de Los Ríos Cristóbal, Egea Javier
Laboratory of Molecular Neuroinflammation and Neuronal Plasticity, Research Unit, Hospital Universitario Santa Cristina. Instituto de Investigación Sanitaria Princesa (IIS-IP), Madrid, Spain.
Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain.
Br J Pharmacol. 2025 Jun 18. doi: 10.1111/bph.70108.
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.
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.
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 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 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.
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.
创伤性脑损伤（TBI）被认为是全球范围内致死和致残的主要原因之一。TBI后，机体通过模式识别受体识别损伤相关分子模式（如ATP释放）快速激活天然免疫。P2X7-NLRP3炎性小体轴被认为是神经炎症的主要驱动因素之一。本研究旨在验证P2X7受体作为创伤性脑损伤治疗靶点的可能性。
采用遗传学和药理学方法研究P2X7受体。评估六种非核苷酸嘌呤衍生物作为P2X7拮抗剂的活性。在雄性小鼠的闭合性颅脑损伤TBI模型中，研究能够阻止LPS + ATP诱导原代神经胶质细胞释放IL-1β的化合物。最后，我们评估了一组TBI患者血浆中可溶性（s）P2X7受体水平。
与对照小鼠相比，P2rx7小鼠在TBI后24小时表现出过度的炎症反应。然而，在TBI后30分钟腹腔注射选择性P2X7拮抗剂JNJ-47965567（30 mg/kg）的动物，其神经和炎症参数得到改善。嘌呤衍生物ITH15004是体外降低IL-1β产生最有效的化合物。在TBI后体内30分钟给予ITH15004（1mg/kg腹腔注射），在24小时时改善了神经行为和炎症指标。在TBI患者中，我们发现TBI后24小时和72小时循环sP2X7受体水平有升高趋势。
这些结果突出了P2X7受体在TBI急性期的重要性，并表明ITH15004是一种有前景的体内对抗P2X7受体依赖性神经炎症的药理学工具。
