title: The neuroprotective effect of a specific P2X₇ receptor antagonist derives from its ability to inhibit assembly of the NLRP3 inflammasome in glial cells.
abstract: Release of interleukin (IL)-1β from immunocompetent cells requires formation of the NACHT, LLR and PYD domains-containing protein 3 (NLRP3) inflammasome and caspase 1 activation. Adenosine 5'-triphosphate (ATP), acting on the P2X(7)  receptor, is one factor that stimulates inflammasome assembly. We show that a novel specific P2X(7)  receptor antagonist, GSK1370319A, inhibits ATP-induced increase in IL-1β release and caspase 1 activation in lipopolysaccharide (LPS)-primed mixed glia by blocking assembly of the inflammasome in a pannexin 1-dependent manner. GSK1370319A also inhibits ATP-induced subregion-specific neuronal loss in hippocampal organotypic slice cultures, which is dependent on its ability to prevent inflammasome assembly in glia. Significantly, GSK1370319A attenuates age-related deficits in long-term potentiation (LTP) and inhibits the accompanying age-related caspase 1 activity. We conclude that inhibiting P2X(7)  receptor-activated NLRP3 inflammasome formation and the consequent IL-1β release from glia preserve neuronal viability and synaptic activity.
authors.affiliation: Trinity College Institute for Neuroscience, Physiology Department, Trinity College, Dublin, Ireland. niamh.murphy@tcd.ie
authors.forename: Niamh
authors.initials: N
authors.lastname: Murphy
authors.forename: Thelma R
authors.initials: TR
authors.lastname: Cowley
authors.forename: Jill C
authors.initials: JC
authors.lastname: Richardson
authors.forename: David
authors.initials: D
authors.lastname: Virley
authors.forename: Neil
authors.initials: N
authors.lastname: Upton
authors.forename: Daryl
authors.initials: D
authors.lastname: Walter
authors.forename: Marina A
authors.initials: MA
authors.lastname: Lynch
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins; D002478:Cells, Cultured; D018920:Coculture Techniques; D017630:Connexins / Q000235:genetics / Q000378:metabolism; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D017630:Connexins; C574198:GSK 1370319A; D058847:Inflammasomes; D053583:Interleukin-1beta; D015850:Interleukin-6; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C573346:Nlrp3 protein, rat; D058920:Purinergic P2X Receptor Antagonists; D011759:Pyrrolidines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D058486:Receptors, Purinergic P2X7; D014409:Tumor Necrosis Factor-alpha; C479936:pannexin 1, rat; D000255:Adenosine Triphosphate