Brain Advance Access originally published online on October 24, 2008
Brain 2008 131(12):3256-3265; doi:10.1093/brain/awn271
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A novel non-transcriptional pathway mediates the proconvulsive effects of interleukin-1β
1Laboratory of Experimental Neurology, Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milan, Italy and 2Molecular and Integrative Neurosciences Department (MIND), The Scripps Research Institute, La Jolla, CA, USA
Correspondence to: A. Vezzani, PhD, Laboratory of Experimental Neurology, Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Via G. La Masa 19, Milan, Italy E-mail: vezzani{at}marionegri.it
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.
Key Words: experimental epilepsy; glia activation; cytokines; NMDA receptor; inflammation
Abbreviations: 3-O-MS, 3-O-methylsphingomyelin; BSA, bovine serum albumin; NMDA, N-methyl-D-aspartate; DMSO, dimethylsulfoxide; ICE, interleukin-1 converting enzyme; icv, intracerebroventricular; IL-1R1, IL-1 receptor type 1; IL-1β, Interleukin-1β; PBS, phosphate-buffered saline
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Received June 13, 2008. Revised August 5, 2008. Accepted September 21, 2008.
*These authors contributed equally to this work.
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