Tumor necrosis factor is a brain damaging cytokine in cerebral ischemia

Malcolm E. Meistrell, Galina I. Botchkina, Haichao Wang, Elena Di Santo, Kevin Cockroft, Ona Bloom, Jaideep M. Vishnubhakat, Pietro Ghezzi, Kevin J. Tracey

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Abstract

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 (PI14) 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). PI14 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.

Original languageEnglish (US)
Pages (from-to)341-348
Number of pages8
JournalShock
Volume8
Issue number5
Publication statusPublished - Dec 1 1997

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All Science Journal Classification (ASJC) codes

  • Emergency Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Meistrell, M. E., Botchkina, G. I., Wang, H., Di Santo, E., Cockroft, K., Bloom, O., ... Tracey, K. J. (1997). Tumor necrosis factor is a brain damaging cytokine in cerebral ischemia. Shock, 8(5), 341-348.