title: Seizure suppression and neuroprotection by targeting the purinergic P2X7 receptor during status epilepticus in mice.
abstract: Prolonged seizures [status epilepticus (SE)] constitute a neurological emergency that can permanently damage the brain. SE results from a failure of the normal mechanisms to terminate seizures; in particular, γ-amino butyric acid-mediated inhibition, and benzodiazepine anticonvulsants are often incompletely effective. ATP acts as a fast neurotransmitter via ionotropic ligand-gated P2X receptors. Here we report that SE induced by intra-amygdala kainic acid in mice selectively increased hippocampal levels of P2X7 receptors relative to other P2X receptors. Using transgenic P2X7 reporter mice expressing enhanced green fluorescent protein, we identify dentate granule neurons as the major cell population transcribing the P2X7 receptor after SE. Pretreatment of mice with an intracerebroventricular microinjection of 1.75 nmol A438079, a P2X7 receptor antagonist, reduced seizure duration by 58% and reduced seizure-induced neuronal death by 61%. Injection of brilliant blue G (1 pmol), another selective antagonist, reduced seizure duration by 48% and was also neuroprotective. A438079 was seizure-suppressive when injected shortly after induction of SE, and coinjection of A438079 with lorazepam 60 min after triggering SE, when electrographic seizure-responsiveness to lorazepam had decreased, also terminated SE. Our results suggest that P2X7 receptor antagonists may be a promising class of drug for seizure abrogation and neuroprotection in SE.
authors.affiliation: Department of Physiology and 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.forename: Rosa
authors.initials: R
authors.lastname: Gomez-Villafuertes
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Tanaka
authors.forename: Guillaume
authors.initials: G
authors.lastname: Mesuret
authors.forename: Amaya
authors.initials: A
authors.lastname: Sanz-Rodriguez
authors.forename: Paula
authors.initials: P
authors.lastname: Garcia-Huerta
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Miras-Portugal
authors.forename: David C
authors.initials: DC
authors.lastname: Henshall
authors.forename: Miguel
authors.initials: M
authors.lastname: Diaz-Hernandez
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D007608:Kainic Acid / Q000494:pharmacology; D008140:Lorazepam / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D058911:Purinergic P2X Receptor Agonists / Q000494:pharmacology; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
chemical_list: D000927:Anticonvulsants; D018690:Excitatory Amino Acid Agonists; D053583:Interleukin-1beta; D018696:Neuroprotective Agents; D058911:Purinergic P2X Receptor Agonists; D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7; D018698:Glutamic Acid; D000255:Adenosine Triphosphate; D008140:Lorazepam; D007608:Kainic Acid