title: Tumor necrosis factor reduces the amplitude of rat cortical spreading depression in vivo.
abstract: OBJECTIVE
  Brain damage and ischemia often trigger cortical spreading depression (CSD), which aggravates brain damage. The proinflammatory cytokine tumor necrosis factor (TNF) is significantly upregulated during brain damage, but it is unknown whether TNF influences spreading depression in cerebral cortex in vivo. This question is important because TNF not only furthers inflammatory reactions but might also be neuroprotective. Here we tested the hypothesis that TNF affects CSD, and we explored the direction in which CSD is modified by TNF.
  
  
  METHODS
  CSD, elicited by pressure microinjection of KCl, was recorded in anesthetized rats and mice. TNF was administered locally into a trough, providing local TNF treatment of a cortical area. For further analysis, antibodies to TNF receptor (TNFR) 1 or 2 were applied, or CSD was monitored in TNFR1 and TNFR2 knockout mice. γ-Aminobutyric acid (GABA)A receptors were blocked by bicuculline. Immunohistochemistry localized the cortical expression of TNFR1 and TNFR2.
  
  
  RESULTS
  Local application of TNF to the cortex reduced dose-dependently the amplitude of CSD. This effect was prevented by blockade or knockout of TNFR2 but not by blockade or knockout of TNFR1. TNFR2 was localized at cortical neurons including parvalbumin-positive inhibitory interneurons, and blockade of GABAA receptors by bicuculline prevented the reduction of CSD amplitudes by TNF.
  
  
  CONCLUSIONS
  We identified a functional link between TNF and CSD. TNF activates TNFR2 in cortical inhibitory interneurons. The resulting release of GABA reduces CSD amplitudes. In this manner, TNF might be neuroprotective in pathological conditions.
authors.affiliation: Institute of Physiology I/Neurophysiology, Jena University Hospital-Friedrich Schiller University Jena, Jena.
authors.forename: Frank
authors.initials: F
authors.lastname: Richter
authors.forename: Wibke
authors.initials: W
authors.lastname: Lütz
authors.forename: Annett
authors.initials: A
authors.lastname: Eitner
authors.forename: Johannes
authors.initials: J
authors.lastname: Leuchtweis
authors.forename: Alfred
authors.initials: A
authors.lastname: Lehmenkühler
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Schaible
mesh_terms: D000818:Animals; D013181:Cortical Spreading Depression / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000502:physiology; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000502:physiology; D048069:Tumor Necrosis Factors / Q000008:administration & dosage / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D048069:Tumor Necrosis Factors; D005680:gamma-Aminobutyric Acid