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

Ann Neurol. 2005 Jun;57(6):804-12. doi: 10.1002/ana.20480.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anticonvulsants / pharmacology*
  • Electroencephalography
  • Epilepsy / chemically induced
  • Epilepsy / drug therapy*
  • Epilepsy / physiopathology*
  • Excitatory Amino Acid Agonists
  • Gene Expression
  • Hippocampus / physiology
  • Kainic Acid
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Receptors, Tumor Necrosis Factor, Type II / genetics*
  • Receptors, Tumor Necrosis Factor, Type II / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Anticonvulsants
  • Excitatory Amino Acid Agonists
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Tumor Necrosis Factor-alpha
  • Kainic Acid