P2X7 Forges Ahead in Neonatal Hypoxia

Abstract

The P2X7 Receptor Contributes to Seizures and Inflammation-Driven Long-Lasting Brain Hyperexcitability Following Hypoxia in Neonatal Mice Smith J, Menéndez Méndez A, Alves M, Parras A, Conte G, Bhattacharya A, Ceusters M, Nicke A, Henshall DC, Jimenez-Mateos EM, Engel T. Br J Pharmacol. 2023. Epub ahead of print. PMID: 36637008. doi:10.1111/bph.16033 Background and Purpose: Neonatal seizures represent a clinical emergency. However, current anti-seizure medications fail to resolve seizures in ∼50% of infants. The P2X7 receptor (P2X7 R) is an important driver of inflammation, and evidence suggests that P2X7 R contributes to seizures and epilepsy in adults. However, no genetic proof has yet been provided to determine what contribution P2X7 R makes to neonatal seizures, its effects on inflammatory signalling during neonatal seizures, and the therapeutic potential of P2X7R-based treatments on long-lasting brain excitability. Experimental Approach: Neonatal seizures were induced by global hypoxia in 7-day-old mouse pups (P7). The role of P2X7Rs during seizures was analysed in P2X7R-overexpressing and knockout mice. Treatment of wild-type mice after hypoxia with the P2X7 R antagonist JNJ-47965567 was used to determine the effects of the P2X7 R on long-lasting brain hyperexcitability. Cell type-specific P2X7 R expression was analysed in P2X7R-EGFP reporter mice. RNA sequencing was used to monitor P2X7R-dependent hippocampal downstream signalling. Key Results: P2X7 R deletion reduced seizure severity, whereas P2X7 R overexpression exacerbated seizure severity and reduced responsiveness to anti-seizure medication. P2X7 R deficiency led to an anti-inflammatory phenotype in microglia, and treatment of mice with a P2X7 R antagonist reduced long-lasting brain hyperexcitability. RNA sequencing identified several pathways altered in P2X7 R knockout mice after neonatal hypoxia, including a down-regulation of genes implicated in inflammation and glutamatergic signalling. Conclusion and Implications: Treatments based on targeting the P2X7 R may represent a novel therapeutic strategy for neonatal seizures with P2X7Rs contributing to the generation of neonatal seizures, driving inflammatory processes and long-term hyperexcitability states.