TUMOR-NECROSIS-FACTOR IS A BRAIN DAMAGING CYTOKINE IN CEREBRAL-ISCHEMIA

Two contrasting roles, one beneficial and the injurious, have been pro posed for tumor necrosis factor (TNF) in the pathogenesis of cerebral ischemia. Reported here are results obtained in a standard model of pe rmanent focal cortical ischemia in rats, in which the volume of cerebr al infarction is measured after permanent occlusion of the middle cere bral artery. Administration of neutralizing anti-rat TNF antibodies (P I14) into the brain cortex significantly reduced ischemic brain damage (85% reduced infarct volume as compared with preimmune-treated contro ls). Similar results were achieved by systemic administration of CNI-1 493, a recently described tetravalent guanylhydrazone compound, which effectively inhibited endogenous brain TNF synthesis and conferred sig nificant 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 cer ebroprotective when given within a clinically relevant time window for up to 2 h after the onset of ischemia. These findings establish an im portant, pathophysiological role of TNF in mediating the progression o f ischemic brain damage, and suggest that inhibiting TNF with CNI-1493 may be beneficial in the future treatment of stroke.