TNF-ALPHA PRETREATMENT INDUCES PROTECTIVE EFFECTS AGAINST FOCAL CEREBRAL-ISCHEMIA IN MICE

Cytokines are recognized to play an important role in acute stroke. Tu mor necrosis factor-alpha (TNF) is one of the pro-inflammatory cytokin es and is expressed in ischemic brain. We hypothesized that TNF might play a role in the regulation of tolerance to ischemia when administer ed prior to the ischemic episode. We studied the effects of pretreatme nt of TNF administered intravenously, intraperitoneally, or intraciste rnally in mice that were subjected to middle cerebral artery occlusion (MCAO) 48 h later. MCAO was performed in BALB/C mice by direct cauter ization of distal MCA, which resulted in pure cortical infarction. A s ignificant reduction in infarct size was noted in mice pretreated by T NF at the dose of 0.5 mu g/mouse (p < 0.01) intracisternally. At the d oses used in this study, administration of TNF by intravenous or intra peritoneal routes was not effective. Immunohistochemical analysis of b rains subjected to 24 h of MCAO revealed a significant decrease in CD1 1b immunoreactivity after TNF pretreatment compared with control MCAO. Preconditioning with TNF affects infarct size in a time- and dose-dep endent manner. TNF induces significant protection against ischemic bra in injury and is likely to be involved in the signaling pathways that regulate ischemic tolerance.