RT Journal Article
T1 Transient P2X7 Receptor Antagonism Produces Lasting Reductions in Spontaneous Seizures and Gliosis in Experimental Temporal Lobe Epilepsy
A1 Jimenez-Pacheco, Alba
A1 Díaz Hernández, Miguel
A1 Arribas Blázquez, Marina
A1 Sanz-Rodriguez, Amaya
A1 Olivos Ore, Luis Alcides
A1 Rodríguez Artalejo, Antonio
A1 Alves, Mariana
A1 Letavic, Michael
A1 Miras Portugal, María Teresa
A1 Conroy, Ronan M.
A1 Delanty, Norman
A1 Farrell, Michael A.
A1 O'Brien, Donncha F.
A1 Bhattacharya, Anindya
A1 Engel, Tobias
A1 Henshall, David C.
AB 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 1÷ 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 monitor-ing that persisted beyond the time of drug presence in the brain. Hippocampal sections from JNJ-47965567-treated animals obtained >5d 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.
PB Society for Neuroscience
SN 0270-6474
SN 1529-2401
YR 2016
FD 2016
LK https://hdl.handle.net/20.500.14352/96713
UL https://hdl.handle.net/20.500.14352/96713
LA eng
NO Jimenez-Pacheco A, Diaz-Hernandez M, Arribas-Blázquez M, Sanz-Rodriguez A, Olivos-Oré LA, Artalejo AR, Alves M, Letavic M, Miras-Portugal MT, Conroy RM, Delanty N, Farrell MA, O'Brien DF, Bhattacharya A, Engel T, Henshall DC. Transient P2X7 Receptor Antagonism Produces Lasting Reductions in Spontaneous Seizures and Gliosis in Experimental Temporal Lobe Epilepsy. J Neurosci. 2016 Jun 1;36(22):5920-32. doi: 10.1523/JNEUROSCI.4009-15.2016. PMID: 27251615; PMCID: PMC6601816.
NO Ministerio de Ciencia, Innovación y Universidades (España)
NO Universidad Complutense de Madrid
NO Comunidad de Madrid
NO Health Research Board (Irlanda)
NO Science Foundation Ireland
DS Docta Complutense
RD 9 abr 2025