کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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5548954 | 1556601 | 2017 | 13 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Effects of P2X7 receptor antagonists on hypoxia-induced neonatal seizures in mice Effects of P2X7 receptor antagonists on hypoxia-induced neonatal seizures in mice](/preview/png/5548954.png)
- 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.
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 15Â 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 24Â h after neonatal hypoxia-induced seizures in mouse pups. EEG recordings in pups determined that injection of the P2X7R antagonist A-438079 (25 mg/kgâ1, 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.
Journal: Neuropharmacology - Volume 116, April 2017, Pages 351-363