title: Effects of P2X7 receptor antagonists on hypoxia-induced neonatal seizures in mice.
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% O2for 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.
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Rodriguez-Alvarez
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Jimenez-Mateos
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Engel
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
authors.forename: Sean
authors.initials: S
authors.lastname: Quinlan
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland.
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Reschke
authors.affiliation: Division of Population Health Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Ronán M
authors.initials: RM
authors.lastname: Conroy
authors.affiliation: Janssen Research & Development, LLC, San Diego, CA, USA.
authors.forename: Anindya
authors.initials: A
authors.lastname: Bhattacharya
authors.affiliation: Irish Centre for Fetal and Neonatal Translational Research (INFANT) Cork, Ireland.
authors.forename: Geraldine B
authors.initials: GB
authors.lastname: Boylan
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland; Irish Centre for Fetal and Neonatal Translational Research (INFANT) Cork, Ireland. Electronic address: dhenshall@rcsi.ie.
authors.forename: David C
authors.initials: DC
authors.lastname: Henshall
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology*; D020170:Caspase 1 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008810:Mice, Inbred C57BL; D019579:Neocortex / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: C523668:3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methylpyridine; D000927:Anticonvulsants; C000590736:JNJ-47965567; D010879:Piperazines; D058920:Purinergic P2X Receptor Antagonists; D011725:Pyridines; D058486:Receptors, Purinergic P2X7; D013777:Tetrazoles; D009536:Niacinamide; D020170:Caspase 1
keywords: Hypoxia; Inflammation; Neonatal seizures; P2X7; Purinergic receptors