Tumor necrosis factor-α inhibits seizures in mice via p75 receptors

Silvia Balosso, Teresa Ravizza, Carlo Perego, Jacques Peschon, Iain L. Campbell, Maria Grazia De Simoni, Annamaria Vezzani

Research output: Contribution to journalArticlepeer-review

Abstract

Brain inflammatory reactions have been described in various neurological disorders, including epilepsy. Although there is clear evidence that cytokines affect neuroglial functions and blood-brain barrier permeability, scarce information is available on the functional consequences of brain inflammation on seizures. We studied the role of tumor necrosis factor-α (TNF)-α and its p55 and p75 receptors in seizure modulation. We found that intrahippocampal injection of murine recombinant TNF-α potently inhibits seizure in mice while human recombinant TNF-α, which shows strong specificity for mouse p55 receptors, was ineffective. p75 receptors were detected in mouse hippocampal neurons, whereas p55 receptors were absent. Transgenic mice with a perturbed TNF-α system showed profound alterations in seizure susceptibility: astrocytic overexpression of TNF-α was associated with reduced seizures, whereas mice lacking TNF-α p75 or both p55 and p75, receptors showed prolonged seizures. Mice deficient in p55 receptor only showed reduced seizures; and both p75 and TNF receptor-associated factor 2 protein levels were upregulated in their hippocampi. Our findings show that increased brain levels of TNF-α result in significant inhibition of seizures in mice, and this action is mediated by neuronal p75 receptors. This evidence highlights a novel function of TNF-α in brain and indicates a new system for anticonvulsive intervention.

Original languageEnglish
Pages (from-to)804-812
Number of pages9
JournalAnnals of Neurology
Volume57
Issue number6
DOIs
Publication statusPublished - Jun 2005

ASJC Scopus subject areas

  • Neuroscience(all)

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