title: P2X7 receptor inhibition interrupts the progression of seizures in immature rats and reduces hippocampal damage.
abstract: OBJECTIVE
  Early-life seizures, particularly when prolonged, may be harmful to the brain. Current pharmacotherapy is often ineffective; therefore, novel neuro- and/or glio-transmitter systems should be explored for targeting. The P2X7 receptor is a cation-permeable channel with trophic and excitability effects on neurons and glia which is activated by high amounts of ATP that may be released in the setting of injury after severe seizures. Here, we tested the effects of A-438079, a potent and selective P2X7 receptor antagonist in a lesional model of early-life status epilepticus.
  
  
  METHODS
  Seizures were induced by intra-amygdala kainic acid in 10-day-old rat pups. Electrographic seizure severity, changes to P2X7 receptor expression, inflammatory responses and histological effects were evaluated.
  
  
  RESULTS
  Seizures induced by intra-amygdala kainic acid increased levels of P2X7 receptor protein and interleukin-1β and caused significant cell death within the ipsilateral hippocampus. A-438079 rapidly reached the brain following systemic injection in P10 rats. Intraperitoneal injection of A-438079 (5 and 15 mg/kg) 60 min after triggering seizures reduced seizure severity and neuronal death within the hippocampus. A-438079 had superior neuroprotective effects compared with an equally seizure-suppressive dose of phenobarbital (25 mg/kg).
  
  
  CONCLUSIONS
  These results suggest P2X7 receptor antagonists may be suitable as frontline or adjunctive treatments of pediatric status epilepticus or other early-life seizures, particularly when associated with brain damage.
authors.affiliation: Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Mesuret
authors.forename: Tobias
authors.initials: T
authors.lastname: Engel
authors.forename: Ellen V
authors.initials: EV
authors.lastname: Hessel
authors.forename: Amaya
authors.initials: A
authors.lastname: Sanz-Rodriguez
authors.forename: Alba
authors.initials: A
authors.lastname: Jimenez-Pacheco
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Miras-Portugal
authors.forename: Miguel
authors.initials: M
authors.lastname: Diaz-Hernandez
authors.forename: David C
authors.initials: DC
authors.lastname: Henshall
mesh_terms: D000679:Amygdala / Q000293:injuries / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D002034:Bumetanide / Q000494:pharmacology / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D058920:Purinergic P2X Receptor Antagonists / Q000627:therapeutic use*; D011725:Pyridines / Q000378:metabolism / Q000627:therapeutic use*; D011799:Quinazolines; D051381:Rats; D017207:Rats, Sprague-Dawley; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D013777:Tetrazoles / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: C523668:3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methylpyridine; D018690:Excitatory Amino Acid Agonists; D058920:Purinergic P2X Receptor Antagonists; D011725:Pyridines; D011799:Quinazolines; D049994:Sodium Potassium Chloride Symporter Inhibitors; D013777:Tetrazoles; C499206:luotonin B; D002034:Bumetanide; D007608:Kainic Acid
keywords: Apoptosis; Development; Hippocampal sclerosis; Neuroinflammation; Status epilepticus
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