Effects of P2X7 receptor antagonists on hypoxia-induced neonatal seizures in mice. (April 2017)

• Record Type: Journal Article
• Authors: Rodriguez-Alvarez, Natalia; Jimenez-Mateos, Eva M.; Engel, Tobias; Quinlan, Sean; Reschke, Cristina R.; Conroy, Ronán M.; Bhattacharya, Anindya; Boylan, Geraldine B.; Henshall, David C.
• Is Part Of: Neuropharmacology. Volume 116(2017)
• Page Start: 351
• Page End: 363
• Publication Date: 2017-04
• Subjects: Neonatal seizures -- Hypoxia -- Purinergic receptors -- P2X7 -- Inflammation; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2017.01.005
• Languages: English
• ISSNs: 0028-3908

Abstract

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. Highlights: P2X receptor family expression evaluated in developing mouse brain. Neonatal hypoxia-induced seizures alter brain levels of P2X7 receptor. Pharmacologic inhibition of P2X7R reduces neonatal hypoxia-induced seizures. Results suggest novel approach to treatment of neonatal seizures.