title: Transient P2X7 Receptor Antagonism Produces Lasting Reductions in Spontaneous Seizures and Gliosis in Experimental Temporal Lobe Epilepsy.
abstract: Neuroinflammation is thought to contribute to the pathogenesis and maintenance of temporal lobe epilepsy, but the underlying cell and molecular mechanisms are not fully understood. The P2X7 receptor is an ionotropic receptor predominantly expressed on the surface of microglia, although neuronal expression has also been reported. The receptor is activated by the release of ATP from intracellular sources that occurs during neurodegeneration, leading to microglial activation and inflammasome-mediated interleukin 1β release that contributes to neuroinflammation. Using a reporter mouse in which green fluorescent protein is induced in response to the transcription of P2rx7, we show that expression of the receptor is selectively increased in CA1 pyramidal and dentate granule neurons, as well as in microglia in mice that developed epilepsy after intra-amygdala kainic acid-induced status epilepticus. P2X7 receptor levels were increased in hippocampal subfields in the mice and in resected hippocampus from patients with pharmacoresistant temporal lobe epilepsy. Cells transcribing P2rx7 in hippocampal slices from epileptic mice displayed enhanced agonist-evoked P2X7 receptor currents, and synaptosomes from these animals showed increased P2X7 receptor levels and altered calcium responses. A 5 d treatment of epileptic mice with systemic injections of the centrally available, potent, and specific P2X7 receptor antagonist JNJ-47965567 (30 mg/kg) significantly reduced spontaneous seizures during continuous video-EEG monitoring that persisted beyond the time of drug presence in the brain. Hippocampal sections from JNJ-47965567-treated animals obtained >5 d after treatment ceased displayed strongly reduced microgliosis and astrogliosis. The present study suggests that targeting the P2X7 receptor has anticonvulsant and possibly disease-modifying effects in experimental epilepsy.
  
  
  
  Temporal lobe epilepsy is the most common and drug-resistant form of epilepsy in adults. Neuroinflammation is implicated as a pathomechanism, but the upstream mechanisms driving gliosis and how important this is for seizures remain unclear. In our study, we show that the ATP-gated P2X7 receptor is upregulated in experimental epilepsy and resected hippocampus from epilepsy patients. Targeting the receptor with a new centrally available antagonist, JNJ-47965567, suppressed epileptic seizures well beyond the time of treatment and reduced underlying gliosis in the hippocampus. The findings suggest a potential disease-modifying treatment for epilepsy based on targeting the P2X7 receptor.
authors.affiliation: Department of Physiology and Medical Physics, and.
authors.forename: Alba
authors.identifier: 0000-0001-6242-0711
authors.initials: A
authors.lastname: Jimenez-Pacheco
authors.affiliation: Departments of Biochemistry and.
authors.forename: Miguel
authors.identifier: 0000-0002-1952-4600
authors.initials: M
authors.lastname: Diaz-Hernandez
authors.affiliation: Toxicology and Pharmacology, Faculty of Veterinary Medicine, and Instituto de Investigación en Neuroquímica, Universidad Complutense de Madrid, Madrid 28040, Spain.
authors.forename: Marina
authors.identifier: 0000-0002-8370-8869
authors.initials: M
authors.lastname: Arribas-Blázquez
authors.affiliation: Department of Physiology and Medical Physics, and.
authors.forename: Amaya
authors.initials: A
authors.lastname: Sanz-Rodriguez
authors.affiliation: Toxicology and Pharmacology, Faculty of Veterinary Medicine, and Instituto de Investigación en Neuroquímica, Universidad Complutense de Madrid, Madrid 28040, Spain.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Olivos-Oré
authors.affiliation: Toxicology and Pharmacology, Faculty of Veterinary Medicine, and Instituto de Investigación en Neuroquímica, Universidad Complutense de Madrid, Madrid 28040, Spain.
authors.forename: Antonio R
authors.initials: AR
authors.lastname: Artalejo
authors.affiliation: Department of Physiology and Medical Physics, and.
authors.forename: Mariana
authors.initials: M
authors.lastname: Alves
authors.affiliation: Janssen Research & Development, LLC, Neuroscience, La Jolla, California 92121, and.
authors.forename: Michael
authors.initials: M
authors.lastname: Letavic
authors.affiliation: Departments of Biochemistry and Instituto de Investigación en Neuroquímica, Universidad Complutense de Madrid, Madrid 28040, Spain.
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Miras-Portugal
authors.affiliation: Division of Population Health Sciences, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Ronan M
authors.identifier: 0000-0001-5983-8682
authors.initials: RM
authors.lastname: Conroy
authors.affiliation: Beaumont Hospital, Beaumont, Dublin 9, Ireland.
authors.forename: Norman
authors.initials: N
authors.lastname: Delanty
authors.affiliation: Beaumont Hospital, Beaumont, Dublin 9, Ireland.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Farrell
authors.affiliation: Beaumont Hospital, Beaumont, Dublin 9, Ireland.
authors.forename: Donncha F
authors.initials: DF
authors.lastname: O'Brien
authors.affiliation: Janssen Research & Development, LLC, Neuroscience, La Jolla, California 92121, and.
authors.forename: Anindya
authors.initials: A
authors.lastname: Bhattacharya
authors.affiliation: Department of Physiology and Medical Physics, and.
authors.forename: Tobias
authors.initials: T
authors.lastname: Engel
authors.affiliation: Department of Physiology and Medical Physics, and dhenshall@rcsi.ie.
authors.forename: David C
authors.initials: DC
authors.lastname: Henshall
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005911:Gliosis / Q000188:drug therapy* / Q000209:etiology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D055815:Young Adult
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; C000590736:JNJ-47965567; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D009536:Niacinamide; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D000255:Adenosine Triphosphate
keywords: anticonvulsant; hippocampal sclerosis; inflammatory cytokine; microglia; purinergic receptor; status epilepticus