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.
© 2011 The Authors; Brain Pathology © 2011 International Society of Neuropathology.
MeSH terms
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Adenosine Triphosphate / pharmacology
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Animals
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Carrier Proteins
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Cells, Cultured
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Coculture Techniques
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Connexins / genetics
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Connexins / metabolism
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Inflammasomes / genetics
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Inflammasomes / metabolism*
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Interleukin-1beta / genetics
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Interleukin-1beta / metabolism
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Neuroglia / drug effects*
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Neuroglia / metabolism
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Neurons / drug effects
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Neurons / metabolism
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Neuroprotective Agents / pharmacology*
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Purinergic P2X Receptor Antagonists / pharmacology*
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Pyrrolidines / pharmacology*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Rats
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Rats, Wistar
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Receptors, Purinergic P2X7 / metabolism*
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Carrier Proteins
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Connexins
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GSK 1370319A
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Inflammasomes
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Interleukin-1beta
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Interleukin-6
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nerve Tissue Proteins
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Neuroprotective Agents
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Nlrp3 protein, rat
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Purinergic P2X Receptor Antagonists
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Pyrrolidines
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RNA, Messenger
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Receptors, Cytoplasmic and Nuclear
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Receptors, Purinergic P2X7
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Tumor Necrosis Factor-alpha
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pannexin 1, rat
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Adenosine Triphosphate