Comparison of saturable transport and extracellular pathways in the passage of interleukin-1 alpha across the blood-brain barrier.

Blood-borne cytokines enter the brain by transport across the blood-brain barrier (BBB) or by leakage through extracellular pathways at sites, such as circumventricular organs (CVOs), without a BBB. We used radioactively labeled albumin (T-Alb) to differentiate the relative contribution of transport and extracellular pathways to the passage of interleukin-1 alpha ([125I]IL-1 alpha) across the BBB. The major mechanism of entry for [125I]IL-1 alpha after intravenous (i.v.) injection was a saturable transport system with extracellular pathways accounting for only a small fraction of entry into brain. CVOs concentrated blood-borne [125I]IL-1 alpha in a saturable manner to a much greater extent than did the cerebral cortex and cerebellum, but accounted for less that 5% of total brain uptake. After intracerebroventricular (i.c.v.) injection, [125I]IL-1 alpha and T-Alb were concentrated in the CVOs, especially the median eminence, although CVOs contained less that 1% of the substances injected. Distribution after i.c.v. injection was largely due to diffusion and leakage through extracellular pathways. We conclude that after i.c.v. injection, leakage across extracellular pathways accounts for the small but concentrated amount of [125I]IL-1 alpha found in CVOs. After i.v. injection, transport across the BBB accounts for the majority of [125I]IL-1 alpha in brain.