A novel non-transcriptional pathway mediates the proconvulsive effects of interleukin-1β

Silvia Balosso, Mattia Maroso, Manuel Sanchez-Alavez, Teresa Ravizza, Angelisa Frasca, Tamas Bartfai, Annamaria Vezzani

Research output: Contribution to journalArticle

Abstract

Interleukin-1β (IL-1β) is overproduced in human and rodent epileptogenic tissue and it exacerbates seizures upon brain application in rodents. Moreover, pharmacological prevention of IL-1β endogenous synthesis, or IL-1 receptor blockade, mediates powerful anticonvulsive actions indicating a significant role of this cytokine in ictogenesis. The molecular mechanisms of the proconvulsive actions of IL-1β are not known. We show here that EEG seizures induced by intrahippocampal injection of kainic acid in C57BL6 adult mice were increased by 2-fold on average by pre-exposure to IL-1β and this effect was blocked by 3-O-methylsphingomyelin (3-O-MS), a selective inhibitor of the ceramide-producing enzyme sphingomyelinase. C2-ceramide, a cell permeable analog of ceramide, mimicked IL-1β action suggesting that ceramide may be the second messenger of the proconvulsive effect of IL-1β. The seizure exacerbating effects of either IL-1β or C2-ceramide were dependent on activation of the Src family of tyrosine kinases since they were prevented by CGP76030, an inhibitor of this enzyme family. The proconvulsive IL-1β effect was associated with increased Tyr418 phosphorylation of Src-family of kinases indicative of its activation, and Tyr1472 phosphorylation of one of its substrate, the NR2B subunit of the N-methyl-d-aspartate receptor, which were prevented by 3-O-MS and CGP76030. Finally, the proconvulsive effect of IL-1β was blocked by ifenprodil, a selective NR2B receptor antagonist. These results indicate that the proconvulsive actions of IL-1β depend on the activation of a sphingomyelinase- and Src-family of kinases-dependent pathway in the hippocampus which leads to the phosphorylation of the NR2B subunit, thus highlighting a novel, non-transcriptional mechanism underlying seizure exacerbation in inflammatory conditions.

Original languageEnglish
Pages (from-to)3256-3265
Number of pages10
JournalBrain
Volume131
Issue number12
DOIs
Publication statusPublished - Dec 2008

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Keywords

  • Cytokines
  • Experimental epilepsy
  • Glia activation
  • Inflammation
  • NMDA receptor

ASJC Scopus subject areas

  • Clinical Neurology

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