Inflammatory events in hippocampal slice cultures prime neuronal susceptibility to excitotoxic injury: A crucial role of P2X7 receptor-mediated IL-1β release

Liliana Bernardino, Silvia Balosso, Teresa Ravizza, Nicola Marchi, George Ku, John C. Randle, João O. Malva, Annamaria Vezzani

Research output: Contribution to journalArticlepeer-review

Abstract

We investigated the consequences of transient application of specific stimuli mimicking inflammation to hippocampal tissue on microglia activation and neuronal cell vulnerability to a subsequent excitotoxic insult. Two-week-old organotypic hippocampal slice cultures, from 7-day-old C57BL/6 donor mice, were exposed for 3 h to lipopolysaccharide (LPS; 10 ng/mL) followed by 3 h co-incubation with 1 mM ATP, or 100 μM 2′3′-O-(4-benzoyl-benzoyl) adenosine 5′-triphosphate triethylammonium, a selective P2X7 receptor agonist. These treatments in combination, but not individually, induced a pronounced activation and apoptotic-like death of macrophage antigen-1 (MAC-1)-positive microglia associated with a massive release of interleukin (IL)-1β exceeding that induced by LPS alone. Antagonists of P2X7 receptors prevented these effects. Transient pre-exposure of slice cultures to a combination of LPS and P2X7 receptor agonists, but not either one or the other alone, significantly exacerbated CA3 pyramidal cell loss induced by subsequent 12 h exposure to 8 μM α-amino-3-hydroxy-5-methyl-4- isoxazole propinate (AMPA). Potentiation of AMPA toxicity was prevented when IL-1β production or its receptor signaling were blocked by an inhibitor of interleukin-converting-enzyme or IL-1 receptor antagonist during application of LPS + ATP. The same treatments did not prevent microglia apoptosis-like death. These findings show that transient exposure to specific pro-inflammatory stimuli in brain tissue can prime neuronal susceptibility to a subsequent excitotoxic insult. P2X7 receptor stimulation, and the consequent IL-1β release, is mandatory for exacerbation of neuronal loss. These mechanisms may contribute to determine cell death/survival in acute and chronic neurodegenerative conditions associated with inflammatory events.

Original languageEnglish
Pages (from-to)271-280
Number of pages10
JournalJournal of Neurochemistry
Volume106
Issue number1
DOIs
Publication statusPublished - Jul 2008

Keywords

  • Apoptosis
  • Cytokines
  • Excitotoxicity
  • Lipopolysaccharide
  • Organotypic slice cultures
  • P2X receptors

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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