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

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.