P2X7R antagonism suppresses long-lasting brain hyperexcitability following traumatic brain injury in mice

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Purpose: Post-traumatic epilepsy (PTE) is one of the most common life-quality reducing consequences of traumatic brain injury (TBI).However, to date there are no pharmacological approaches to predict or to prevent the development of PTE.The P2X7 receptor (P2X7R) is a cationic ATP-dependent membrane channel that is expressed throughout the brain.While increasing evidence suggests a role for the P2X7R during seizures and epilepsy, it is unclear if changes in P2X7R expression can predict TBI-induced epilepsy development, and whether P2X7R antagonism can protect against long-lasting brain hyperexcitability caused by TBI.Methods: TBI was induced in adult male mice using the controlled cortical impact model (CCI).To test the anti-epileptogenic effects of P2X7R antagonism, mice were treated with brain-penetrant P2X7R antagonists JNJ-54175446 (30 mg/kg) or AFC-5128 (30 mg/kg) for 7 days post-CCI.The cell-type specific effects of P2X7Rs on TBI-induced hyperexcitability were analyzed in mice lacking exon 2 of the P2rx7 gene selectively in microglia (P2rx7:Cx3cr1-Cre).Static positron emission tomography (PET) via an intravenous injection of the P2X7R radioligand 18 F-JNJ-64413739 and magnetic resonance imaging (MRI) were conducted twice during the first-and third-week post-injury.Results: Following TBI, while there were no obvious changes in P2X7R protein levels in the ipsilateral hippocampus post-injury, there was a delayed increase in P2X7R protein levels in the ipsilateral cortex at Ivyspring International

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