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

Academic Article
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Overview

authors

  • Balosso, S.
  • Maroso, M.
  • Sanchez-Alavez, Manuel
  • Ravizza, T.
  • Frasca, A.
  • Bartfai, Tamas
  • Vezzani, A.

publication date

  • December 2008

journal

  • Brain  Journal

abstract

  • Interleukin-1beta (IL-1beta) is overproduced in human and rodent epileptogenic tissue and it exacerbates seizures upon brain application in rodents. Moreover, pharmacological prevention of IL-1beta 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-1beta 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-1beta 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-1beta action suggesting that ceramide may be the second messenger of the proconvulsive effect of IL-1beta. The seizure exacerbating effects of either IL-1beta 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-1beta effect was associated with increased Tyr(418) phosphorylation of Src-family of kinases indicative of its activation, and Tyr(1472) 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-1beta was blocked by ifenprodil, a selective NR2B receptor antagonist. These results indicate that the proconvulsive actions of IL-1beta 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.

subject areas

  • Animals
  • Astrocytes
  • Ceramides
  • Hippocampus
  • Interleukin-1beta
  • Kainic Acid
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • Receptors, Interleukin-1
  • Receptors, N-Methyl-D-Aspartate
  • Recombinant Proteins
  • Seizures
  • Signal Transduction
  • Sphingomyelin Phosphodiesterase
  • src-Family Kinases
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Research

keywords

  • NMDA receptor
  • cytokines
  • experimental epilepsy
  • glia activation
  • inflammation
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Identity

PubMed Central ID

  • PMC2724908

International Standard Serial Number (ISSN)

  • 0006-8950

Digital Object Identifier (DOI)

  • 10.1093/brain/awn271

PubMed ID

  • 18952671
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Additional Document Info

start page

  • 3256

end page

  • 3265

volume

  • 131

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