P2X7 receptor inhibition interrupts the progression of seizures in immature rats and reduces hippocampal damage.

Abstract

AIMS:

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: Guillaume Mesuret, Tobias Engel, Ellen V Hessel, Amaya Sanz-Rodriguez, Alba Jimenez-Pacheco, M Teresa Miras-Portugal, Miguel Diaz-Hernandez, David C Henshall
• Journal: CNS neuroscience & therapeutics (CNS Neurosci Ther) Vol. 20 Issue 6 Pg. 556-64 (Jun 2014) ISSN: 1755-5949 [Electronic] England
• PMID: 24750893 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 John Wiley & Sons Ltd.

Chemical References

• 3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methylpyridine
• Excitatory Amino Acid Agonists
• Purinergic P2X Receptor Antagonists
• Pyridines
• Quinazolines
• Sodium Potassium Chloride Symporter Inhibitors
• Tetrazoles
• luotonin B
• Bumetanide
• Kainic Acid

Topics

• Amygdala (injuries, physiology)
• Animals
• Animals, Newborn
• Bumetanide (pharmacology, therapeutic use)
• Cell Death (drug effects)
• Disease Models, Animal
• Disease Progression
• Dose-Response Relationship, Drug
• Excitatory Amino Acid Agonists (toxicity)
• Female
• Hippocampus (drug effects, metabolism)
• Kainic Acid (toxicity)
• Male
• Purinergic P2X Receptor Antagonists (therapeutic use)
• Pyridines (metabolism, therapeutic use)
• Quinazolines
• Rats
• Rats, Sprague-Dawley
• Sodium Potassium Chloride Symporter Inhibitors (pharmacology, therapeutic use)
• Status Epilepticus (chemically induced, drug therapy, pathology)
• Tetrazoles (metabolism, therapeutic use)