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Updated: Mar 8, 2026
Continuous Video Electroencephalogram during Hypoxia-Ischemia in Neonatal Mice
Published on: June 11, 2020
Effects of P2X7 receptor antagonists on hypoxia-induced neonatal seizures in mice
Natalia Rodriguez-Alvarez1, Eva M Jimenez-Mateos1, Tobias Engel1
1Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
Insights
Neonatal seizures from hypoxic-ischemic encephalopathy (HIE) are common. Targeting the P2X7 receptor (P2X7R) with antagonists reduced seizure activity during hypoxia in a mouse model, suggesting a potential therapeutic role.
Area of Science:
- Neuroscience
- Neonatal Neurology
- Neuroinflammation
Background:
- Neonatal seizures frequently result from hypoxic-ischemic encephalopathy (HIE).
- Current treatments like phenobarbital are often ineffective for neonatal seizures.
- The P2X7 receptor (P2X7R), activated by ATP, is implicated in tissue injury and seizures.
Purpose of the Study:
- To investigate the role of the P2X7 receptor (P2X7R) in neonatal seizures induced by hypoxia.
- To assess the efficacy of P2X7R antagonists in a mouse model of neonatal hypoxia-induced seizures.
Main Methods:
- Neonatal seizures were induced in P7 mouse pups via global hypoxia (5% O2 for 15 min).
- P2X7R expression levels were analyzed post-hypoxia.
- EEG recordings were used to evaluate seizure activity following administration of P2X7R antagonists (A-438079 and JNJ-47965567).
Main Results:
- Hypoxia induced electrographic seizures in mouse pups, with increased P2X7R expression in the hippocampus and neocortex.
- P2X7R antagonists A-438079 and JNJ-47965567 significantly reduced seizure number and EEG power during hypoxia.
- Antagonist treatment also decreased markers of inflammation and microglia activation, but did not affect post-hypoxia seizures.
Conclusions:
- Hypoxia-induced neonatal seizures alter purinergic and neuroinflammatory signaling pathways.
- P2X7R antagonists show potential for treating seizures during acute hypoxic events.
- Limitations exist for P2X7R antagonists in managing post-hypoxia seizures in HIE.
Abstract:
Neonatal seizures are a common consequence of hypoxic/ischemic encephalopathy (HIE). Phenobarbital remains the frontline treatment for neonatal seizures but is often ineffective. The P2X7 receptor (P2X7R) is a cell surface-expressed ionotropic receptor activated by high amounts of ATP which may be released during seizures or as a consequence of tissue injury. Here, we explored the role of the P2X7R in a mouse model of neonatal seizures induced by hypoxia. Exposure of postnatal day 7 (P7) mouse pups to global hypoxia (5% O2 for 15 min) produced electrographically-defined seizures with behavioural correlates that persisted after restitution of normoxia. Expression of the P2X7R showed age-dependent increases in the hippocampus and neocortex of developing mice and was present in human neonatal brain. P2X7R transcript and protein levels were increased 24 h after neonatal hypoxia-induced seizures in mouse pups. EEG recordings in pups determined that injection of the P2X7R antagonist A-438079 (25 mg/kg-1, intraperitoneal) reduced electrographic seizure number, EEG power and spiking during hypoxia. A-438079 did not reduce post-hypoxia seizures. Caspase-1 processing and molecular markers of inflammation and microglia were reduced in A438079-treated mice. Electrographic seizure-suppressive effects were also observed with a second P2X7R antagonist, JNJ-47965567, in the same model. The present study shows hypoxia-induced seizures alter expression of purinergic and neuroinflammatory signalling components and suggest potential applications but also limitations of the P2X7R as a target for the treatment of HIE and other causes of neonatal seizures.
