title: P2X7 receptor antagonism reduces the severity of spontaneous seizures in a chronic model of temporal lobe epilepsy.
abstract: The available pharmacotherapy for patients with epilepsy primarily address the symptoms and are ineffective in about 40% of patients. Brain inflammation gained support as potential target for developing new therapies, especially the P2X7 receptor (P2X7R), involved in processing of IL-1β, might be an interesting candidate. This study was designed to investigate the effect of a novel P2X7R antagonist on the severity and on the number of chronic spontaneous recurrent seizures (SRS), which was unexplored until now.
  
  
  
  After one-week of vehicle treatment (20% HP-β-cyclodextrin), JNJ-42253432 was administered subcutaneously for another week under continuous video-electroencephalography monitoring (n = 17) in Sprague Dawley rats 3 months after kainic acid-induced status epilepticus. The proportion of different seizure classes, as well as the number of SRS/day were calculated for the vehicle and treatment period. In addition, post-mortem microglial activation and astrogliosis were assessed.
  
  
  
  A significant decrease of the proportion of type 4-5 SRS (p < 0.05), while an increase of type 1-3 was demonstrated (p < 0.05) from the vehicle to the treatment period. There was no effect of the P2X7R antagonist on the number of SRS/day or the glial markers.
  
  
  
  The P2X7R antagonist gave rise to a less severe profile of the chronic seizure burden without suppressing the SRS frequency. More studies are needed to unravel the underlying mechanisms of the beneficial effect on seizure severity and whether the administration of the compound during early epileptogenesis could induce long-term disease-modifying effects.
authors.affiliation: Department of Translational Neurosciences, University of Antwerp, Wilrijk, Belgium.
authors.forename: Halima
authors.initials: H
authors.lastname: Amhaoul
authors.affiliation: Department of Translational Neurosciences, University of Antwerp, Wilrijk, Belgium.
authors.forename: Idrish
authors.initials: I
authors.lastname: Ali
authors.affiliation: Department of Translational Neurosciences, University of Antwerp, Wilrijk, Belgium.
authors.forename: Marco
authors.initials: M
authors.lastname: Mola
authors.affiliation: Department of Translational Neurosciences, University of Antwerp, Wilrijk, Belgium.
authors.forename: Annemie
authors.initials: A
authors.lastname: Van Eetveldt
authors.affiliation: Department of Translational Neurosciences, University of Antwerp, Wilrijk, Belgium.
authors.forename: Krystyna
authors.initials: K
authors.lastname: Szewczyk
authors.affiliation: Department of Translational Neurosciences, University of Antwerp, Wilrijk, Belgium.
authors.forename: Stephan
authors.initials: S
authors.lastname: Missault
authors.affiliation: Laboratory of Cell Biology and Histology, University of Antwerp, Antwerp, Belgium.
authors.forename: Kenny
authors.initials: K
authors.lastname: Bielen
authors.affiliation: Department of Translational Neurosciences, University of Antwerp, Wilrijk, Belgium; Laboratory of Cell Biology and Histology, University of Antwerp, Antwerp, Belgium.
authors.forename: Samir
authors.initials: S
authors.lastname: Kumar-Singh
authors.affiliation: Neuroscience Therapeutic Area, Janssen Research & Development, San Diego, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Rech
authors.affiliation: Neuroscience Therapeutic Area, Janssen Research & Development, San Diego, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Lord
authors.affiliation: Neuroscience Therapeutic Area, Janssen Research & Development, Beerse, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Ceusters
authors.affiliation: Neuroscience Therapeutic Area, Janssen Research & Development, San Diego, USA.
authors.forename: Anindya
authors.initials: A
authors.lastname: Bhattacharya
authors.affiliation: Department of Translational Neurosciences, University of Antwerp, Wilrijk, Belgium. Electronic address: stefanie.dedeurwaerdere@uantwerpen.be.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dedeurwaerdere
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000150:complications; D004833:Epilepsy, Temporal Lobe / Q000150:complications / Q000503:physiopathology* / Q000517:prevention & control*; D005911:Gliosis / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007546:Isoquinolines / Q000008:administration & dosage* / Q000494:pharmacology*; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage* / Q000494:pharmacology*; D058920:Purinergic P2X Receptor Antagonists / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058486:Receptors, Purinergic P2X7 / Q000502:physiology*; D012640:Seizures / Q000150:complications / Q000503:physiopathology* / Q000517:prevention & control*; D013226:Status Epilepticus / Q000150:complications / Q000503:physiopathology / Q000517:prevention & control
chemical_list: D053583:Interleukin-1beta; D007546:Isoquinolines; C000620093:JNJ-42253432; D010446:Peptide Fragments; D010879:Piperazines; D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7; C052994:interleukin-1beta (163-171)
keywords: Antagonist; Epilepsy; Microglia; P2X7 receptor; Seizure