Tumor necrosis factor alpha expression produces increased blood-brain barrier permeability following temporary focal cerebral ischemia in mice

Brain Res Mol Brain Res. 1999 May 21;69(1):135-43. doi: 10.1016/s0169-328x(99)00007-8.


Alteration of blood-brain barrier (BBB) function occurs in both permanent and temporary cerebral ischemia. Studies in vivo and in vitro have shown that tumor necrosis factor-alpha (TNFalpha) is involved in changes of BBB permeability. However, the relationship between TNFalpha expression and BBB disruption during reperfusion is unclear. The aim of this study is to find the cell source of TNFalpha and to determine the relationship between TNFalpha expression and BBB disruption following temporary focal cerebral ischemia in mice. Adult CD-1 mice received 1 h middle cerebral artery occlusion (MCAO) followed by 2 h, 6 h, 12 h, 24 h, and 48 h of reperfusion. MCAO was achieved using an intraluminal suture technique and reperfusion was performed by the suture withdrawal. Neutralizing monoclonal anti-mouse TNFalpha antibody was administrated intraventricularly immediately after reperfusion. TNFalpha expression was determined by double labeling immunohistochemistry. BBB permeability was determined by albumin immunostaining. TNFalpha immunoreactivity (IR) was observed in the ipsilateral hemisphere from 1 h MCAO with 2 h reperfusion. TNFalpha positive cells included neurons, astrocytes, and ependymal cells. BBB disruption was detected beginning at 6 h reperfusion but was not present at 2 h of reperfusion. The areas of BBB disruption were significantly enlarged at 12 h reperfusion and plateaued at 24 h to 48 h reperfusion. BBB disruptions were significantly attenuated in the anti-TNFalpha antibody treated mice (p<0.05). Our results demonstrate that TNFalpha IR existed in neurons, astrocytes, and ependymal cells during reperfusion. TNFalpha IR following temporary focal cerebral ischemia precedes increased BBB permeability. Treatment with TNFalpha antibody reduces BBB disruption, suggesting TNFalpha may be an important mediator in altering BBB permeability during reperfusion.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Age Factors
  • Animals
  • Antibodies
  • Arterial Occlusive Diseases / physiopathology
  • Blood-Brain Barrier / physiology*
  • Brain Chemistry / physiology
  • Fluorescent Antibody Technique
  • Gene Expression / physiology
  • Ischemic Attack, Transient / physiopathology*
  • Male
  • Mice
  • Mice, Inbred Strains
  • Reperfusion Injury / physiopathology*
  • Tumor Necrosis Factor-alpha / analysis
  • Tumor Necrosis Factor-alpha / genetics*
  • Tumor Necrosis Factor-alpha / immunology


  • Antibodies
  • Tumor Necrosis Factor-alpha