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The Neuroprotective Effect of a Specific P2X7 Receptor Antagonist Derives from its Ability to Inhibit Assembly of the NLRP3 Inflammasome in Glial Cells

Authors


Niamh Murphy, PhD, Trinity College Institute for Neuroscience, Physiology Department, Trinity College, Dublin 2, Ireland (E-mail: niamh.murphy@tcd.ie)

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 P2X7 receptor, is one factor that stimulates inflammasome assembly. We show that a novel specific P2X7 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 P2X7 receptor-activated NLRP3 inflammasome formation and the consequent IL-1β release from glia preserve neuronal viability and synaptic activity.

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