title: Tumor necrosis factor-alpha inhibits seizures in mice via p75 receptors.
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-alpha (TNF)-alpha and its p55 and p75 receptors in seizure modulation. We found that intrahippocampal injection of murine recombinant TNF-alpha potently inhibits seizure in mice while human recombinant TNF-alpha, 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-alpha system showed profound alterations in seizure susceptibility: astrocytic overexpression of TNF-alpha was associated with reduced seizures, whereas mice lacking TNF-alpha 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-alpha 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-alpha in brain and indicates a new system for anticonvulsive intervention.
authors.affiliation: Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Balosso
authors.forename: Teresa
authors.initials: T
authors.lastname: Ravizza
authors.forename: Carlo
authors.initials: C
authors.lastname: Perego
authors.forename: Jacques
authors.initials: J
authors.lastname: Peschon
authors.forename: Iain L
authors.initials: IL
authors.lastname: Campbell
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: De Simoni
authors.forename: Annamaria
authors.initials: A
authors.lastname: Vezzani
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004569:Electroencephalography; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology*; D018690:Excitatory Amino Acid Agonists; D015870:Gene Expression; D006624:Hippocampus / Q000502:physiology; D007608:Kainic Acid; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D018690:Excitatory Amino Acid Agonists; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D007608:Kainic Acid