Tumor necrosis factor alpha and Fas receptor contribute to cognitive deficits independent of cell death after concussive traumatic brain injury in mice

Jugta Khuman, William P. Meehan, Xiaoxia Zhu, Jianhua Qiu, Ulrike Hoffmann, Jimmy Zhang, Eric Giovannone, Eng H. Lo, Michael J. Whalen

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

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 (P0.001 versus sham injured). In wild-type (WT) mice, CHI produced hidden platform (P0.009) and probe deficits (P0.001) in the Morris water maze versus sham. Surprisingly, injured TNFα/Fas knockout (KO) mice performed worse in hidden platform trials (P0.036) but better in probe trials than did WT mice (P0.0001). 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.

Original languageEnglish (US)
Pages (from-to)778-789
Number of pages12
JournalJournal of Cerebral Blood Flow and Metabolism
Volume31
Issue number2
DOIs
StatePublished - Feb 2011
Externally publishedYes

Keywords

  • cognition
  • concussion
  • inflammation
  • mice
  • traumatic brain injury
  • tumor necrosis factor

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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