Effect of lipopolysaccharide on the transport of pituitary adenylate cyclase activating polypeptide across the blood-brain barrier

Pituitary adenylate cyclase activating polypeptide (PACAP) has neuroprotective effects against ischemia, even when given by intravenous (iv) administration 24 h after stroke. Transport of PACAP across the blood-brain barrier (BBB) by peptide transport system (PTS)-6 underlies its effectiveness after iv administration. However, PACAP transport is modified after central nervous system (CNS) injury, raising the question of whether cytokines or BBB disruption affects PTS-6 activity. Lipopolysaccharide (LPS) is derived from bacterial cell walls and affects the passage of other proteins across the BBB through its release of cytokines and disruption of the BBB. Here, we examined by several methods the transport of radioactively labeled PACAP (I-PACAP) across the BBB after intraperitoneal (ip) injection of LPS. After three doses of LPS, studies at a single time point found a differential effect of LPS on the brain/serum ratio for I-PACAP and radioactively labeled albumin (I-Albumin). Whereas LPS increased the ratio for I-Albumin, demonstrating BBB disruption, it decreased the ratio for I-PACAP. Multiple-time regression analysis, capillary depletion, and brain perfusion showed that this decrease was fully explained by a decrease in the initial, reversible binding of I-PACAP to brain endothelium, while the rate of transport of PACAP into the brain was not altered. These methods also showed that the LPS-treated mice were volume contracted. This volume contraction concentrated the amount of I-PACAP in the blood and so increased the amount of I-PACAP presented to the BBB. Lack of change in transport rate combined with volume contraction resulted in a net increase of about 30% of the iv dose of I-PACAP entering the brain. LPS did not alter the efflux of I-PACAP from the CNS. In conclusion, PTS-6 remains active and should be able to deliver therapeutic amounts of PACAP to the CNS in brain injuries involving cytokine release and BBB disruption.