Histopathological effects of intracerebral injections of human recombinant tumor necrosis factor-? in the rat

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Abstract
Human recombinant tumor necrosis factor-α (rTNF-α) was administered to normal Fischer 344 rats by stereotaxic intracerebral (IC) injection. Animals received a single injection of either 6×104 UrTNF-α or excipient in their right parietal lobe. Others received three consecutive daily injections of either 6×104 U rTNF-α or excipient to examine effects of higher accumulative doses. Histological examination of the brain revealed that both single and multiple IC injections of rTNF-α triggered an immigration of circulating leukocytes into the site of TNF-α injection. After one injection, this cell population was composed mainly of macrophages and neutrophils. Maximal leukocytic influx occurred by 48 h and was composed mostly of neutrophils which were limited to the injection site and perivascular space. Quantitation of the inflammatory reaction by measurement of tissue myeloperoxidase levels supported these histological observations. One day after multiple rTNF-α injections, leukocytic adhesion to endothelium, vascular cuffing and leukocytic infiltration into the neuropil was observed at levels comparable to those seen 3 days following a single rTNF-α injection. We conclude that while one or more IC injection(s) of 6×104 U rTNF-α was well tolerated in normal rats, at this dose the cytokine triggers a pronounced leukocytic infiltration at the site of injection. These results support a role for TNF-α as a mediator in inflammatory responses within the central nervous system.

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