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Pharmacological evaluation of novel non-nucleotide purine derivatives as P2X7R antagonists for the treatment of neuroinflammation in traumatic brain injury
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  • Ines Valencia,
  • Andrea Pastor-Martínez,
  • Celine Decouty-Pérez,
  • Ana Lopez-Rodriguez,
  • María Álvarez-Rubal,
  • Francesco Calzaferri,
  • Jorge Zamorano-Fernández,
  • Javier Giner-García,
  • Alexis Palpán-Flores,
  • Victor Rodríguez-Domínguez,
  • Javier Rodriguez-De-Cía,
  • Borja Hernández-García,
  • Cristobal de los Rios,
  • Javier Egea
Ines Valencia
Laboratory of Molecular Neuroinflammation and Neuronal Plasticity, Research Unit, Hospital Universitario Santa Cristina. Instituto de Investigación Sanitaria Princesa
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Andrea Pastor-Martínez
Laboratory of Molecular Neuroinflammation and Neuronal Plasticity, Research Unit, Hospital Universitario Santa Cristina. Instituto de Investigación Sanitaria Princesa
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Celine Decouty-Pérez
Laboratory of Molecular Neuroinflammation and Neuronal Plasticity, Research Unit, Hospital Universitario Santa Cristina. Instituto de Investigación Sanitaria Princesa
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Ana Lopez-Rodriguez
Laboratory of Molecular Neuroinflammation and Neuronal Plasticity, Research Unit, Hospital Universitario Santa Cristina. Instituto de Investigación Sanitaria Princesa
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María Álvarez-Rubal
Laboratory of Molecular Neuroinflammation and Neuronal Plasticity, Research Unit, Hospital Universitario Santa Cristina. Instituto de Investigación Sanitaria Princesa
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Francesco Calzaferri
Royal College of Surgeons in Ireland
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Jorge Zamorano-Fernández
Servicio de Neurocirugía, Hospital Universitario La Paz
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Javier Giner-García
Servicio de Neurocirugía, Hospital Universitario La Paz
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Alexis Palpán-Flores
Servicio de Neurocirugía, Hospital Universitario La Paz
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Victor Rodríguez-Domínguez
Servicio de Neurocirugía, Hospital Universitario La Paz
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Javier Rodriguez-De-Cía
Hospital Universitario Santa Cristina
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Borja Hernández-García
Servicio de Neurocirugía, Hospital Universitario La Paz
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Cristobal de los Rios
Universidad Rey Juan Carlos
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Javier Egea
Laboratory of Molecular Neuroinflammation and Neuronal Plasticity, Research Unit, Hospital Universitario Santa Cristina. Instituto de Investigación Sanitaria Princesa

Corresponding Author:[email protected]

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Abstract

Background and purpose. Traumatic brain injury (TBI) is an acute brain lesion considered as one of the leading causes of mortality and disability worldwide. After TBI, innate immunity is rapidly activated in response to damage-associated molecular patterns, such as ATP release, recognized by P2X7 purinergic receptors (P2X7R). The P2X7R-NLRP3 inflammasome axis has been identified as one of the main actors in neuroinflammation. Therefore, this study aimed to validate P2X7R as therapeutic target in TBI. Experimental approach. P2X7R was validated through genetic and pharmacological approaches. Six non-nucleotide purine derivatives were evaluated as P2X7R 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. Finally, we evaluated sP2X7R plasmatic levels in a cohort of TBI patients. Key results. p2x7 -/- mice showed an exaggerated inflammatory response 24 h post-TBI compared to control mice. However, animals treated with the selective P2X7R 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 neurobehavioral and inflammatory markers at 24 h. In TBI patients, enhanced levels of circulating sP2X7R correlated with the lesion severity 72 h post-TBI and with unfavourable outcomes 24 h post-TBI. Conclusion and implications. These results highlight the importance of P2X7R in the acute phase of TBI and present ITH15004 as a new pharmacological tool to counteract P2X7R-dependent neuroinflammation in vivo.