Tumor Necrosis Factor Alpha and Fas Receptor Contribute to Cognitive Deficits Independent of Cell Death After Concussive Traumatic Brain Injury in Mice

J Cereb Blood Flow Metab. 2011 Feb;31(2):778-89. doi: 10.1038/jcbfm.2010.172. Epub 2010 Oct 13.

Abstract

Tumor necrosis factor alpha (TNFα) and Fas receptor contribute to cell death and cognitive dysfunction after focal traumatic brain injury (TBI). We examined the role of TNFα/Fas in postinjury functional outcome independent of cell death in a novel closed head injury (CHI) model produced with weight drop and free rotational head movement in the anterior-posterior plane. The CHI produced no cerebral edema or blood-brain barrier damage at 24 to 48 hours, no detectable cell death, occasional axonal injury (24 hours), and no brain atrophy or hippocampal cell loss (day 60). Microglia and astrocytes were activated (48 to 72 hours). Tumor necrosis factor-α mRNA, Fas mRNA, and TNFα protein were increased in the brain at 3 to 6 hours after injury (P<0.001 versus sham injured). In wild-type (WT) mice, CHI produced hidden platform (P=0.009) and probe deficits (P=0.001) in the Morris water maze versus sham. Surprisingly, injured TNFα/Fas knockout (KO) mice performed worse in hidden platform trials (P=0.036) but better in probe trials than did WT mice (P=0.0001). Administration of recombinant TNFα to injured TNFα/Fas KO mice reduced probe trial performance to that of WT. Thus, TNFα/Fas influence cognitive deficits independent of cell death after CHI. Therapies targeting TNFα/Fas together may be inappropriate for patients with concussive TBI.

Publication types

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

MeSH terms

  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Astrocytes / physiology
  • Blood-Brain Barrier / pathology
  • Brain Concussion / pathology*
  • Brain Concussion / psychology*
  • Brain Edema / pathology
  • Brain Edema / psychology
  • Brain Injuries / pathology*
  • Brain Injuries / psychology*
  • Cell Count
  • Cell Death / physiology*
  • Cognition Disorders / etiology*
  • Cognition Disorders / psychology*
  • Enzyme-Linked Immunosorbent Assay
  • Hand Strength / physiology
  • Head Injuries, Closed / pathology
  • Head Injuries, Closed / psychology
  • Hippocampus / pathology
  • Immunohistochemistry
  • Male
  • Maze Learning / physiology
  • Mice
  • Microglia / physiology
  • NF-kappa B / biosynthesis
  • Neutrophils / physiology
  • Permeability
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Necrosis Factor-alpha / physiology*
  • fas Receptor / physiology*

Substances

  • Amyloid beta-Protein Precursor
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • fas Receptor