BLOOD-BRAIN-BARRIER CHANGES FOLLOWING INTRACEREBRAL INJECTION OF HUMAN RECOMBINANT TUMOR-NECROSIS-FACTOR-ALPHA IN THE RAT

Human recombinant tumor necrosis factor-alpha (rTNF-alpha) was administered to normal Fischer 344 rats by stereotaxic intracerebral (IC) injection. Animals receiving a single injection of either 6 x 10(4) U rTNF-alpha or an equivalent volume of excipient (vehicle) in their right parietal lobe. In order to demonstrate any effects rTNF-alpha might have on the blood-brain barrier (BBB), two studies were conducted, one employing exogenous horseradish peroxidase (HRP, 44 kD) as a tracer of BBB permeability and the other using endogenous IgG (150 kD). Rats given rTNF-alpha showed transitory BBB permeability to HRP by 24 hours post-injection; this BBB compromise was determined to be no longer than 60 hours. In the other study, IgG was seen to cross the BBB by 48 hours post-rTNF-alpha injection. Alternatively, rats injected IC with excipient showed only limited BBB opening as a result of injection-induced trauma. We conclude that human rTNF-alpha, injected IC into normal rats triggers a temporary breakdown in BBB integrity which begins sometimes between 12 and 24 hours post-injection, is large enough to permit macromolecules of at least 150 kD to pass, and resolves by 72 hours post-injection.