Tumor necrosis factor is a brain damaging cytokine in cerebral ischemia

Shock. 1997 Nov;8(5):341-8.


Two contrasting roles, one beneficial and the injurious, have been proposed for tumor necrosis factor (TNF) in the pathogenesis of cerebral ischemia. Reported here are results obtained in a standard model of permanent focal cortical ischemia in rats, in which the volume of cerebral infarction is measured after permanent occlusion of the middle cerebral artery. Administration of neutralizing anti-rat TNF antibodies (P114) into the brain cortex significantly reduced ischemic brain damage (85% reduced infarct volume as compared with preimmune-treated controls). Similar results were achieved by systemic administration of CNI-1493, a recently described tetravalent guanylhydrazone compound, which effectively inhibited endogenous brain TNF synthesis and conferred significant protection against the development of cerebral infarction (80% reduced infarct volume as compared with vehicle controls treated 1 h postischemia with 10 mg/kg). P114 anti-TNF and CNI-1493 were each cerebroprotective when given within a clinically relevant time window for up to 2 h after the onset of ischemia. These findings establish an important, pathophysiological role of TNF in mediating the progression of ischemic brain damage, and suggest that inhibiting TNF with CNI-1493 may be beneficial in the future treatment of stroke.

MeSH terms

  • Animals
  • Antibodies / administration & dosage
  • Brain Ischemia / etiology*
  • Brain Ischemia / physiopathology*
  • Brain Ischemia / prevention & control
  • Cerebral Cortex / metabolism
  • Cerebrovascular Disorders / drug therapy
  • Cerebrovascular Disorders / physiopathology
  • Humans
  • Hydrazones / pharmacology
  • Immunohistochemistry
  • Male
  • Neuroprotective Agents / pharmacology
  • Rats
  • Rats, Inbred Lew
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / physiology*
  • Tumor Necrosis Factor-alpha / toxicity*


  • Antibodies
  • Hydrazones
  • Neuroprotective Agents
  • Tumor Necrosis Factor-alpha
  • semapimod